1. Mr. Hanumant Suryawanshi
School of Technology
Swami Ramanand Teerth Marathwada University
Sub Center, Latur (Maharashtra)

2. Chapter - 1
Drug Design

3.  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.

4.  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.

5.  1) Ligand Based Drug Design
 2) Structure Based Drug design

6.  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.

7.  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.

8. Chapter - 2
Computer Aided
Drug Discovery
( Design)

9.  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.

10. ????
How Drugs Are
Discovered?

11.  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

12.  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.

13.  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.

14. Chapter - 3
Basics of
Mechanism Of
Drug Design

15.  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.

16.  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.

17.  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.

18.  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.

19.  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.

20. Chapter - 4
QUANTITATIVE
STRUCTURE ACTIVITY
RELATIONSHIP
(QSAR)

21.  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.

22. 1) Fragment Based
2) 3D- QSAR
3) Modeling

23. Chapter- 5
Uses Of Computer
Graphics in CADD

24.  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.

25. Computer Graphic Displays
Molecular Modeling
 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.

26.  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

27.  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

28.  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.

29.  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

30. Chapter- 6
Important
Techniques of
Drug Design

31.  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

32.  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.

33.  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.

34.  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

35.  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.

36. 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

37.  1) 3rd Annual Biotechnology Conference For Students
organized by International Institute of Information
Technology (I2IT) Pune, During 12 - 13 Nov.2011.

38. 2) National Conference on Frontiers in Biological Sciences’ organized by ‘Veer
Bahadur Singh Purvanchal University, Jaunpur (U.P) during 4- 5 Dec.2011.
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