Computer Assisted Dug Design: A Review

Anand M. Kudal

The search for new, effective and safe drugs has become increasing, sophisticated and costly. The process of drug discovery and development is a long, tedious and difficult one.

Occasionally new drugs are found by accident. More frequently they are developed as a part of an organized effort to discover new ways to treat human disease but also to improve the quality of life. In general the computer aided drug design technique has the ability to accomplish both these goals and to improve the efficiency of the process as well.

The cost of taking a compound with potential therapeutic value from the laboratory bench to the pharmacy shelf has become almost prohibitive in recent years, safety, efficacy and economy are the three criteria which should be considered during search of a new drug.

¨ Computer-Assisted Drug Design (CADD) : It involves all computer-assisted techniques used to discover, design, and optimize biologically active compounds with effective use as drugs.

¨Computer-Assisted Molecular Design (CAMD) : It involves all computer-assisted techniques used to discover, design, and optimize compounds with desired structure and properties.

Computer-Assisted Molecular Modeling (CAMM) : It involves the investigation of molecular structures and properties using computational chemistry and graphical visualization techniques.

The following ways through which new drugs had their origin

DRUG DISCOVERY¹     

The drug discovery involves following steps 

1) Screening for New Drugs

The traditional way to discover new drugs has been to screen a large number of synthetic chemical compounds or natural products for desirable effects although this approach for the development of new pharmaceutical agent has been successful in the past, it is not an ideal one for a number of reasons.

2) Modifications of lead compounds

After determination of chemical structure, modifications are done in this structure to improve activity, reduce side effects and to improve performance. Modification of lead compound are often carried out using chemical or bio fermentative means to make changes in the lead structure or its intermediates.

Examples of this approach are development of chlorpromazine (anti psychotic) from promethazine (   antihistaminic )  and development of second and third generation cephalosporins from first generation cephalosporins.

3) Mimicking of Natural Compounds

New drugs having structural similarity with the natural products were synthesized and their activities observed, e.g., synthetic steroids, prostaglandin’s and anti-metabolite.

Mechanism Based Drug Design

As still more information becomes available about the biological basis of a disease, it is possible to begin to design drugs using a mechanistic approach to the disease process, when the disease process is understood at the molecular level and the target molecules are defined, drugs can be designed specifically to interact with the target molecules in such a way to disrupt the disease. Because of the massive amount of information that must be harnessed to develop drugs by this technique, it is in this area where computer aided drug design will have its greatest impact.

Combining Techniques

Potentially drug developed by modifying a lead structure are certain to be sent through selective screening process to confirm activity and select for the best candidate to go on for further development. Likewise, drugs developed by mechanistically will likely be both, screened and later modified in order to produce the best candidate drug.

Furthermore, every new chemical entity that affects the disease process, whether found by accident, screening, modification or mechanistic drug design, provides useful information for developing still better compounds.         Each new chemical increases the database of information about the disease target drug interaction. This in turn is the basis for rational drug design.  Fig. 1.1 present schematically some of the various interaction that can occur in discovery of new drug.

Fig.1.1 Flow diagram of some of the potential interaction that can occur in the process of discovery in new chemical entity.

Rational Drug Design Process²

The rational drug design process has changed the way in which potential new drugs are discovered. In the past, many drugs were developed through a search of natural sources. The increasing cost of screening compounds and the decreasing yield of new and unique lead compounds from the natural sources has made this approach less favourable in recent years. One estimate  holds, that only one compound in every 20,000 screened randomly will make it into the clinic and this already low yield is expected to decrease even further in the future.

The cost of taking a compound with potential therapeutic value from the laboratory bench to the pharmacy shelf is almost prohibited in recent years. Commonly used pharmaceutical industry figures indicate that in the late 1980s and early 1990s, bringing a drug to market required approximately $ 120 to $ 150 million and about 8 to 10 years of its expected useful product life.

 Drug development includes several stages

(1)The compounds synthesis and its initial screening for the pharmacological activity.

(2)The requisite pre-clinical animal studies for both short term and long term toxicity.

(3)Phase I clinical trials in healthy volunteers.

(4)Phase II clinical trials in a limited cohort of patients with the targeted disease.

(5)Phase II clinical trials in a broad population of affected patients.

The built in costs are the result of the thoroughness and caution prescribed by these processes in the drug product development.

Another significant cost built into the drug product development process is the expense of synthesis and testing the entire unsuccessful drug candidate investigated along the way towards approval of the successful drug candidate.

