Docking (molecular)

From Wikipedia, the free encyclopedia Docking glossary Receptor or host The "receiving" molecule, most commonly a protein or other biopolymer. Ligand or guest The complementary partner molecule which binds to the receptor. Ligands are most often small molecules but could also be another biopolymer. Docking Computational simulation of a candidate ligand binding to a receptor. Binding mode The orientation of the ligand relative to the receptor as well as the conformation of the ligand and receptor when bound to each other. Pose A candidate binding mode. Scoring The process of evaluating a particular pose by counting the number of favorable intermolecular interactionssuch as hydrogen bonds and hydrophobic contacts. Ranking The process of classifying which ligands are most likely to interact favorably to a particular receptor based on the predicted free-energy of binding.

Schematic diagram illustrating the docking of a small moleculeligand (brown) to a protein receptor (green) to produce a complex.

Small molecule docked to a protein.

In the field of molecular modeling, docking is a method which predicts the preferred orientation of one molecule to a second when bound to each other to form a stable complex.[1] Knowledge of the preferred orientation in turn may be used to predict the strength of association or binding affinitybetween two molecules using for example scoring functions. The associations between biologically relevant molecules such as proteins,nucleic acids, carbohydrates, and lipids play a central role in signal transduction. Furthermore, the relative orientation of the two interacting partners may affect the type of signal produced (e.g., agonism vsantagonism). Therefore docking is useful for predicting both the strength and type of signal produced. Docking is frequently used to predict the binding orientation of small molecule drug candidates to their protein targets in order to in turn predict the affinity and activity of the small molecule. Hence docking plays an important role in the rational design of drugs.[2] Given the biological andpharmaceutical significance of molecular docking, considerable efforts have been directed towards improving the methods used to predict docking .
Contents
[hide]

1 Definition of problem 2 Docking approaches

o o

2.1 Shape complementarity 2.2 Simulation

3 Mechanics of docking

3.1 Search algorithm

  o

3.1.1 Ligand flexibility 3.1.2 Receptor flexibility

3.2 Scoring function

4 Applications 5 See also 6 References 7 External links

[ ]Definition

of problem

Molecular docking can be thought of as a problem of lock-and-key, where one is interested in finding the correct relative orientation of the key which will open up the lock (where on the surface of the lock is the key hole, which direction to turn the key after it is inserted, etc.). Here, the protein can be thought of as the lock and the ligand can be thought of as a key. Molecular docking may be defined as an optimization problem, which would describe the best-fit orientation of a ligand that binds to a particular protein of interest. However since both the ligand and the protein are flexible, ahand-in-glove analogy is more appropriate than lock-andkey.[3] During the course of the process, the ligand and the protein adjust their conformation to achieve an overall best-fit and this kind of conformational adjustments resulting in the overall binding is referred to as induced-fit.[4] The focus of molecular docking is to computationally simulate the molecular recognition process. The aim of molecular docking is to achieve an optimized conformation for both the protein and ligand and relative orientation between protein and ligand such that the free energy of the overall system is minimized.

[ ]Docking

approaches

Two approaches are particularly popular within the molecular docking community. One approach uses a matching technique that describes the protein and the ligand as complementary surfaces.[5][6] The second approach simulates the actual docking process in which the ligand-protein pairwise interaction energies are calculated.[7] Both approaches have significant advantages as well as some limitations. These are outlined below.

[ ]Shape

complementarity

Geometric matching/ shape complementarity methods describe the protein and ligand as a set of features that make them dockable.[8]These features may include molecular surface/ complementary surface descriptors. In this case, the receptors molecular surface is described in terms of its solvent-accessible surface area and the ligands molecular surface is described in terms of its matching surface description. The complementarity between the two surfaces amounts to the shape matching description that may help finding the complementary pose of docking the target and the ligand molecules. Another approach is to describe the hydrophobic features of the protein using turns in the main-chain atoms. Yet another approach is to use a Fourier shape descriptor technique.[9][10][11] Whereas the shape complementarity based approaches are typically fast and robust, they cannot usually model the movements or dynamic changes in the ligand/ protein conformations accurately, although recent developments allow these methods to investigate ligand flexibility. Shape complementarity methods can quickly scan through several thousand ligands in a matter of seconds and actually figure out whether they can bind at the proteins active site, and are usually scalable to even protein-protein interactions. They are also much more amenable to pharmacophore based approaches, since they use geometric descriptions of the ligands to find optimal binding.

[ ]Simulation
The simulation of the docking process as such is a much more complicated process. In this approach, the protein and the ligand are separated by some physical distance, and the ligand finds its position into the proteins active site after a certain number of moves in its conformational space. The moves incorporate rigid body transformations such as translations and rotations, as well as internal changes to the ligands structure including torsion angle rotations. Each of these moves in the conformation space of the ligand induces a total energetic cost of the system, and hence after every move the total energy of the system is calculated. The obvious advantage of the method is that it is more amenable to incorporate ligand flexibility into its modeling whereas shape complementarity techniques have to use some ingenious methods to incorporate flexibility in ligands. Another advantage is that the process is physically closer to what happens in reality, when the protein and ligand approach each other after molecular recognition. A clear disadvantage of this technique is that it takes longer time to evaluate the optimal pose of binding since they have to explore a rather large energy landscape. However grid-based techniques as well as fast optimization methods have significantly ameliorated these problems.

[ ]Mechanics

of docking

To perform a docking screen, the first requirement is a structure of the protein of interest. Usually the structure has been determined using a biophysical technique such as x-ray crystallography, or less often, NMR spectroscopy. This protein structure and a database of potential ligands serve as inputs to a docking program. The success of a docking program depends on two components: the search algorithm and thescoring function.

