COMPUTING IN INDUSTRIAL PHARMACY

INTRODUCTION

Computing can be simply defined as the use or operation of computers,

according to oxford dictionary. Computing can be broadly defined as any

goal-oriented activity requiring, benefiting from, or creating algorithmic

processese.g. through computers. Computing includes designing,

developing and building hardware and software systems; processing,

structuring, and managing various kinds of information; doing scientific

research on and with computers; making computer systems behave

intelligently; and creating and using communications and entertainment

media. (Wikipedia, 2016)

How far has computers and related computer programs taken us

from the Egyptian era of pharmacy to present modern pharmacy?

Modern pharmacy has provided us a world of drugs; Drugs for diseases,

allergies, pleasure, mental health and other medical conditions. These

drugs have been rationally designed and engineered, synthesized from

plants, animals or minerals and are sterile or non-toxic to the body.

Modern pharmacy has provided the world drugs that, for the most part,

actually do what they are supposed to. Effectively. Safely.

From the beginning of time till the 20th century, drugs were concocted with

a mixture of empiricism and prayer, Trial and error, inherited lore, or

mystical theories with the process and technology of making drugs non

sterile and crude. Rational treatments and rational drug design of this era

were based on either the doctrine of humors (a pseudo astrological form

of alchemical medicine oriented to the fluids of the body: blood, phlegm

and black and yellow bile) or the doctrine of signatures. (If a plant looks

like a particular body part, it must be designed by nature to influence that

part.)

Modern pharmacy is majorly divided into three broad categories (and

other minor categories) - industry based pharmacy, community based

pharmacy and hospital based pharmacy with each category playing a

huge role on every aspect of pharmacy.

Industrial pharmacy is a discipline which includes manufacturing,

development, marketing and distribution of drug products including

quality assurance of these activities. This broad research area relates to

different functions in pharmaceutical industry and having contact areas

with engineering and economics.

COMPUTING IN PHARMACEUTICAL RESEARCH AND DEVELOPMENT

OVERVIEW

Pharmaceutical research and development is an aspect of industrial

pharmacy that deals with investigative activities that pharmaceutical

industries choose to conduct with the intention of making a drug

discovery that can either lead to the development of new drug products or

procedures, or to improvement of existing drug products or procedures.

Research and development is one of the means by which pharmaceutical

industries can experience future growth by developing new drug products

or processes to improve and expand their operations.

The use of computers has helped in the development of new drug

products in research and development both industrially and academically,

thereby leading to great improvement of drugs produced by modern

pharmacy.

The use of computers in pharmaceutical research and development has

come a long way in modern pharmacy.

In order to produce new drugs, research has to be done by industrial

scientists, in which the use of computers to publish these papers come

into play. Before the advent of computers, the number of research

publications by industrial pharmacist were increasing but at a slow pace.

Then, from 1986 through 1992, the annual number of papers grew rapidly.

This period is when the superminicomputers, supercomputers, and

workstations appeared on the scene. In this period, the number of annual

paper produced by industries increased drastically.

As the twentieth century came to a close, the job market for

computational chemists had recovered from the 19921994 debacle. In

fact, demand for computational chemists leaped to new highs each year

in the second half of the 1990s. Most of the new jobs were in industry, and

most of these industrial jobs were at pharmaceutical or biopharmaceutical

companies. The outlook for computational chemistry is therefore very

much linked to the health of the pharmaceutical industry itself. Forces that

adversely affect pharmaceutical companies will have a negative effect on

the scientists who work there as well as at auxiliary companies such as

software vendors that develop programs and databases for use in drug

discovery and development.

Over the last four decades, we have witnessed waves of new technologies

sweep over the pharmaceutical industry. Sometimes these technologies

tended to be oversold at the beginning and turned out to not be a

panacea to meet the quota of the number of new chemical entities that

each company would like to launch each year.

The successful medicinal chemist will combine atoms such that amazing

therapeutic effect is achieved with the resulting molecule. The

computational chemists goal should be to help the medicinal chemist by

providing information about structural and electronic requirements to

enhance activity, namely, information about which regions of compound

space are most propitious for exploration. Fortunately, all the effort that

goes into pharmaceutical R&D does benefit society. In nations where

modern medicines are available, life expectancy has increased and

disability rates among the elderly have declined. Considering all of the

things that can go wrong with the human body, many challenges remain

for the pharmaceutical researcher. (ed. Ekins 2006)

APPLICATION.