Although some progress has been made in recent years towards reducing the time and cost of drug product development by modifying the approval and clinical trial process, a successful drug product will never be either cheap or easy to produce. One way to make the drug product development process more cost effective is to improve the yield of promising drug candidates. This improvement can be accomplished by “working smarter” during the drug design process, applying both our knowledge of the mechanistic basis of a target disease and our knowledge of the molecular characteristic of the compounds to have an effect on the disease state, thereby reducing the number of unsuccessful drug candidates. This approach to therapeutic development is called the Rational Drug Design approach.

Molecular modeling in all of its form is intimately linked to our ability to carry out rational drug design.

IMPORTANT TECHNIQES IN DRUG DESIGN

To obtain the structural information about molecules necessary for mechanistic design of drugs, a variety of chemical, physical and theoretical techniques, must be used. Different techniques provide complementary types of information, which together can be used to determine how molecules interacts.³

Two techniques are commonly used

1) Direct Drug Design

2) Indirect Drug Design

1) Direct Designing

In this the 3D feature of the receptor site are directly considered for the design of new drug molecule. The 3D features of a receptor consist of electronic features, charge distribution, steric features and hydrophobic features. It is based on the lock-key fit of drug and receptor., e.g. highly active drug molecule for the inhibition of HIV I protease has been designed by direct drug design.^{4 ­}. The direct drug design include

X-Ray crystallography ⁵

X-ray crystallography is often the starting point for gathering information for mechanistic drug design. This technology has potential to determine the total structural information about a molecule. Furthermore, it provides the critically important coordinates needed for the handling of the data by computer modifying systems. The technology is very important for determining the structure of drugs target and the interaction too.

NMR-Spectroscopy

The major limitation of X-ray crystallography are the necessity to obtain good crystals and the fact that 3-D data obtained with crystals may not reflect the molecular structure under biological conditions that involve molecules in solution. NMR gives 3D information which are more representative of the molecule in its biological environment.

2) Indirect Drug Design ⁶

This is used when detailed 3D structure of a known receptor site is not available in this case new compounds are designed on the basis of statistical model derived from QSAR analysis. In this approach a hypothetical receptor site is generated by comparing the known set of molecule and the new molecule is designed to fit this receptor site. The molecule which provides the best lock and key arrangement with hypothetical receptor site is considered.

The analysis is based on the comparison of the stereo chemical and physicochemical feature of a set of known active and inactive molecules and is interpreted in terms of complementarily with the receptor site.

Type of indirect drug design:

1)QSAR analysis

2)Molecular shape analysis.

3)Receptor surface model generation.

4)Comparative molecular field analysis.

5)Pharmacophore mapping.

6)Non linear COMFA using QPLS (Quadratic Partial Least Square).

7)COMSIA (Comparative Molecular Similarity Index Analysis).

Computerized Molecular Modeling ⁷

Computerized molecular modeling can provide scientists with few major types of information that are important for mechanistic design of drugs:

(1)The 3-D structure of molecules.

(2)The chemical and physical characteristics of molecule.

(3)Comparison of the structure of one molecule with other different molecules.

(4)Visualization of complex formed between different molecules.

(5)Prediction about how related molecules might look.

Other Important Consideration:

The initial application of molecular modeling to design drugs generally begin with the use of rigid constructs for structure and their targets. The flexibility of molecule information, both in single molecule and in molecule interacting with each other is an important and challenging concept in drug design.

The various phases involved in drug discovery and development process are ⁸:

(1)The search  for lead

(2)Molecular manipulations

(3)The design of suitable application forms of drugs

(4)The design of suitable dosage regimens

(5)Clinical evaluation.

Contributions and Achievements of CADD⁹

(1)Design of thymidylate synthetase inhibitor as anticancer agents.

(2)Design of HIV protease inhibitors as antiviral agents.

(3)Design of CAI as antiglaucoma agents.

(4)Design of neutrophil elastase.

(5)Discovery of novel sweeteners using a sweet taste receptor model.

MOLECULAR MODELING :

‘Molecular’ clearly implies some connection with molecules. The

Oxford English Dictionary defines ‘model’ as a simplified or idealized description of ‘a system or process, often in mathematical terms, devised to facilitate calculations and predictions’. Molecular modeling would therefore appear to be concerned with ways to mimic the behavior of molecular and molecular systems.¹⁰

Principles of molecular graphics¹¹

Modern computer graphics techniques allow the three dimensional visualization and manipulation of structures to allow visualization of different parts of the molecule, to change the orientation of specific function, while holding other constant and to look at different feasible conformations. Computer techniques have enabled model building to approximate structures of biomolecules to be accomplished with greater speed and precision and has allowed incorporation of information not previously available into the modeling process. Molecular graphics allows the chemist to use the power of computer to quantify stereo chemical relationships including detailed measurement of molecular geometry and conformation, calculations of electron densities, electrostatic potentials and energies and direct comparison of the key structural features of a range of biologically active structures. It also allows to study the drug-target interactions. It has potential power to design theoretical new molecules to satisfy predetermined steps.