[ ]Search

algorithm

Main article: Searching the Conformational Space for Docking The search space in theory consists of all possible orientations and conformations of the protein paired with the ligand. However in practice with current computational resources, it is impossible to exhaustively explore the search spacethis would involve enumerating all possible distortions of each molecule (molecules are dynamic and exist in an ensemble of conformational states) and all possible rotational and translational orientations of the ligand relative to the protein at a given level of granularity. Most docking programs in use account for a flexible ligand, and several attempt to model a flexible protein receptor. Each "snapshot" of the pair is referred to as a pose. A variety of conformational search strategies have been applied to the ligand and to the receptor. These include: systematic or stochastic torsional searches about rotatable bonds molecular dynamics simulations

 

 [ ]Ligand flexibility

genetic algorithms to "evolve" new low energy conformations

Conformations of the ligand may be generated in the absence of the receptor and subsequently docked[12] or conformations may be generated on-the-fly in the presence of the receptor binding cavity.[13] Force field energy evaluation are most often used to select energetically reasonable conformations,[14] but knowledge-based methods have also been used.[15]

[ ]Receptor flexibility
Computational capacity has increased dramatically over the last decade making possible the use of more sophisticated and computationally intensive methods in computer-assisted drug design. However, dealing with receptor flexibility in docking methodologies is still a thorny issue. The main reason behind this difficulty is the large number of degrees of freedom that have to be considered in this kind of calculations. However, neglecting it, leads to poor docking results in terms of binding pose prediction.[16] Multiple static structures experimentally determined for the same protein in different conformations are often used to emulate receptor flexibility.[17] Alternatively rotamer libraries of amino acid side chains that surround the binding cavity may be searched to generate alternate but energetically reasonable protein conformations.[18][19]

[ ]Scoring

function

Main article: Scoring Functions for Docking The scoring function takes a pose as input and returns a number indicating the likelihood that the pose represents a favorable binding interaction. Most scoring functions are physics-based molecular mechanics force fields that estimate the energy of the pose; a low (negative) energy indicates a stable system and thus a likely binding interaction. An alternative approach is to derive a statistical potential for interactions from a large database of protein-ligand complexes, such as the Protein Data Bank, and evaluate the fit of the pose according to this inferred potential. There are a large number of structures from X-ray crystallography for complexes between proteins and high affinity ligands, but comparatively fewer for low affinity ligands as the later complexes tend to be less stable and therefore more difficult to crystallize. Scoring functions trained with this data can dock high affinity ligands correctly, but they will also give plausible docked conformations for ligands that do not bind. This gives a large number of false positive hits, i.e., ligands predicted to bind to the protein that actually don't when placed together in a test tube. One way to reduce the number of false positives is to recalculate the energy of the top scoring poses using (potentially) more accurate but computationally more intensive techniques such as Generalized Born or Poisson-Boltzmann methods.[7]

[ ]Applications
A binding interaction between a small molecule ligand and an enzyme protein may result in activation or inhibition of the enzyme. If the protein is a receptor, ligand binding may result in agonism or antagonism. Docking is most commonly used in the field of drug design most drugs are small organic molecules, and docking may be applied to: hit identification docking combined with a scoring function can be used to quickly screen large databases of potential drugs in silico to identify molecules that are likely to bind to protein target of interest (see virtual screening).

lead optimization docking can be used to predict in where and in which relative orientation a ligand binds to a protein (also referred to as the binding mode or pose). This information may in turn be used to design more potent and selective analogs.

 [ ]References

Bioremediation Protein ligand docking can also be used to predict pollutants that can be degraded by enzymes.[20]

1.

^ Lengauer T, Rarey M (1996). "Computational methods for biomolecular docking". Curr. Opin. Struct. Biol. 6 (3): 4026. doi:10.1016/S0959440X(96)80061-3. PMID 8804827.

2.

^ Kitchen DB, Decornez H, Furr JR, Bajorath J (2004). "Docking and scoring in virtual screening for drug discovery: methods and applications".Nature reviews. Drug discovery 3 (11): 935 49. doi:10.1038/nrd1549. PMID 15520816.

3.

^ Jorgensen WL (1991). "Rusting of the lock and key model for protein-ligand binding". Science 254 (5034): 954 5.doi:10.1126/science.1719636. PMID 1719636.

4.

^ Wei BQ, Weaver LH, Ferrari AM, Matthews BW, Shoichet BK (2004). "Testing a flexible-receptor docking algorithm in a model binding site". J. Mol. Biol. 337 (5): 116182. doi:10.1016/j.jmb.2004.02.015. PMID 15046985.

5.

^ Meng EC, Shoichet BK, Kuntz ID (2004). "Automated docking with gridbased energy evaluation". Journal of Computational Chemistry 13 (4): 505 524. doi:10.1002/jcc.540130412.

6.

^ Morris GM, Goodsell DS, Halliday RS, Huey R, Hart WE, Belew RK, Olson AJ (1998). "Automated docking using a Lamarckian genetic algorithm and an

