Mr. Hanumant Suryawanshi

School of Technology

Swami Ramanand Teerth Marathwada University

Sub Center Latur

COMPUTER AIDED DRUG DESIGN

Drug Design

Chapter - 1

Drug A chemical substance that affects the

processes of the mind or body. Any chemical compound used in the diagnosis,

treatment, or prevention of disease or other abnormal condition.

A substance used recreationally for its effects on the central nervous system, such as a narcotic.

Drug & Drug Design

Drug design, sometimes referred to as rational drug design or more simply rational design, is the inventive process of finding new medications based on the knowledge of a biological 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 small 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 modeling techniques.

This type of modeling 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.

Drug Design

1) Ligand Based Drug Design

2) Structure Based Drug design

Types of Drug Design

Ligand-based drug design (or indirect drug design) relies on knowledge of other molecules that bind to the biological target of interest.

These other molecules may be used to derive a pharmacophore model that defines the minimum necessary structural characteristics a molecule must possess in order to bind to the target.

 In other words, a model of the biological target may be built based on the knowledge of what binds to it, and this model in turn may be used to design new molecular entities that interact with the target.

Alternatively, a Quantitative Structure-Activity Relationship (QSAR), in which a correlation between calculated properties of molecules and their experimentally determined biological activity, may be derived. These QSAR relationships in turn may be used to predict the activity of new analogs. 

1) Ligand Based Drug Design

Structure-based drug design (or direct drug design) relies on knowledge of the three dimensional structure of the biological target obtained through methods such as x-ray crystallography or NMR spectroscopy.

If an experimental structure of a target is not available, it may be possible to create a homology model of the target based on the experimental structure of a related protein.

Using the structure of the biological target, candidate drugs that are predicted to bind with high affinity and selectivity to the target may be designed using interactive graphics and the intuition of a medicinal chemist.

Alternatively various automated computational procedures may be used to suggest new drug candidates.

2) Structure Based Drug Design

Chapter - 2

Computer

Aided Drug

Discovery

( Design)

Computer-aided drug design uses computational chemistry to discover, enhance, or study drugs and related biologically active molecules.

The most fundamental goal is to predict whether a given molecule will bind to a target and if so how strongly. Molecular mechanics or molecular dynamics are most often used to predict the conformation of the small molecule and to model conformational changes in the biological target that may occur when the small molecule binds to it. 

Semi-empirical, ab initio quantum chemistry methods, or density functional theory are often used to provide optimized parameters for the molecular mechanics calculations and also provide an estimate of the electronic properties (electrostatic potential, polarizability, etc.) of the drug candidate that will influence binding affinity.

Computer Aided Drug Design

How Drugs Are

Discovered?

? ? ? ?

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 agents has been successful in the past, it is not an ideal one for a number of reasons

1) Screening For New Drugs

Modifications to improve performance are often carried out using chemical or bio fermentative means to make changes in the lead structure or its intermediates.

Alternatively, for some natural products, the gene itself may be engineered so that the producer organism synthesizes the modified compound directly.

2) Modifications For Improvement

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 molecule(s) are defined, drugs can be designed specifically to interact with the target molecule in such a way as to disrupt the disease.

3) Mechanism Based Drug Design

Chapter - 3

Basics of

Mechanism Of

Drug Design

Defining the DISEASE Process :- The first step in the mechanistic design of drugs to treat

diseases is to determine the biochemical basis of the disease process. Ideally, one would know the various steps involved in the physiological pathway that carries out the normal function.

In addition, one would know the exact step(s) in the pathway that are altered in the diseased state. Knowledge about the regulation of the pathway is also important. Finally, one would know the three-dimensional structures of the molecules involved in the process.

Basic Mechanism Of Drug Design

There are potentially many ways in which biochemical pathways could become abnormal and result in disease. Therefore, knowledge of the molecular basis of the disease is important in order to select a target at which to disrupt the process.

Target for mechanistic drug design usually fall into three categories: enzymes, receptors and nucleic acids.

Defining The Target

Enzymes are frequently the target of choice for disruption of a disease. If a disease is the result of the overproduction of a certain compound, then one or more of the enzymes involved in its synthesis can often be inhibited, resulting in a disease in production of the compound and disruption of the disease process.

Enzyme As Target

Sometimes a disease can be modulated by blocking the action of an effectors at its cellular receptor.

Receptors that are easily isolated are the most amenable to rational design of effectors. An illustrative use of this concept is in the three-dimensional structural determination of rhinoviruses, which then can serve as a receptor-type target for the design of antiviral drugs.

Receptor As Target

Nucleic Acid As Target Diseases can also potentially

be blocked by preventing the synthesis of undesirable proteins at the nucleic acid level.

This strategy has frequently been employed in the antimicrobial and antitumor areas, where DNA blocking drugs are used to prevent the synthesis of critical proteins.

Chapter - 4

QUANTITATIVE

STRUCTURE ACTIVITY

RELATIONSHIP

(QSAR)

QSAR models relate measurements on a set of "predictor" variables to the behavior of the response variable.