Graphic Hardware:

Predominant systems for molecular modeling calculations are work stations with UNIX operating system, e.g., 3D graphics work station from Silicon  Graphics, Sg. Inc & Evans and Sutherland multipicture systems. The entire range of computer hardware being used are Desktop, Macintosh, MS-Dos PC, Computer servers, Super-Computer as Cray super computers¹²

Software :

The software used by molecular modelers ranges from simple programs that perform just a single task to highly complex packages that integrate many different methods as shown in the table.

Molecular modeling softwares ¹³

Uses of Computer Aided Drug Design:

Computer graphics has many uses in drug design and related fields.

Crystallography:

Chemical crystallography produces a set of coordinates defining the location of atoms in a molecule. From this a picture can be easily generated as a stick figure using any molecular modeling system. e.g., the crystal packing structure of nalixidic acid can be examined to find why it is so insoluble and what can be done to increase its solubility.

Receptor Mapping :

In the drug-receptor model of drug activity the complementarity of drugs and receptor is important ¹⁴

If the receptor is perfectly complementary to the drug, then its shape can be inferred from the drug. As there are many molecules having similar drug activity, there is no ideal drug fit or ideal receptor. From the group of drugs that are all relatively active, one can hypothesize that the overlap of all those molecules define a volume that receptor must be able to accommodate.¹⁵ The surface that is inferred from the overlap of the active molecule is referred to as a receptor map.

One way of constructing a receptor map is by using the molecule on solvent accessible surfaces. The set of active molecules to be used to compute the volume is first constructed. The molecules are superimposed by matching certain parts and then the surface of the group of superimposed molecules is computed.

To test whether this surface is good map of the receptor one considers molecules that were tested and found to be inactive yet that retain some or all of the pharmacophoric moieties of the series in question. These molecules should present new volumes, outside the allowed volume for the receptor map formed by active molecules. These extra volumes then explain why a drug is inactive, because of collisions with the intended receptor.

Molecular mechanics and dynamics :

Graphics is routinely used to prepare input structure and look at resulting structures. Molecular dynamics produces many molecular conformations. These can be displayed on computer graphics screen in rapid succession if one has a real-time graphics system. they can then be easily categorized and the important conformational transitions are detected.

In conformation from molecular dynamics calculations, bond lengths and angles are distorted compared to results from molecular mechanics. A problem with molecular mechanics is that it finds only the local and not global minimum. This can be overcome by using results from molecular dynamics calculations as starting points for systematically varied or using graphics to interact with the molecular model and see which conformation might be important.

NMR and Computer Graphics :

The analysis or NMR spectra on biological molecules in solution can provide many structural details. One such information is distance between specific hydrogen atoms in a molecule. Using a molecular model and see whether the distances in that model agree with those from the molecular operating environmental  (MOE) experiment. The distance between all pairs of hydrogen atoms can be computed and dashed line is displayed between those pairs whose separation falls within specified limits. This is an easy way to compare model distances with MOE distances and to see distances in the model that ought to appear in the NMR spectrum, if the model is correct.

Molecular docking, surfaces and hydrogen bonds:

The act of coupling two or more orbiting objects, the operation of mechanically connecting together, or in some manner bringing together, orbital payloads is called docking. Interactive computer graphics is a great aid in intermolecular docking. Intramolecular reactions have more constraints than intermolecular reactions so a minimizer cannot be used to put two molecules together. To overcome the problem of intermolecular docking, qualitative NMR results were incorporated into quantitative models by using interactive computer graphics for docking two molecules with the use of three dimensional tracking device, the object on a computer graphics screen can be controlled. It also gives control of rotational and translational degrees of freedom which must be adjusted while docking of two molecules.

If colour coded electrostatic potential energy surfaces are drawn for each molecule, then the optimal docked orientation will be that in which the two surfaces are optimally complementary in shape and charge distribution.

Quantum mechanics:

Quantum mechanics is a way to produce an energy minimized conformation of a molecule. It offers a much better description of electronic structure than molecular mechanics. Computer graphics can be used by analyzing and assigning normal modes of vibration from quantum mechanical results .¹⁶ Graphical analysis speeds up the process.

