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Drug Design - A multiple task

Drug design may be approached in various ways, but basic concepts about drugs, receptors, and drugreceptor interactions are of highest importance. Conceiving drug design may be divided into three logical steps: Step 1-The drug: Know what properties turn a synthesized molecule into a drug. Step 2-The drug receptor: Know what properties turn a macromolecule from the human body into a drug receptor Step 3-The fitness: Know how to design and synthesize the drug in order to fit into a receptor The process of drug design must be validated by actually making and testing the drug molecule. An ideal synthesis should be simple, be efficient, and produce the drug in high yield and high purity.

Step 1
involves knowing WHAT PROPERTIES TURN A MOLECULE INTO A DRUG. [intermediately a drug-like molecule (DLM)] Drug molecules are small organic molecules (molecular weight usually below 800 g/mol, often below 500); should present certain properties (geometric, conformational, stereochemical, electronic) appropriate to make it a drug-like molecule (DLM). are complex and have sub-unit parts (biophores) in order to: interact with the receptor(s) (go to Step 2), permit the body to absorb, distribute, metabolize, and excrete (A-D-M-E) the drug molecule. When designing a molecule, a design tool is used, such as Computeraided molecular design (CAMD), which incorporates molecular mechanics and quantum mechanics.

Step 2
involves knowing WHAT PROPERTIES TURN A MACROMOLECULE FROM THE BODY INTO A RECEPTOR. Receptor macromolecules are frequently proteins or glycoproteins or parts of them as fluid, flexible surfaces or pockets most receptors are already sites for natural ligands should present certain properties appropriate in order to make them druggable target(s). should be intimately connected with the disease in question

Step 3
involves CONNECTING A DRUGRECEPTOR INTERACTION TO A HUMAN DISEASE DESIGNING A SPECIFIC DRUG-LIKE MOLECULE TO FIT INTO A PARTICULAR DRUGGABLE TARGET. This phase of drug design requires the understanding of biochemistry and of the molecular pathology of the disease being treated. This phase of drug development, which connects the drugreceptor interaction to human disease, is based on three logical approaches (that mark the three main drug targets): Aproach A. Know how to manipulate the bodys endogenous control systems Approach B. Know how to manipulate the bodys endogenous macromolecules. Approach C. Know how to inactivate a harmful exogenous agent The prototype compound (the lead compound) is then optimized by QSAR studies and finally validated by synthesis and tests.

How drug act ? Paul Ehrlich : Corpora non agunt nisi fixata, i.e.

A drug will not work unless it is bound

The traditional model for Receptors was a rigid Lock and Key Lock Receptor surface Key Drug or Ligand Receptor can change 3-D structure as ligand docks



The therapeutic goal is to bring back the human body to its normal balanced, harmonious state, called homeostasis. The approaches to attaining this govern also one of the drugs classification: A. To know the bodys normal inner (endogenous) control systems for maintaining homeostasis through day-to-day or minute-to-minute adjustments. These control systems (for example, neurotransmitters, hormones, immunomodulators,) are the first line of defense against perturbations of homeostasis. B. If there are no data on the endogenous control systems, how about identifying other targets on endogenous cellular structures or macromolecules? C. Alternatively, it may be easier to attack the cause of the pathology. If there is a harmful microorganism or toxin in the environment (exogenous), then it may be possible to directly attack this exogenous threat to health and inactivate it.

Approach C.

Both the three steps (Step 1, Step 2, and Step 3, above mentioned) and the three Approaches (A, B, C) are the milestones of drug design.

A Drug as a Composite of Molecular Fragments

Drug molecules are conceptualized as being assembled from biologically active building blocks (biophores) that are covalently snapped together to form an overall molecule. Thus, a drug molecule is a multiphore, composed of a fragment that enables it to bind to a receptor (pharmacophore), a fragment that influences its metabolism in the body (metabophore), and one or more fragments that may contribute to toxicity (toxicophores). The drug designer should have the ability to optimize the pharmacophore while minimizing the number of toxicophores. To achieve this design strategy, these fragments or building blocks may be replaced or interchanged to modify the drug structure. Certain building blocks (called bioisosteres), which are biologically equivalent but not necessarily chemically equivalent, may be used to promote the optimization of the drugs biological properties.

A drug molecule possesses one or more functional groups positioned on a structural framework (e.g. the hydrocarbonate skeleton, any aromatic rings, any rigid conformations/configurations, etc) that holds the functional groups in a defined geometrical array that enables the molecule to bind specifically to a targeted biological macromolecule, the receptor.