Computers has been applied in so many ways to pharmaceutical research

and development. Without the advent or creation of computers, the

development of new drugs to meet the unending demand for new drug

products for various disease conditions would have not been met by
industrial pharmacist, or better still, the demand would have been met but

at a slow pace. Needless to say, the wide use of computers has

tremendously increased efficiency and productivity in pharmaceutical

development. On the other hand, it has also created unique problems and

challenges for the industry.

Computers can be applied to pharmaceutical research and development

as follows;

THE USE OF COMPUTERS AS DATA ANALYSIS AND DATA

MANAGEMENT TOOLS IN PRECLINICAL DEVELOPMENT.

Scientists from many different disciplines participate in pharmaceutical

development. Their research areas may be very different, but they all

generate scientific data (and text documents), which are the products of

development laboratories. One way or another, every single data point

has to go through the acquiring, analysing, managing, reporting, auditing,

and archiving process according to a set of specific rules and regulations.

Considering the pervasiveness of computer applications in every

scientists daily activities, special emphases are put on three widely used

computer systems:

CDSchromatographic data systems

LIMSlaboratory information management systems

TIMStext information management systems

COMPUTING IN DRUG DESIGN

Drug design, sometimes referred to as rational drug design or simply

rational design, is the inventive process of finding new medications based

on the knowledge of a target. The drug is most commonly an organic

small molecule that activates or inhibits the function of a biomolecule

such as a protein, which in turn results in a therapeutic benefit to the

patient. In the most basic sense, drug design involves the design of

molecules that are complementary in shape and charge to the

biomolecular target with which they interact and therefore will bind to it.

Drug design frequently but not necessarily relies on computer modelling

techniques. This type of modelling is often referred to as computer-aided

drug design. Finally, drug design that relies on the knowledge of the three-

dimensional structure of the biomolecular target is known as structure-

based drug design. (Wikipedia, 2016)

Figure 1; the cycle of drug design, synthesis and biological

testing

In 1981, the Designing Drugs by Computer, that is, computer-aided drug

design (CADD) was in progress, but the potential for high-throughput

screening (HTS) had begun to take precedence as a means for finding

novel therapeutics. This brute force approach relies on automation to

screen high numbers of molecules in search of those that elicit the desired

biologic response. The method has the advantage of requiring minimal

compound design or prior knowledge, and technologies required to screen

large libraries have become more efficient. However, although traditional

HTS often results in multiple hit compounds, some of which are capable of

being modified into a lead and later a novel therapeutic, the hit rate for

HTS is often extremely low. This low hit rate has limited the usage of HTS

to research programs capable of screening large compound libraries. In

the past decade, CADD has re-emerged as a way to significantly decrease

the number of compounds necessary to screen while retaining the same

level of lead compound discovery. Many compounds predicted to be

inactive can be skipped, and those predicted to be active can be

prioritized. This reduces the cost and workload of a full HTS screen without

compromising lead discovery. Additionally, traditional HTS assays often

require extensive development and validation before they can be used.

Because CADD requires significantly less preparation time, experimenters

can perform CADD studies while the traditional HTS assay is being

prepared. The fact that both of these tools can be used in parallel provides

an additional benefit for CADD in a drug discovery project.

For example, researchers at Pharmacia (now part of Pfizer) used CADD

tools to screen for inhibitors of tyrosine phosphatase-1B, an enzyme

implicated in diabetes. Their virtual screen yielded 365 compounds, 127 of

which showed effective inhibition, a hit rate of nearly 35%.

Simultaneously, this group performed a traditional HTS against the same

target. Of the 400,000 compounds tested, 81 showed inhibition, producing

a hit rate of only 0.021%. This comparative case effectively displays the

power of CADD (Doman et al., 2002).

CADD is capable of increasing the hit rate of novel drug compounds

because it uses a much more targeted search than traditional HTS and
combinatorial chemistry. It not only aims to explain the molecular basis of

therapeutic activity but also to predict possible derivatives that would

improve activity. In a drug discovery campaign, CADD is usually used for

three major purposes:

1. filter large compound libraries into smaller sets of predicted active

compounds that can be tested experimentally

2. guide the optimization of lead compounds, whether to increase its

affinity or optimize drug metabolism and pharmacokinetics (DMPK)

properties including absorption, distribution, metabolism, excretion,

and the potential for toxicity (ADMET)

3. design novel compounds, either by growing" starting molecules

one functional group at a time or by piecing together fragments into

novel chemotypes.