empirical binding free energy function". Journal of Computational Chemistry 19 (14): 16391662. doi:10.1002/(SICI)1096987X(19981115)19:14<1639::AID-JCC10>3.0.CO;2-B. 7. ^ a b Feig M, Onufriev A, Lee MS, Im W, Case DA, Brooks CL (2004). "Performance comparison of generalized born and Poisson methods in the calculation of electrostatic solvation energies for protein structures". Journal of Computational Chemistry 25 (2): 265 84.doi:10.1002/jcc.10378. PMID 14648625. 8. ^ Shoichet BK, Kuntz ID, Bodian DL (2004). "Molecular docking using shape descriptors". Journal of Computational Chemistry 13 (3): 380 397.doi:10.1002/jcc.540130311. 9. ^ Cai W, Shao X, Maigret B (January 2002). "Protein-ligand recognition using spherical harmonic molecular surfaces: towards a fast and efficient filter for large virtual throughput screening". J. Mol. Graph. Model. 20 (4): 313 28. doi:10.1016/S1093-3263(01)00134-6.PMID 11858640. 10. ^ Morris RJ, Najmanovich RJ, Kahraman A, Thornton JM (May 2005). "Real spherical harmonic expansion coefficients as 3D shape descriptors for protein binding pocket and ligand comparisons". Bioinformatics 21 (10): 2347 55. doi:10.1093/bioinformatics/bti337. PMID 15728116. 11. ^ Kahraman A, Morris RJ, Laskowski RA, Thornton JM (April 2007). "Shape variation in protein binding pockets and their ligands". J. Mol. Biol.368 (1): 283301. doi:10.1016/j.jmb.2007.01.086. PMID 17337005. 12. ^ Kearsley SK, Underwood DJ, Sheridan RP, Miller MD (October 1994). "Flexibases: a way to enhance the use of molecular docking methods".J. Comput. Aided Mol. Des. 8 (5): 565 82. doi:10.1007/BF00123666. PMID 7876901. 13. ^ Friesner RA, Banks JL, Murphy RB, Halgren TA, Klicic JJ, Mainz DT, Repasky MP, Knoll EH, Shelley M, Perry JK, Shaw DE, Francis P, Shenkin PS (March 2004). "Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy". J. Med. Chem. 47 (7): 173949. doi:10.1021/jm0306430. PMID 15027865. 14. ^ Wang Q, Pang YP (2007). "Preference of small molecules for local minimum conformations when binding to proteins". PLoS ONE 2 (9): e820. doi:10.1371/journal.pone.0000820. PMID 17786192.

15. ^ Klebe G, Mietzner T (October 1994). "A fast and efficient method to generate biologically relevant conformations". J. Comput. Aided Mol. Des. 8(5): 583606. doi:10.1007/BF00123667. PMID 7876902. 16. ^ Cerqueira NM, Bras NF, Fernandes PA, Ramos MJ (January 2009). "MADAMM: a multistaged docking with an automated molecular modeling protocol". Proteins 74 (1): 192206. doi:10.1002/prot.22146. PMID 18618708. 17. ^ Totrov M, Abagyan R (April 2008). "Flexible ligand docking to multiple receptor conformations: a practical alternative". Curr. Opin. Struct. Biol.18 (2): 17884. doi:10.1016/j.sbi.2008.01.004. PMID 18302984. 18. ^ Hartmann C, Antes I, Lengauer T (February 2009). "Docking and scoring with alternative side-chain conformations". Proteins 74 (3): 712 26.doi:10.1002/prot.22189. PMID 18704939. 19. ^ Taylor RD, Jewsbury PJ, Essex JW (October 2003). "FDS: flexible ligand and receptor docking with a continuum solvent model and soft-core energy function". J Comput Chem 24 (13): 1637 56. doi:10.1002/jcc.10295. PMID 12926007. 20. ^ Suresh PS, Kumar A, Kumar R, Singh VP (January 2008). "An in silico [correction of insilico] approach to bioremediation: laccase as a case study". J. Mol. Graph. Model. 26 (5): 845 9. doi:10.1016/j.jmgm.2007.05.005. PMID 17606396.

[ ]External

links

Bikadi Z, Kovacs S, Demko L, Hazai E. "Molecular Docking Server - Ligand Protein Docking & Molecular Modeling". Virtua Drug Ltd. Retrieved 2008-0715. "Internet service that calculates the site, geometry and energy of small molecules interacting with proteins"

Malinauskas T. "Step by step installation of MGLTools 1.5.2 (AutoDockTools, Python Molecular Viewer and Visual Programming Environment) on Ubuntu Linux 8.04". Retrieved 2008-07-15.

Malinauskas T. "High-throughput molecular docking using free tools: ZINC 8, AutoDockTools 1.5.2 and Docker 1.0". Retrieved 2008-07-23.

 

AutoDock and MGLTools for Debian Docking@GRID Project of Conformational Sampling and Docking on Grids : one aim is to deploy some intrinsic distributed docking algorithms on computational Grids, download Docking@GRID open-source Linux version

 

Docking software Click2Drug.org - Directory of computational drug design tools.

Drug discovery
From Wikipedia, the free encyclopedia

In the fields of medicine, biotechnology and pharmacology, drug discovery is the process by which drugs are discovered and/or designed. In the past most drugs have been discovered either by identifying the active ingredient from traditional remedies or by serendipitous discovery. A new approach has been to understand how disease and infection are controlled at the molecular and physiological level and to target specific entities based on this knowledge. The process of drug discovery involves the identification of candidates, synthesis, characterization, screening, and assays for therapeutic efficacy. Once a compound has shown its value in these tests, it will begin the process of drug development prior to clinical trials. Despite advances in technology and understanding of biological systems, drug discovery is still a lengthy, "expensive, difficult, and inefficient process" with low rate of new therapeutic discovery.[1] Currently, the research and development cost of each new molecular entity (NME) is approximately US$1.8 billion.[2] Information on the human genome, its sequence and what it encodes has been hailed as a potential windfall for drug discovery, promising to virtually eliminate the bottleneck in therapeutic targets that has been one limiting factor on the rate of therapeutic discovery.[citation needed]However, data indicates that "new targets" as opposed to "established targets" are more prone to drug discovery project failure in general[citation needed] This data corroborates some thinking underlying a pharmaceutical industry trend beginning at the turn of the twenty-first century and continuing today which finds more risk aversion in target selection among multi-national pharmaceutical companies.[citation needed]
Contents
[hide]