The general pattern of drug action [D = drug, R = receptor (druggable target)] Not every area of the receptor is fit for a particular drug binding

The framework upon which the functional groups are displayed is typically a hydrocarbon structure (e.g., aromatic ring, alkyl chain) and is usually chemically inert so that it does not participate in the binding process. The structural framework should also be relatively rigid (conformationally constrained) to ensure that all of the functional groups are not flexible in geometry, thus preventing the drug from interacting with untargeted receptors by altering its molecular shape. The desired biological response should be beneficial (by inhibiting pathological processes) No other binding (if possible) to other untargeted receptors is intended, thus minimizing the probability of toxicity/side effects.

Also drug-like molecules (DLM) should possess the chemical and physical properties that will enable it to become a drug molecule if an appropriate receptor is identified What are the properties that enable a common molecule to become a druglike molecule? The molecule should be # small enough to be transported throughout the body, # hydrophilic enough to dissolve in the blood stream, # lipophilic enough to cross fat barriers within the body. # It should contain enough polar groups to enable it to bind to a receptor, but not so many that it would cause to be excreted too quickly from the body, limiting thus the therapeutic effect. Lipinskis Rule of Five does a good job of quantifying these properties. a drug-like molecule should have a molecular weight less than 500, a logP (logarithm of its octanolwater partition coefficient) value < 5 < 5 hydrogen bonding donors, < 10 hydrogen bonding acceptors.

According to the above mentioned theory of the drug & receptor relationship, a druggable target should also posess features to support the model: Druggable targets R : are macromolecules are usually proteins show biological response Conclusion: Certain properties permit a molecule to become a drug-like molecule and certain properties permit a macromolecule to become a druggable target. When a drug-like molecule interacts with a druggable target to give a biological response, the drug-like molecule becomes a drug molecule and the druggable target becomes a receptor.

Biophores Structural Fragments of a Drug Molecule: Pharmacophore, Toxicophore, Metabophore


The three-dimensional arrangement of atoms within a drug molecule that permits a specific binding interaction with a desired receptor is called the pharmacophore. This is the bioactive face of the drug
The molecular baggage: the Toxicophore & Metabophore

The other portions of the drug molecule that are not part of the pharmacophore constitute the molecular baggage. The role of this molecular baggage is to hold the functional group atoms of the pharmacophore in a fixed geometric arrangement (with minimal conformational flexibility) to permit a specific receptor interaction. The molecular baggage consists of two other less frequently discussed fragments of a drug molecule, i.e. the toxicophore and the metabophore. Conceptually, these two fragments are analogous to the pharmacophore.

The toxicophore
the three-dimensional arrangement of atoms in a drug molecule that is responsible for a toxicity-eliciting interaction. Several toxicophores multiple toxicities arising from several undesirable interactions if a toxicophore does not overlap with the pharmacophore in a given drug molecule, then it may be possible to redesign the molecule to eliminate the toxicity. if the pharmacophore and toxicophore are congruent molecular fragments, then the toxicity is inseparable from the desired pharmacological properties.

The metabophore
responsible for the metabolic properties. Since functional groups are responsible not only for drug receptor interactions but also for metabolic properties, the metabophore and the pharmacophore tend to be inextricably overlapped. Nevertheless, from the viewpoint of drug design, it is sometimes possible to manipulate the structure of either the pharmacophore or the molecular baggage portions of the drug molecule to achieve a convenient metabophore (e.g. that either hastens or delays renal excretion).

It is sometimes possible to replace all or part of the pharmacophore with a biologically equivalent fragment called a bioisostere. When designing or constructing a drug molecule, one can thus pursue a fragment-by-fragment building block approach. Certain molecular fragments, although structurally distinct from each other, may behave identically within the biological milieu of the receptor microenvironment. E.g. replacing the sulphonate (SO42) with a bioisosterically equivalent carboxylate (CO32) group, would bring a prolonged half-life (the interval within which the concentration of the drug decreases to half of its initial one) for the drug molecule since the carboxylate is less polar than the sulphonate and is thus less susceptible to rapid renal excretion.

Structural Properties of Drug Molecules

In a drug molecule the collection of molecular fragments are held in a three-dimensional arrangement that determines and defines all of the properties of the drug molecules. These properties dictate the therapeutic, toxic, and metabolic characteristics of the overall drug molecule. These properties also completely control the ability of the drug to resist to the chemical changes that may occur from the point of administration to the receptor site buried deep within the body. These physical properties of drug molecules may be categorized into the following major groupings: 1. Physicochemical properties 2. Shape properties 3. Electronic properties

The structural characteristics of a drug molecule (size, shape, topology, polarity, chirality) that influence its ability to interact with a receptor. Each of these properties is required for the unique pharmacological activity of a drug molecule.

1. Physicochemical properties

Physicochemical properties are crucial to the pharmaceutical and pharmacokinetic phases of drug action determining the pharmacodynamic interaction of the drug with its receptor. Physicochemical properties reflect the solubility and absorption characteristics of the drug and its ability to cross barriers, such as the bloodbrain barrier, on its way to the receptor.