CADD can be classified into two general categories:

structure-based CADD
ligand-based CADD

Structure-based CADD relies on the knowledge of the target protein

structure to calculate interaction energies for all compounds tested,

whereas ligand-based CADD exploits the knowledge of known active

and inactive molecules through chemical similarity searches or

construction of predictive, quantitative structure-activity relation (QSAR)

models

Figure 2; ILLUSRATION OF CADD AND ITS POSITION IN DRUG

DESIGN

LIGAND BASED CADD (LB - CADD)

Ligand-based CADD exploits the knowledge of known active and inactive

molecules through chemical similarity searches or construction of

predictive, quantitative structure-activity relation (QSAR) models, AND

pharmacophore perception.

Molecular fingerprint-based techniques and Similarity search

Molecular fingerprint-based techniques attempt to represent molecules in

such a way as to allow rapid structural comparison in an effort to identify

structurally similar molecules or to cluster collections based on structural

similarity. These methods are less hypothesis driven and less

computationally expensive than pharmacophore mapping or QSAR

models. They rely entirely on chemical structure and omit compound

known biologic activity, making the approach more qualitative in nature

than other LB-CADD approaches (Auer and Bajorath, 2008).

Similarity Searches in LB-CADD.

Fingerprint methods may be used to search data bases for compounds

similar in structure to a lead query, providing an extended collection of

compounds that can be tested for improved activity over the lead. In

many situations, 2D similarity searches of data bases are performed using

chemotype information from first generation hits, leading to modifications

that can be evaluated computationally or ordered for in vitro testing

(Talele et al., 2010).

PharmacophoreConcept, Methods, and Applications

The pharmacophore concept has now been widely accepted and used in

the medicinal chemistry community as well as the field of computational

molecular modelling.

The very first definition of a pharmacophore was offered by Paul Ehrlich in

the early 1900s, which states that a pharmacophore is a molecular

framework that carries the essential features

responsible for a drugs biological activity. This definition is still used

today, mostly by medicinal chemists.

In 1977, Peter Gund defined a pharmacophore as a set of structural

features in a molecule that is recognized at a receptor site and is

responsible for that molecules biological activity

By this definition, a pharmacophore can be a set of disconnected features

in 3D space that are required and recognized by the receptor and could be

held together by different molecular frameworks.

There are two broad categories of pharmacophore construction techniques

depending on what initial information is used. The first is the active

analog based approach, where no receptor information is employed

and only a set of relevant active molecules are provided. These active

molecules are believed to act at the same receptor site. In this case,

computer algorithms have been developed to perceive the common

features shared by the set of molecules.

The second approach is the receptor structure-based approach,

where the target structure is known and employed to derive the

pharmacophore features. Various approaches have been developed to

derive critical features from the target structure or the structure of a

ligand-receptor complex. Catalyst and GASP belong to the first category,

whereas the alpha-shape technique in MOE (www.chemcomp.com)

belongs to the second category.

Quantitative Structure-Activity Relationship Models

Quantitative structure-activity relationship (QSAR) models describe the

mathematical relation between structural attributes and target response

of a set of chemicals (Zhang, 2011). Classic QSAR is known as the Hansch-

Fujita approach and involves the correlation of various electronic,

hydrophobic, and steric features with biologic activity

The general workflow of a QSAR-based drug discovery project is to first

collect a group of active and inactive ligands and then create a set of
mathematical descriptors that describe the physicochemical and

structural properties of those compounds. A model is then generated to

identify the relationship between those descriptors and their experimental

activity, maximizing the predictive power. Finally, the model is applied to

predict activity for a library of test compounds that were encoded with the

same descriptors. Success of QSAR, therefore, depends not only on the

quality of the initial set of active/inactive compounds but also on the

choice of descriptors and the ability to generate the appropriate

mathematical relationship.

QSAR has been used to screen for novel therapeutics in the same way

both pharmacophore models and fingerprint similarity methods have been

applied to virtual libraries.