1 Drug targets 2 Screening and design 3 Historical background 4 Nature as source of drugs

o o o

4.1 Plant-derived 4.2 Microbial metabolites 4.3 Marine invertebrates

5 Chemical diversity of natural products 6 Natural product drug discovery

o o

6.1 Screening 6.2 Structural elucidation

7 See also 8 References 9 Further reading 10 External links

[ ]Drug

targets

The definition of "target" itself is something argued within the pharmaceutical industry. Generally, the "target" is the naturally existing cellular or molecular structure involved in the pathology of interest that the drug-indevelopment is meant to act on. However, the distinction between a "new" and "established" target can be made without a full understanding of just what a "target" is. This distinction is typically made by pharmaceutical companies engaged in discovery and development of therapeutics. "Established targets" are those for which there is a good scientific understanding, supported by a lengthy publication history, of both how the target functions in normal physiology and how it is involved in human pathology. This does not imply that the mechanism of action of drugs that are thought to act through a particular established targets is fully understood. Rather, "established" relates directly to the amount of background information available on a target, in particular functional information. The more such information is available, the less investment is (generally) required to develop a therapeutic directed against the target. The process of gathering such functional information is called "target validation" in pharmaceutical industry parlance. Established targets also include those that the pharmaceutical industry has had experience mounting drug discovery campaigns against in the past; such a history provides information on the chemical feasibility of developing a small molecular therapeutic against the target and can provide licensing opportunities and freedom-to-operate indicators with respect to small-molecule therapeutic candidates. In general, "new targets" are all those targets that are not "established targets" but which have been or are the subject of drug discovery campaigns. These typically include newly discovered proteins, or proteins whose function has now become clear as a result of basic scientific research. The majority of targets currently selected for drug discovery efforts are proteins. Two classes predominate: Gprotein-coupled receptors (or GPCRs) and protein kinases.

[ ]Screening

and design

The process of finding a new drug against a chosen target for a particular disease usually involves highthroughput screening (HTS), wherein large libraries of chemicals are tested for their ability to modify the target. For example, if the target is a novel GPCR, compounds will be screened for their ability to inhibit or stimulate that receptor (see antagonist and agonist): if the target is a protein kinase, the chemicals will be tested for their ability to inhibit that kinase. Another important function of HTS is to show how selective the compounds are for the chosen target. The ideal is to find a molecule which will interfere with only the chosen target, but not other, related targets. To this end, other screening runs will be made to see whether the "hits" against the chosen target will interfere with other related targets - this is the process of cross-screening. Cross-screening is important, because the more unrelated targets a compound hits, the more likely that off-target toxicity will occur with that compound once it reaches the clinic. It is very unlikely that a perfect drug candidate will emerge from these early screening runs. It is more often observed that several compounds are found to have some degree of activity, and if these compounds share common chemical features, one or more pharmacophores can then be developed. At this point, medicinal chemists will attempt to use structure-activity relationships (SAR) to improve certain features of thelead compound: increase activity against the chosen target reduce activity against unrelated targets improve the "drug-like" or ADME properties of the molecule.

  

This process will require several iterative screening runs, during which, it is hoped, the properties of the new molecular entities will improve, and allow the favoured compounds to go forward to in vitro and in vivo testing for activity in the disease model of choice. While HTS is a commonly used method for novel drug discovery, it is not the only method. It is often possible to start from a molecule which already has some of the desired properties. Such a molecule might be extracted from a natural product or even be a drug on the market which could be improved upon (so-called "me too" drugs). Other methods, such as virtual high throughput screening, where screening is done using computergenerated models and attempting to "dock" virtual libraries to a target, are also often used. Another important method for drug discovery is drug design, whereby the biological and physical properties of the target are studied, and a prediction is made of the sorts of chemicals that might (eg.) fit into an active site. One example is fragment-based lead discovery (FBLD). Novel pharmacophores can emerge very rapidly from these exercises.

Once a lead compound series has been established with sufficient target potency and selectivity and favourable drug-like properties, one or two compounds will then be proposed for drug development. The best of these is generally called the lead compound, while the other will be designated as the "backup".

[ ]Historical

background

The idea that effect of drug in human body are mediated by specific interactions of the drug molecule with biological macromolecules, (proteins or nucleic acids in most cases) led scientists to the conclusion that individual chemicals are required for the biological activity of the drug. This made for the beginning of the modern era in pharmacology, as pure chemicals, instead of crude extracts, became the standard drugs. Examples of drug compounds isolated from crude preparations are morphine, the active agent in opium, and digoxin, a heart stimulant originating from Digitalis lanata. Organic chemistry also led to the synthesis of many of the cochemicals isolated from biological sources.

[ ]Nature

as source of drugs

Despite the rise of combinatorial chemistry as an integral part of lead discovery process, the natural products still play a major role as starting material for drug discovery.[3] A report was published in 2007 [4], covering years 1981-2006 details the contribution of biologically occurring chemicals in drug development. According to this report, of the 974 small molecule new chemical entities, 63% were natural derived or semisynthetic derivatives of natural products. For certain therapy areas, such as antimicrobials, antineoplastics, antihypertensive and anti-inflammatory drugs, the numbers were higher. Natural products may be useful as a source of novel chemical structures for modern techniques of development of antibacterial therapies.[5] Despite the implied potential, only a fraction of Earths living species has been tested for bioactivity.

[ ]Plant-derived
Prior to Paracelsus, the vast majority of traditionally used crude drugs in Western medicine were plant-derived extracts. This has resulted in a pool of information about the potential of plant species as an important source of starting material for drug discovery. A different set of metabolites is sometimes produced in the different anatomical parts of the plant (e.. root, leaves and flower), and botanical knowledge is crucial also for the correct identification of bioactive plant materials.