Computer graphics can be used to show some of the results of electronic structure from quantum mechanical calculations. Molecular orbitals can be represented by a contour diagram. This is often done with flat molecules with electron density contoured in only some particular plane above the molecular plane. A true 3-D contour is possible using interactive computer graphics. Though point charges are used to represent charge distribution in a molecule this is poor represented for one pair of electrons. In some studies for SAR for drug molecules, it is seen that the energy of highest occupied molecular orbital for a molecule correlates with drug activity ¹⁷.

Application to structure activity relationship:

The most extensive use of molecular graphics to date has been in the field of structure activity relationship. At the macromolecular level Hansch and his colleagues have extended their QSAR studies on inhibitors of enzyme such as dihydrofolate reductase, to discover how electronic, hydrophobic and steric properties that emerges from QSAR analysis are related to actual three dimensional interaction between the inhibitors and active site¹⁸

At the small molecular level Marshall ¹⁹ & his colleagues have pioneered the use of molecular graphics to compare the three dimensional characteristics of drugs of endogeneous with similar biological activities.

REFERENCES

1 Perun, T.J and Propst, C.L., In: Computer Aided Drug Design Methods and Application, Marcel Dekker Inc., New York, 1989,1-5.

2 Foye, W.O., Lemke, T.L. Williams, D.A., In : Principle of Medicinal Chemistry, 4^th Edition, Waverly Pvt Ltd, New Delhi, 1995,58-59.

3 Perun, T.J and Propst, C.L., In: Computer Aided Drug Design Methods and Application, Marcel Dekker Inc., New York, 1989, 11-12.

4 Foye, W.O., Lemke, T.L. Williams, D.A., In : Principle of Medicinal Chemistry, 4^th Edition, Waverly Pvt Ltd, New Delhi, 1995,58.

5 Perun, T.J and Propst, C.L., In: Computer Aided Drug Design Methods and Application, Marcel Dekker Inc., New York, 1989, 11-12.

6 Cohen, N.C. , Blaney J.M., Humblet, C. , Gund, P. and Barry, D.C. , J. Med. Chem.,1990 , 33, 883

7 Perun, T.J and Propst, C.L., In: Computer Aided Drug Design Methods and Application, Marcel Dekker Inc., New York, 1989, 12-13.

8 Ariens, E.J. , Drug, Design, Vol. I, Academic Press, New York, 1971, 42-93.

9 Appelt, K., Design of Enzyme Inhibitors Using Interactive Protein Crystallographic Analysis , J. Med. Chem.. , 1991,34, 1834.

10. Leach, A.R. In : Molecular Modelling ,Principles and Applications , 2^nd Edition, Pearson Education Ltd. , England, 2001,1 

11. Langride. R.; Ferrin. T.E.; Kuntez. I. D.; and Connoly, M.L.; Science, 1981,221,661.

12. Menkel, J.G. and Billings, Em, In: Foye, W.O.Lemke, T.L. and Willams, D.A., Eds, Principles of Medicinal Chemistry 4^th Edition, B.I. Waverly Pvt Ltd, New Delhi, 1995,58.

13. Choplin, F, In ; Hansch, C, Sammes, P.G. and Tailors, J.B. Eds, Comprehensive Medicinal Chemistry, Vol. 4, Pergamon Press, New York , 1990,36.

14. Kuntz, F.D.; Blaney. J.M.; Oatley. S.J.; Langridge. R. And Ferrin. T.E.; J.Mol. Biol., 1982,161,269-288.

15. Marshall. G.R., In: Quantative Approaches To Drug Design, J.C. Dearden, Eds, Elsevier Publisher, Amsterdam, 1983,129-136.

16. Perun, T.J and Propst, C.L., In: Computer Aided Drug Design Methods and Application, Marcel Dekker Inc., New York, 1989,52.

17. Martin, Y.N. ; In : Quantative Drug Design, Marcell Dekkaer, New York, 1978,103-107.

18. Blaney. J.M.; Hansch. C.; Silpoc. A and Vitoria. A.; Chem. Rev, 1984,84,333.

19. Humblet. C. And Marshall. G.R.; Drug Dev Res, 1981,1,409.

About authors:

Anand M. Kudal* and Satish A. Polshettiwar
MAEER’S, Maharastra Institute of Pharmacy, Paud road, Pune-411038

Anand M. Kudal*

Lecturer at MAEER’S, Maharastra Institute of Pharmacy, Paud road, Pune- 411038. Email:anand_kudal@yahoomail.com ,Phone no:9371182099

Satish A. Polshettiwar

Lecturer at MAEER’S, Maharastra Institute of Pharmacy, Paud road, Pune- 411038.