2. Shape properties

geometric, steric, conformational, topological)

describe the structural arrangement of the atoms within the drug molecule and influence the geometry of approach as the drug molecule enters the realm of the receptor.

3. Electronic properties
reflect electron distribution within the drug molecule and determine the nature of the interaction between the drug and its receptor (by hydrogen bonding and other forms of electrostatic interaction). From the perspective of the drug designer, they are among the most difficult to predict and to engineer. Accordingly, extensive use is now made of quantum mechanics and classical mechanics force field calculations to determine electronic and structural properties of drug molecules

Drugs formulation. A pill is a complicated mixture of non-toxic excipient additives: Fillers (to ensure that the pill is large enough to be seen and handled; Fillers include dextrose, lactose, calcium triphosphate, sodium chloride, and microcrystalline cellulose) Binders (to permit the pill to be compressed into a tablet; binders include acacia, ethyl cellulose, gelatin, starch mucilage, glucose syrup, sodium alginate, and polyvinyl pyrrolidone) Lubricants (to pass through the gastrointestinal tract without sticking; lubricants include magnesium stearate, stearic acid, talc, colloidal silica, and polyethylene glycol) Disintegrants (to be absorbed in the small intestine; disintegrants include starch, alginic acid, and sodium lauryl sulphate ) Colouring agents Flavoring agents

Drug Names
Drugs have three or more names including a: chemical name (according to rules of nomenclature), brand or trade name (always capitalized and selected by the manufacturer) generic or common name (refers to a common established name irrespective of its manufacturer). In most cases, a drug bearing a generic name is equivalent to the same drug with a brand name. However, this equivalency is not always true. Although drugs are chemically equivalent, different manufacturing processes may cause differences in pharmacological action. Several differences may be crystal size or form, isomers, crystal hydration, purity-(type and number of impurities), vehicles, binders, coatings, dissolution rate, and storage stability.

Drugs design (for connecting diseases to molecules) may be elaborated according to several approaches:
THE PHYSIOLOGICAL SYSTEMS APPROACH (the same organizational lines as conventional medicine) Focused on the ten fundamental physiological systems of the human body and the particular diseases associated with these systems: 1. Cardiovascular system 2. Dermatological system Disease 3. Endocrine system 4. Gastrointestinal system 5. Genitourinary system 6. Hematological system biochemical and 7. Immune system molecular processes 8. Musculoskeletal system involved in disease 9. Nervous system 10. Respiratory system It is not ideal in connecting disease to molecule. For example, when designing drugs for the cardiovascular system, many different receptors (adrenergic, cholinergic) and many different pathological processes (atherosclerosis, inflammation) are involved.

THE PATHOLOGICAL PROCESS APPROACH This classification system is based on a traditional pathology approach to disease with emphasis on etiology (causative factors) and pathogenesis (mechanism of disease, particularly at a cellular level). This approach focuses on ten fundamental pathological processes: 1. Traumatic (pathology from injury) 2. Toxic (pathology from poisons) 3. Hemodynamic/vascular (pathology from disorders of blood vessels) 4. Hypoxic (pathology from inadequate supply or excessive demand for oxygen by a tissue) 5. Inflammatory (pathology from abnormal inflammatory response in the body) 6. Infectious (pathology from microbes or infectious agents) 7. Neoplastic (pathology from tumors, cancer) 8. Nutritional (pathology from too much/too little food intake) 9. Developmental (pathology in the chemistry of heredity) 10. Degenerative (pathology from age-related tissue breakdown)


drug design that targets a pathology (e.g. neoplasia) may lead to drugs with many applications, (e.g. lung cancer, bowel cancer, or brain cancer).

this approach focuses more on cellular targets than on molecular targets.

THE MOLECULAR MESSENGER AND NONMESSENGER TARGET SYSTEM A third conceptual approach, is to focus on the biochemical and molecular processes of human disease. It may be classified as follows: 1. Messenger targets INeurotransmitters (fast messengers), 2. Messenger targets IIHormones (intermediate messengers), such as the Steroid hormones and their receptors and the Peptide hormones and their receptors 3. Messenger targets IIIImmunomodulators (slow messengers), such as the Immunosuppressants and their receptors and the Immunomodulators/immunostimulants and their receptors 4. Non-messenger targets IEndogenous cellular structures, such as Membrane targets , Nuclear targets, etc. 5. Non-messenger targets IIEndogenous macromolecules, such as Proteins , Nucleic acids, Lipids, Carbohydrates, etc 6. Non-messenger targets IIIExogenous pathogens, such as Microbes , Environmental toxins , etc