[ ]Microbial

metabolites

Microbes compete for living space and nutrients. To survive in these conditions, many microbes have developed abilities to prevent competing species from proliferating. Microbes are the main source of antimicrobial drugs. Streptomyces species have been a source of antibiotics. The classical example of an

antibiotic discovered as a defense mechanism against another microbe is the discovery of penicillin in bacterial cultures contaminated by Penicillium fungi in 1928.

[ ]Marine

invertebrates

Marine environments are potential sources for new bioactive agents.[6] Arabinose nucleosides discovered from marine invertebates in 1950s, demonstrating for the first time that sugar moieties other than ribose and deoxyribose can yield bioactive nucleoside structures. However, it was 2004 when the first marine-derived drug was approved. The cone snail toxin ziconotide, also known as Prialt, was approved by the Food and Drug Administration to treat severe neuropathic pain. Several other marine-derived agents are now in clinical trials for indications such as cancer, anti-inflammatory use and pain. One class of these agents are bryostatin-like compounds,under investigation as anti-cancer therapy.

[ ]Chemical

diversity of natural products

As above mentioned, combinatorial chemistry was a key technology enabling the efficient generation of large screening libraries for the needs of high-throughput screening. However, now, after two decades of combinatorial chemistry, it has been pointed out that despite the increased efficiency in chemical synthesis, no increase in lead or drug candidates has been reached [4]. This has led to analysis of chemical characteristics of combinatorial chemistry products, compared to existing drugs and/or natural products. The chemoinformatics concept chemical diversity, depicted as distribution of compounds in the chemical space based on their physicochemical characteristics, is often used to describe the difference between the combinatorial chemistry libraries and natural products. The synthetic, combinatorial library compounds seem to cover only a limited and quite uniform chemical space, whereas existing drugs and particularly natural products, exhibit much greater chemical diversity, distributing more evenly to the chemical space [3] . The most prominent differences between natural products and compounds in combinatorial chemistry libraries is the number of chiral centers (much higher in natural compounds), structure rigidity (higher in natural compounds) and number of aromatic moieties (higher in combinatorial chemistry libraries). Other chemical differences between these two groups include the nature of heteroatoms (O and N enriched in natural products, and S and halogen atoms more often present in synthetic compounds), as well as level of non-aromatic unsaturation (higher in natural products). As both structure rigidity and chirality are both well-established factors in medicinal chemistry known to enhance compounds specificity and efficacy as a drug, it has been suggested that natural products compare favourable to today's combinatorial chemistry libraries as potential lead molecules.

[ ]Natural

product drug discovery

[ ]Screening
Two main approaches exist for the finding of new bioactive chemical entities from natural sources: random collection and screening of material; and exploitation of ethnopharmacological knowledge in the selection. The

former approach is based on the fact that only a small part of Earths biodiversity has ever been tested for pharmaceutical activity, and organisms living in a species-rich environment need to evolve defensive and competitive mechanisms to survive. A collection of plant, animal and microbial samples from rich ecosystems might give rise to novel biological activities. One example of a successful use of this strategy is the screening for antitumour agents by the National Cancer Institute, started in the 1960s. Paclitaxel was identified from Pacific yew tree Taxus brevifolia. Paclitaxel showed anti-tumour activity by a previously undescribed mechanism (stabilization of microtubules) and is now approved for clinical use for the treatment of lung, breast and ovarian cancer, as well as for Kaposi's sarcoma. Ethnobotany is the study of the use of plants in the society, and ethnopharmacology, an area inside ethnobotany, is focused on medicinal use of plants. Both can be used in selecting starting materials for future drugs. Artemisinin, an antimalarial agent from sweet wormtreeArtemisia annua, used in Chinese medicine since 200BC is one drug used as part of combination therapy for multiresistant Plasmodium falciparum.

[ ]Structural

elucidation

The elucidation of the chemical structure is critical to avoid the re-discovery of a chemical agent that is already known for its structure and chemical activity. Mass spectrometry, often used to determine structure, is a method in which individual compounds are identified based on their mass/charge ratio, after ionization. Chemical compounds exist in nature as mixtures, so the combination of liquid chromatography and mass spectrometry (LC-MS) is often used to separate the individual chemicals. Databases of mass spectras for known compounds are available. Nuclear magnetic resonance spectroscopy is another important technique for determining chemical structures of natural products. NMR yields information about individual hydrogen and carbon atoms in the structure, allowing detailed reconstruction of the molecules architecture.

[ ] [ ]References
1. ^ Anson, Blake D.; Ma, Junyi; He, Jia-Qiang (1 May 2009), "Identifying Cardiotoxic Compounds", Genetic Engineering & Biotechnology News, TechNote (Mary Ann Liebert) 29 (9): 3435, ISSN 1935472X, OCLC 77706455, archived from the original on 25 July 2009, retrieved 25 July 2009 2. ^ Steven M. Paul, Daniel S. Mytelka, Christopher T. Dunwiddie, Charles C. Persinger, Bernard H. Munos, Stacy R. Lindborg & Aaron L. Schacht (2010). "How to improve R&D productivity: the pharmaceutical industry's grand challenge". Nature Reviews Drug Discovery 9 (3): 203 214.doi:10.1038/nrd3078. PMID 20168317.