In addition to predicting the behavior of novel compounds within a virtual

library, QSAR has been used to improve compound libraries used in

traditional HTS

QSAR has also been applied to de novo drug design techniques when

structural information regarding the target is unknown. Descriptor and

model generation is performed and is used to score the de novo-

generated molecules in place of other structure-based scoring techniques

such as docking. Most commonly, compound generation involves iterative

algorithms in which structures are repeatedly modified and their biologic

activities are estimated using QSAR models

STRUCTURE AND THE DRUG DISCOVERY PROCESS

There are three main contributions that structural methods are making to

the drug discovery processstructural biology, structure-based design,

and structure-based discovery.

Structural Biology

The determination of the structure of a protein target, perhaps complexed

to partner proteins, lipids, nucleic acid, or substrate, can provide a clear

insight into the mechanism of action of a protein, which in turn can often

be related to its biological or therapeutic role. It is now possible to

generate structures for an increasing number of therapeutically important

targets, such as nuclear receptors, kinases, proteases,

phosphodiesterases, phosphatases, metabolic enzymes, and key proteins

in the life cycle of bacteria or viruses.

Structure-Based Design
The crystal structure of a ligand bound to a protein provides a detailed

insight into the interactions between the protein and the ligand. Such

understanding can be used to design changes to the ligand to introduce

new interactions to modify the affinity and specificity of the ligand for a

particular protein. In addition, the structure can be used to identify where

the ligand can be changed to modulate the physicochemical and

absorption, distribution, metabolism, excretion, and toxicology properties

of the compound, by showing which parts of the compound are important

for affinity and which parts can be altered without affecting binding.

Structure-Based Discovery

As the availability of crystal structures increased in the early 1990s, a

number of experimental and computational methods were developed to

use the structure of the protein target as a route to discover novel hit

compounds. The methods include de novo design, virtual screening, and

fragment-based discovery.

Virtual screening uses computational docking methods to assess which of

a large database of compounds will fit into the unliganded structure of the

target protein. Current protocols and methods can, with up to 80%

success, predict the binding position and orientation of ligands that are
known to bind to a protein. However, identifying which ligands bind into a

particular binding site is much less successful, with many falser positive

hits being identified. The major challenge remains the quality of the

scoring functions

De novo design attempts to use the unliganded structure of the protein to

generate novel chemical structures that can bind. There are varying

algorithms, most of which depend on identifying initial hot spots of

interactions that are then grown into complete ligands. As well as the

ubiquitous issue of scoring functions, the major challenge facing these

methods is generation of chemical structures that are synthetically

accessible.

Fragment-based discovery is based on the premise that most ligands that

bind strongly to a protein active site can be considered as a number of

smaller fragments or functionalities. Fragments are identified by screening

a relatively small library of molecules (40020,000) by X-ray

crystallography, NMR spectroscopy, or functional assay. The structures of

the fragments binding to the protein can be used to design new ligands by

adding functionality to the fragment, by merging together or linking

various fragments, or by grafting features of the fragments onto existing

ligands. The main issues are designing libraries of sufficient diversity and

the synthetic challenges of fragment evolution.

REFERENCES

(www.chemcomp.com)

Doman TN, McGovern SL, Witherbee BJ, Kasten TP, Kurumbail R, Stallings WC,

Connolly DT, and Shoichet BK (2002) Molecular docking and high-throughput screening for

novel inhibitors of protein tyrosine phosphatase-1B. J Med Chem 45; 2213 2221

Auer J and Bajorath J (2008) Molecular similarity concepts and search calculations. Methods

Mol Biol 453: 327 347

Talele TT, Khedkar SA, and Rigby AC (2010) Successful applications of computer aided

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Zhang S, Cao ZX, Tian H, Shen G, Ma Y, Xie H, Liu Y, Zhao C, Deng S, and Yang Y, et al.

(2011) SKLB1002, a novel potent inhibitor of VEGF receptor 2 signaling, inhibits

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Sean Ekins (ed.) 2006, Computer Applications in Pharmaceutical Research

and Development, John Wiley & Sons, Inc., Hoboken, New Jersey.

Gregory Sliwoski, Sandeepkumar Kothiwale, Jens Meiler, and Edward W.

Lowe, Jr 2013, Computational Methods in Drug Discovery, Vanderbilt

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