Drug Design

1. What is medicinal chemistry?

The science that deals with the discovery or design of new therapeutic agents and their
development into useful medicines.
It involves:
1. Synthesis
2. Structure-Activity Relationships (SAR)
3. Receptor interactions
4. Absorption, distribution, metabolism, and excretion (ADME)

2. What is Drug Design?

Drug design is the inventive process of finding new medications based on the knowledge of a
biological target.
In the most basic sense, drug design involves the design of molecules that are complementary
in shape and charge to the molecular target with which they interact and bind.

3. Purposes of Drug Design?

Drug design seeks to explain:
(a) Effects of biological compounds on the basis of molecular interaction in terms of molecular
structures or precisely the physicochemical properties of the molecules involved.
(b) Various processes by which the drugs usually produce their pharmacological effects.
(c) How the drugs specifically react with the protoplasm to elicit a particular pharmacological
response.
(d) How the drugs usually get modified, metabolized or eliminated by the organism.
(e) Probable relationship between biological activity with chemical structure.
4. FACTORS GOVERNING DRUG-DESIGN?
A few cardinal factors governing the efficacy towards the evaluation of drug design include:
1. The smaller the expenditure of human and material resources involved to evolve a new
drug, the more viable is the design of the programme.
2. Experimental animal and clinical screening operations of the new drugs.
1. Relationships between chemical features and biological properties need to be
established retrospectively.
2. Quantitative structure-activity relationships (QSARs) vary to an appreciable extent based
on the nature of evaluation of structure or activity(steric factors, electronic features of
functional groups)
3. Introduction of functional groups in a molecule that are capable of undergoing bonding
interactions with important functional groups of biochemical components of living
organisms are important basis for exploration.
4. Disease etiologies and various biochemical processes involved prove useful.

5. RATIONAL APPROACH TO DRUG DESIGN?

There are many approaches to drug designing in relation with physiochemical parameters and
electronic features taken into consideration for designing a drug,
1. Approach with quantum mechanics
2. Approach with molecular orbital theory
3. Approach with molecular connectivity
4. Approach of linear free-energy

1. Approach with quantum mechanics:

 This also called as wave mechanics, comprises the fundamental physical properties of
a molecule.
 These include the properties of protons, neutrons, and electrons, which are explained
by quantum mechanics.
 The electronic features of the molecules responsible for chemical alterations.
2. Approach with molecular orbital theory:
 The electrons present in the molecules are linked with orbitals to change the electronic
feature.
 The molecular orbital approach is the change on electronic charges, and also on
molecular conformation.
 Molecular orbital calculations are achievable by sophisticated computers.
3. Approach with molecular connectivity:
 This is based on the structural features of a molecule.
 All steric and electronic parameters varies according to their configuration.
 These includes cyclization, unsaturation, presence of heteroatom, skeletal branching,
and position in molecules and the series of functional attachments.

4. Approach of linear free-energy:

 This method establishes the vital link between selection of physiochemical parameters
of a molecule with a specific biological activity.
 This method helps rational drug design by identifying and prioritizing potential drug
candidates based on their predicted activities and properties.

6. Approaches to Lead Discovery?

A. RANDOM SCREENING;
 Random screening in lead discovery is a method where compounds are tested without
prior knowledge of their biological activity.
 Random screening may produce unexpected active medicines.
 Antibiotics, such as streptomycin, tetramycins, and fungal metabolites, such as
lovastatin and cyclosporins, were found through this method.
 This approach needs more manpower, and it is expensive and time-consuming and the
success rate is considerably low.

B. NONRANDOM SCREENING;
 Nonrandom screening also known as Targeted Screening or Rational Screening
involves selecting compounds for testing based on specific criteria against a particular
biological target.
C. PHARMACOKINETIC STUDIES;
 Pharmacokinetic study involves how body absorbs, distribute, metabolizes and
excretes a potential drug candidate.
 For example, the discovery of sulphanilamide is reported through the metabolic studies
of prontosil.
D. PHARMACODYNAMIC STUDIES;
 Pharmacodynamic studies involves finding a lead molecule by structural modification
which shows different mechanism of action, therapeutic effect and side effect.
 For example, sulphonamide used specifically for the treatment of typhoid, lowered the
blood sugar levels drastically.

7. Structure Activity Relationships (SAR)

The relationship between the chemical structure of a molecule and its biological activity. (e.g.,
enzyme inhibitory activity, antimicrobial activity, toxicity etc.)

Purposes of structural activity relationship;

1. Understanding the interaction between a ligand and a target active site.
2. Guide the synthesis of new compounds.
3. Screening drug candidates.
4. Optimizing their properties.
5. Personalized medicine by tailoring of drug.
6. To explain various ways a ligand interacts with a receptor.
7. To predict biological activity from molecular structure.
8. To improve drug potency, reduce toxicity, increase bioavailability etc.

Capturing SAR
There are mainly two methods that are used to capture and quantify SAR:
1. Statistical or data mining methods (e.g., regression models)
2. Based on physical approaches (e.g., pharmacophore models).
Applications of SAR

1. Pharmacokinetic studies;
 The pharmacokinetic approach entails studying the four steps ADME of a certain
drug.
 SAR can be used to determine the solubility, rate of reaction, metabolism, and
other factors between drugs.

2. Drug-receptor interaction;
 The interaction between drugs and receptors occurs by reversible binding where
weak ionic bonds may form between the drug and receptor.
 Another method is irreversible binding, in the case of covalent bonds.
 SAR can be determined using various in silico methods that have been developed
to understand the interaction between target receptors and drugs.

3. Modification of drugs;
 SAR method is extensively used to
A. Optimize and develop various types of drugs.
B. Synthesis of new compounds
C. Optimizing existing compound
D. Enhancing Activity
 The in silico methods developed using SAR include the statistical method,
quantum analysis, artificial network modeling, validation method etc.

4. Toxicity Studies;
 The toxicity of a drug can be determined by SAR
 It is critically linked to its dose.
 If the dosage of a drug is too high, it can cause toxicity, and if it is too low, it can
lead to no or less activity.

5. Formulation of chemical and physical properties;

 SAR has emerged as a great tool to understand and develop the chemical and
physical properties of drugs.
SAR of Sulphonamides :

The major features of SAR of sulphonamides include the following:

1. Sulphanilamide skeleton is the minimum structural requirement for

antibacterial activity.
2. The amino and sulphonyl-groups on the benzene ring are essential and
should be in 1 and 4 position.
3. The N-4 amino group could be modified to be prodrugs
4. Sulphur atom should be directly linked to the benzene ring.
5. Replacement of benzene ring by other ring systems or the introduction of
additional substituents on it decreases or abolishes its activity.
6. Exchange of the –SO2NH group by –CONH reduces the activity.
7. Heterocyclic substituents lead to highly potent derivatives,
8. Sulphonamides, which contain a single benzene ring at N-1 position, are
considerably more toxic than heterocyclic ring analogues.
9. The lipid solubility influences the pharmacokinetic and antibacterial
activity, and so increases the half-life and antibacterial activity in vitro.
10.The active form of sulphonamide is the ionized, maximum activity that is
observed between the pKa values 6.6–7.4.