In QSAR modeling, the predictors consist of properties of chemicals; the QSAR response-variable is the biological activity of the chemicals.

QSAR models first summarize a supposed relationship between chemical structures and biological activity in a data-set of chemicals. Second QSAR models predict the activities of new chemicals.

QUANTITATIVE STRUCTURE ACTIVITY RELATIONSHIP (QSAR)

1) Fragment Based

2) 3D- QSAR

3) Modeling

Types Of QSAR

Uses Of

Computer

Graphics in

CADD

Chapter- 5

Computers are essential tool in modern mechanical chemistry and are important in both drug discovery and development.

The development of this powerful desktop enabled the chemist to predict the structure and the value of the properties of known, unknown, stable and unstable molecular species using mathematical equation. Solving this equation gives required data.

Graphical package convert the data for the structure of a chemical species into a variety of visual formats. Consequently, in medicinal chemistry, it is now possible to visualize the three dimensional shape of both the ligands and their target sites.

Uses of Computer Graphics in CADD

Computer Graphic Displays

In molecular modeling, the data produced are converted into visual image on the computer screen by graphic packages.

These images may be displayed in a variety of styles like fill, CPK (Corey-Pauling-Koltum), stick, ball and stick, mesh and ribbon and colour scheme with visual aids. Ribbon presentation is used for larger molecules like nucleic acid and protein.

1) Molecular Modeling

Molecular Modeling

2) Molecular Mechanics Molecular mechanics is the more

popular of the methods used to obtain molecular models as it is simple to use and requires considerably less computing time to produce a model. In this technique the energy of structure is calculated.

The equation used in molecular mechanics follow the laws of classical physics and applies them to molecular nuclei without consideration of the electrons

3) Molecular Dynamics Molecular mechanics

calculations are made at zero Kelvin, that is on structure that are frozen in time and so do not show the natural motion in the structure.

Molecular dynamics programs allow the modular to show the dynamic nature of the molecule by stimulating the natural motion of the atom in a structure

4) Conformational Analysis

Using molecular mechanics (MM2), it is possible to generate a variety or different conformations by using a molecular dynamics program which ‘heats’ the molecule to 800-900K. Of course, this does not mean that the inside of your computer is about to melt.

It means that the program allows the structure to undergo bond stretching and bond rotation as if it was being heated.

5) Quantom Mechanics Unlike molecular

mechanisms the quantum mechanics approach to molecular modeling does not require the use of parameters similar to those used in molecular mechanics.

It is based on the realization that electrons and all material particles exhibit wave like properties

Chapter- 6

Important

Techniques of

Drug Design

1) X-Ray Crystallography X-ray crystallography is often

the starting point for gathering information from mechanistic drug design.

This technology has the potential to determine total structural information about a molecule.

Furthermore it provides the critically important coordinates needed for the handling of data by computer modeling syste

2) NMR Spectroscopy NMR uses much softer radiation

which can examine molecules in the more mobile liquid phase, so the three-dimensional information obtained may be more representative of the molecule in its biological environment

Another advantage of NMR is its ability to examine small molecule-macromolecule complexes, such as an enzyme inhibitor in the active site of the enzyme.

Use of computing power to streamline drug discovery and development process

Leverage of chemical and biological information about ligands and/or targets to identify and optimize new drugs

Design of in silico filters to eliminate compounds with undesirable properties (poor activity and/or poor Absorption, Distribution, Metabolism, Excretion and Toxicity, ADMET) and select the most promising candidates.

Applications Of CADD

Role of computer-aided molecular modeling in the design of novel inhibitors of Rennin.

Inhibitors of Dihydrofolate reductase.

Approaches to Antiviral drug design.

Conformation biological activity relationships for receptor- selective, conformationally constrained opioid peptides.

Design of conformationally restricted cyclopeptides for the inhibition of cholate uptake of Heepatocytes

Applications

The process of drug discovery and development is a long and difficult one, and the costs of developing are increasing rapidly. Today it takes appropriately 10years and $100million to bring a new drug to market.

Conclusion

Mechanism-based drug design tackles medical problems directly. It provides an opportunity to discover entirely new

lead compounds not possible using other techniques for drug development

The emphasis now is not just on finding new ways to treat human disease, but also on improving the quality of life of people in general.

The use of new computer-based drug design techniques has the ability to accomplish both of these goals and to improve the

efficiency of the process as well, thus reducing costs.

1) 3rd Annual Biotechnology Conference For Students organized by International Institute of Information Technology (I2IT) Pune, During 12 - 13 Nov.2011.

List of National Seminars & Conferences where the study Abstract was Presented (Poster Presentation)

3) ‘National Seminar on Drug Discovery from Plants: Promises And Challenges’ (DDPC 2012) Organized by ‘School of Life Sciences, S.R.T.M.University, Nanded during 14 – 15

Feb.2012

2) National Conference on Frontiers in Biological Sciences’ organized by ‘Veer Bahadur Singh Purvanchal University,

Jaunpur (U.P) during 4- 5 Dec.2011.

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