3.

a b

Feher M, Schmidt JM (2003). "Property distributions: differences

between drugs, natural products, and molecules from combinatorial chemistry". J Chem Inf Comput Sci 43 (1): 218 27. doi:10.1021/ci0200467. PMID 12546556. 4. ^ a b Newman DJ, Cragg GM (March 2007). "Natural products as sources of new drugs over the last 25 years". J. Nat. Prod. 70 (3): 461 77.doi:10.1021/np068054v. PMID 17309302. 5. ^ von Nussbaum F, Brands M, Hinzen B, Weigand S, Hbich D (August 2006). "Antibacterial natural products in medicinal chemistry--exodus or revival?". Angew. Chem. Int. Ed. Engl. 45 (31): 5072 129. doi:10.1002/anie.200600350. PMID 16881035. "The handling of natural products is cumbersome, requiring nonstandardized workflows and extended timelines. Revisiting natural products with modern chemistry and targetfinding tools from biology (reversed genomics) is one option for their revival.". 6. ^ John Faulkner D, Newman DJ, Cragg GM (February 2004). "Investigations of the marine flora and fauna of the Islands of Palau". Nat Prod Rep 21 (1): 5076. doi:10.1039/b300664f. PMID 15039835.

[ ]Further

reading

Gad, Shayne C. (2005). Drug discovery handbook. Hoboken, N.J: WileyInterscience/J. Wiley. ISBN 0-471-21384-5.

Madsen, Ulf; Krogsgaard-Larsen, Povl; Liljefors, Tommy (2002). Textbook of drug design and discovery. Washington, DC: Taylor & Francis.ISBN 0-41528288-8.

[ ]External

links
 
Introduction to Drug Discovery - Combinatorial Chemistry Review In Focus "Medical Research involving Minors: Medical, legal and ethical aspects" (German Reference Centre for Ethics in the Life Sciences)

International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)

   

Food and Drug Administration (FDA) CDER Drug and Biologic Approval Reports Pharmaceutical Research and Manufacturers of America (PhRMA) European Medicines Agency (EMEA)

  

Pharmaceuticals and Medical Devices Agency (PMDA) WHO Model List of Essential Medicines Innovation and Stagnation: Challenge and Opportunity on the Critical Path to New Medical Products - FDA

Priority Medicines for Europe and the World Project "A Public Health Approach to Innovation" - WHO

  

International Union of Basic and Clinical Pharmacology IUPHAR Committee on Receptor Nomenclature and Drug Classification Advanced Cell Classifier program for high-content screen analysis (ETH Zurich)

Drugdiscovery@home Early in silico drug discovery by volunteer computing.

Supercomputing Facility for Bioinformatics & Computational Biology, IIT Delhi

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What is Drug Design ?

Drug discovery and development is an intense, lengthy and an interdisciplinary endeavor. Drug discovery is mostly portrayed as a linear, consecutive process that starts with target and lead discovery, followed by lead optimization and pre-clinical in vitro and in vivo studies to determine if such compounds satisfy a number of pre-set criteria for initiating clinical development. For the pharmaceutical industry, the number of years to bring a drug from discovery to market is approximately 12-14 years and costing upto $1.2 - $1.4 billion dollars. Traditionally, drugs were discovered by synthesizing compounds in a time-consuming multi-step processes against a battery of in vivo biological screens and further investigating the promising candidates for their pharmacokinetic properties, metabolism and potential toxicity. Such a development process has resulted in high attrition rates with failures attributed to poor pharmacokinetics (39%), lack of efficacy (30%), animal toxicity (11%), adverse effects in humans (10%) and various commercial and miscellaneous factors. Today, the process of drug discovery has been revolutionized with the advent of genomics, proteomics, bioinformatics and efficient technologies like, combinatorial chemistry, high throughput screening (HTS), virtual screening, de novo design, in vitro, in silicoADMET screening and structure-based drug design. What is in-silico Drug Design ?

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In silico methods can help in identifying drug targets via bioinformatics tools. They can also be used to analyze the target structures for possible binding/ active sites, generate candidate molecules, check for their drug likeness , dock these molecules with the target , rank them according to their binding affinites , further optimize the molecules to improve binding characteristics The use of computers and computational methods permeates all aspects of drug discovery today and forms the core of structure-based drug design. High-performance computing, data management software and internet are facilitating the access of huge amount of data generated and transforming the massive complex biological data into workable knowledge in modern day drug discovery process. The use of complementary experimental and informatics techniques increases the chance of success in many stages of the discovery process, from the identification of novel targets and elucidation of their functions to the discovery and development of lead compounds with desired properties. Computational tools offer the advantage of delivering new drug candidates more quickly and at a lower cost. Major roles of computation in drug discovery are; (1) Virtual screening & de novo design, (2) in silicoADME/T prediction and (3) Advanced methods for determining protein-ligand binding

Why in-silico Drug Design is significant ? As structures of more and more protein targets become available through crystallography, NMR and bioinformatics methods, there is an increasing demand for computational tools that can identify and analyze active sites and suggest potential drug molecules that can bind to these sites specifically. Also to combat life-threatening diseases such as AIDS, Tuberculosis, Malaria etc., a global push is essential. Millions for Viagra and pennies for the diseases of the poor is the current situation of investment in Pharma R&D. Time and cost required for designing a new drug are immense and at an unacceptable level. According to some estimates it costs about $880 million and 14 years of research to develop a new drug before it is introduced in the market Intervention of computers at some plausible steps is imperative to bring down the cost and time required in the drug discovery process

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Introduction to Drug Discovery

Drug discovery and development is an expensive process due to the high costs of R&D and human clinical tests. The average total cost per drug development varies from US$ 897 million to US$ 1.9 billion. The typical development time is 10-15 years. R&D of a new drug involves the identification of a target (e.g. protein) and the discovery of some suitable drug candidates that can block or activate the target. Clinical testing is the most extensive and expensive phase in drug development and is done in order to obtain the necessary governmental approvals. In the US drugs must be approved by the Food and Drug Administration (FDA).
R&D Finding the Drug

One of the most successful ways to find promising drug candidates is to investigate how the target protein interacts with randomly chosen compounds, which are usually a part of compound libraries. This testing is often done in so called high-thoughput screening (HTS) facilities. Compound libraries are commercially available in sizes of up to several millions of compounds. The most promising compounds obtained from the screening are called hits these are the compounds that show binding activity towards the target. Some of these hits are then promoted to lead compounds candidate structures which are further refined and modified in order to achieve more favorable interactions and less side-effects.
Drug Discovery Methods

The following are methods for finding a drug candidate, along with their pros and cons: 1. Virtual screening (VS) based on the computationally inferred or simulated real screening; The main advantages of this method compared to laboratory experiments are: -low costs, no compounds have to be purchased externally or synthesized by a chemist; -it is possible to investigate compounds that have not been synthesized yet; -conducting HTS experiments is expensive and VS can be used to reduce the initial number of compounds before using HTS methods; -huge amount of chemicals to search from. The number of possible virtual molecules available for VS is exceedingly higher than the number of compounds presently available for HTS; The disadvantage of virtual screening is that it can not substitute the real screening. 2. The real screening, such as high-throughput screening (HTS), can

experimentally test the activity of hundreds of thousands of compounds against the target a day. This method provides real results that are used for drug discovery. However, it is highly expensive.
Virtual Screening in Drug Discovery

Computational methods can be used to predict or simulate how a particular compound interacts with a given protein target. They can be used to assist in building hypotheses about desirable chemical properties when designing the drug and, moreover, they can be used to refine and modify drug candidates. The following three virtual screening or computational methods are used in the modern drug discovery process: Molecular Docking, Quantitative Structure-Activity Relationships (QSAR) and Pharmacopoeia Mapping.
Molecular Docking

When the structure of the target is available, usually from X-ray crystallography, the most commonly used virtual screening method is molecular docking. Molecular docking can also be used to test possible hypotheses before conducting costly laboratory experiments. Molecular docking programs predict how a drug candidate binds to a protein target. This software consists of two core components: 1. A search algorithm, sometimes called an optimisation algorithm. The search algorithm is responsible for finding the best conformations of the ligand, a small drug-like molecule and protein system. A conformation is the position and orientation of the ligand relative to the protein. In flexible docking the conformation also contains information about the internal flexible structure of the ligand and in some cases about the internal flexible structure of the protein. Since the number of possible conformations is extremely large, it is not possible to test all of them. Therefore, sophisticated search techniques have to be applied. Examples of some commonly used methods are Genetic Algorithms and Monte Carlo simulations. 2. An evaluation function, sometimes called a score function. This is a function providing a measure of how strongly a given ligand will interact with a particular protein. Energy force fields are often used as evaluation functions. These force fields calculate the energy contribution from different terms such as the known electrostatic forces between the atoms in the ligand and in the protein, forces arising from deformation of the ligand, pure electron-shell repulsion between atoms and effect from the solvent in which the interaction takes place. It is not possible to guarantee that the search algorithm will find the same solution as the true natural process, but more efficient search algorithms will be more likely to find the true solution if the evaluation functions properly reflect the natural processes. Metaphorically, the active site of the protein can be viewed as a lock, and the ligand can be thought of as a key. Molecular docking is the process of testing whether a given key fits a particular lock. This description is slightly oversimplified due to the fact that neither the ligand nor the proteins are completely rigid structures. Their shapes are somewhat flexible and may adapt to each other.

Quantitative Structure-Activity Relationships (QSAR)

As mentioned in the previous paragraph it is necessary to know the geometrical structure of both the ligand and the target protein in order to use molecular docking methods. QSAR (Quantitative StructureActivity Relationships) is an example of a method which can be applied regardless of whether the structure is known or not. QSAR formalizes what is experimentally known about how a given protein interacts with some tested compounds. As an example, it may be known from previous experiments that the protein under investigation shows signs of activity against one group of compounds, but not against another group. In terms of the lock and key metaphor, we do not know what the lock looks like, but we do know which keys work, and which do not. In order to build a QSAR model for deciding why some compounds show sign of activity and others do not, a set of descriptors are chosen. These are assumed to influence whether a given compound will succeed or fail in binding to a given target. Typical descriptors are parameters such as molecular weight, molecular volume, and electrical and thermodynamical properties. QSAR models are used for virtual screening of compounds to investigate their appropriate drug candidates descriptors for the target.
Pharmacopoeia Mapping

Where QSAR focused on a set of descriptors like electrostatic and thermodynamic properties, Pharmacopoeia Mapping is a geometrical approach. A pharmacophore can be thought of as a 3D model of characteristic features of the binding site of the investigated protein (target). It may describe properties like: "In this region of the target a positive charge is needed, in this region there is a hydrogen donor, that region may not be occupied" and so on. On a pharmacophore model the spheres indicate regions where a certain feature (e.g. a cation or an anion) is required. The pharmacophores are also used to define the essential features of one or more molecules with the same biological activity. Like QSAR models, pharmacophores can be built without knowing the structure of the target. This can be done by extracting features from compounds which are known experimentally to interact with the target in question. Afterwards, the derived pharmacophore model can be used to search compound databases (libraries) thus screening for potential drug candidates that may be of interest.

2004-2010 Combinatorial Chemistry Review.

In silico
From Wikipedia, the free encyclopedia

For other uses, see In silico (disambiguation). In silico is an expression used to mean "performed on computer or via computer simulation." The phrase was coined in 1989[citation needed]as an analogy to the Latin phrases in vivo and in vitro which are commonly used in biology (see also systems biology) and refer to experiments done in living organisms and outside of living organisms, respectively.
Contents
[hide]

1 Drug discovery with virtual screening 2 Cell models 3 Genetics 4 Other examples 5 History

5.1 In silico versus in silicio

6 See also 7 References 8 External links

]Drug

discovery with virtual screening

Main article: virtual screening In silico research in medicine is thought to have the potential to speed the rate of discovery while reducing the need for expensive lab work and clinical trials. One way to achieve this is by producing and screening drug candidates more effectively. In 2010, for example, using the protein docking algorithm EADock (see Proteinligand docking), researchers found potential inhibitors to an enzyme associated with cancer activity in silico. Fifty percent of the molecules were later shown to be active inhibitors in vitro.[1][2] This approach differs from use of expensive high-throughput screening (HTS) robotic labs to physically test thousands of diverse compounds a day often with an expected hit rate on the order of 1% or less with still fewer expected to be real leads following further testing (see drug discovery).

]Cell

models

Efforts have been made to establish computer models of cellular behavior. For example, in 2007 researchers developed an in silico model oftuberculosis to aid in drug discovery with a prime benefit cited as being faster

than real time simulated growth rates allowing phenomena of interest to be observed in minutes rather than months.[3] More work can be found that focus on modeling a particular cellular process like, for example, the growth cycle of Caulobacter crescentus.[4] These efforts fall far short of an exact, fully predictive, computer model of a cell's entire behavior. Limitations in the understanding of molecular dynamics and cell biology as well as the absence of available computer processing power force large simplifying assumptions that constrain the usefulness of present in silico models.

]Genetics

Digital genetic sequences obtained from DNA sequencing may be stored in sequence databases, be analyzed (see Sequence analysis), be digitally altered and/or be used as templates for creating new actual DNA using artificial gene synthesis.

]Other

examples

In silico computer-based modeling technologies have also been applied in: Whole cell analysis of prokaryotic and eukaryotic hosts e.g. E. coli, B. subtilis, yeast, CHO- or human cell lines

  [ ]History

Bioprocess development and optimization e.g. optimization of product yields Analysis, interpretation and visualization of heterologous data sets from various sources e.g. genome, transcriptome or proteome data

The expression in silico was first used in public in 1989 in the workshop "Cellular Automata: Theory and Applications" in Los Alamos, New Mexico. Pedro Miramontes, a mathematician from National Autonomous University of Mexico (UNAM) presented the report "DNA and RNAPhysicochemical Constraints, Cellular Automata and Molecular Evolution". In his talk, Miramontes used the term "in silico" to characterize biological experiments carried out entirely in a computer. The work was later presented by Miramontes as his PhD dissertation.[5] In silico has been used in white papers written to support the creation of bacterial genome programs by the Commission of the European Community. The first referenced paper where "in silico" appears was written by a French team in 1991.[6] The first referenced book chapter where "in silico" appears was written by Hans B. Sieburg in 1990 and presented during a Summer School on Complex Systems at the Santa Fe Institute.[7] The phrase "in silico" originally applied only to computer simulations that modeled natural or laboratory processes (in all the natural sciences), and did not refer to calculations done by computer generically.

[ ]In

silico versus in silicio

"In silico" was briefly challenged by "in silicio," which is correct Latin for "in silicon" (the Latin term for silicon, silicium, was created at the beginning of the 19th century by Berzelius. Silex is also a correct latin word).[citation needed] But the phrase "in silice" means "in flint" in Latin. "In silico" was perceived as catchier, possibly through similarity to the words "vivo" and "vitro"[citation needed] "In silico" is now almost universal; it even occurs in a journal title (In Silico Biology: http://www.bioinfo.de/isb/). In silico is reasonable from the viewpoint of (ancient) Greek case endings; the "-on" ending for certain elements is from Greek. In Greek, "silicon" would take the form "silico" in such a phrase. Latin typically uses the correct Greek forms for Greek words when they are used in Latin.

[ [ ]References
1. ^ Ludwig Institute for Cancer Research (2010) Rational Design of Indoleamine 2,3-Dioxygenase Inhibitors. Journal of Medicinal Chemistry, 2010, 53 (3), pp 11721189 DOI: 10.1021/jm9014718 2. ^ Ludwig Institute for Cancer Research (2010, February 4). New computational tool for cancer treatment. ScienceDaily. Retrieved February 12, 2010, from http://www.sciencedaily.com/releases/2010/01/100129151756.htm 3. ^ University Of Surrey (2007, June 25). In Silico Cell For TB Drug Discovery. ScienceDaily. Retrieved February 12, 2010, fromhttp://www.sciencedaily.com/releases/2007/06/070624135714.htm 4. ^ Li S, Brazhnik P, Sobral B, Tyson JJ, 2009 Temporal Controls of the Asymmetric Cell Division Cycle in Caulobacter crescentus. PLoS Comput Biol 5(8): e1000463. doi:10.1371/journal.pcbi.1000463 5. ^ Miramontes P. Un modelo de autmata celular para la evolucin de los cidos nucleicos [A cellular automaton model for the evolution of nucleic acids]. Tesis de doctorado en matemticas. UNAM. 1992. 6. ^ Danchin A, Medigue C, Gascuel O, Soldano H, Henaut A. From data banks to data bases. Res Microbiol. 1991 Sep-Oct;142(7-8):913-6. PMID 1784830. 7. ^ Sieburg, H.B. (1990). Physiological Studies in silico. Studies in the Sciences of Complexity 12, 321-342.

]External

links

World Wide Words: In silico

CADASTER Seventh Framework Programme project aimed to develop in silico computational methods to minimize experimental tests for REACH Registration, Evaluation, Authorisation and Restriction of Chemicals

Journal of In Silico Biology