Basic Principles of Drug Design

Learning outcomes

The student will be able to:

• List methods used for lead discovery

• Discuss lead modification to improving pharmacokinetic properties

• Recognize the effect of physicochemical properties on oral bioavailability

• Discuss and apply current QSAR methods

Process of drug design

• Identification of a lead

• Synthesis and initial biological evaluation of the lead

• Optimization of the lead compound for the pharmacodynamic, pharmacokinetic and pharmaceutical phases

• Pre-clinical and clinical evaluation of the optimized lead analog

Lead Discovery Approaches • A lead is an organic molecule selected for future optimization

• The lead has desired activity but also other undesirable characteristics, e.g., toxicity, other activities, insolubility, metabolism problems, oral bioavailability

• lead compounds is discovered by:

1. Random screening - screen every compound you have; (e.g. streptomycin and tetracyclines)

2. Nonrandom (or Targeted or Focused) screening - only screen compounds related to active compounds

3. Drug metabolism studies - metabolites produced are screened for the same or other activities (e.g. Fexofenadine (Allegra) from Terfenadine)

4. Clinical observations - new activities found in clinical trials; (e.g Dramamine tested as antihistamine (allergy) - found to relieve motion sickness)

5. Rational approaches - de novo design of lead compounds on the basis of the structure of the target

Optimizing the lead • The lead is composed of two parts

• Pharmacophore - the relevant groups on the compound that interact with the receptor and produce activity

• Auxophore - the rest of the molecule

• First step in optimization is to identifying the pharmacophore through Structure–Activity Relationships (SAR) studies

Example of Pharmacophore Identification • One approach to determine pharmacophore is to cut away pieces of the lead and

measure the effect on potency. • Let us assume morphine as the lead compounds. The darkened part was

identified as a pharmacophore

Optimization of pharmacodynamics properties

• These are structural modifications that increase the potency and therapeutic index (TI)

They include:

• Homologation

• Chain branching

• Ring chain transformation

• Bioisosterism

Note: Therapeutic index - measure of the ratio of the concentration of a drug that gives undesirable effects to that which gives desirable effects

e.g., LD50/ED50

Homologation

• Homologation is increasing compounds by a constant unit (e.g., CH2)

• Pharmacokinetic explanation:

– Increasing chain length increases lipophilicity and ability to cross membranes; if too high lipophilicity, it remains in the membrane

• Pharmacodynamic explanation:

– Hydrophobic pocket increases binding with increasing length; too large and does not fit into hydrophobic pocket

Effect of carbon chain length on drug potency

Homologation – examples

antibacterial activity of 4-alkyl substituted resorcinols.

Inhibition of ACE by enalaprilat analogues (Thorsett). The values in parentheses are the IC50 values for that analogue

Chain Branching

• Often lowers potency and/or changes activity; interferes with receptor binding

Ring-Chain Transformations

Transformation of alkyl substituents into cyclic analogs, which generally does not affect potency.

Chlorpromazine and its cyclopentane analog have

equivalent tranquilizing effects

Note: Ring-chain transformation can have pharmacokinetic effects, such as increased lipophilicity or decreased metabolism.

Bioisosteres • Bioisosteres are substituents or groups with chemical

or physical similarities that produce similar biological properties

• They are divided into classical and nonclassical

Classical isosteres Noncalssical isosteres

satisfy chemical isosteric

definitions

do not obey steric and electronic

definitions

Bioisosteric modification can attenuate toxicity, modify activity of lead, and/or alter pharmacokinetics of lead.

Nonclassical isosteres

Nonclassical isosteres

Nonclassical isosteres

Nonclassical isosteres

Nonclassical isosteres

• Changes

Size, shape, electronic distribution, lipid solubility, water solubility, pKa, chemical reactivity, hydrogen bonding

• Effects

Solubility, receptor interactions, pharmacokinetics properties, metabolism

Change and effects of bioisosteric replacement

Modifications to increase oral bioavailability

• Mostly done by Quantitative Structure-Activity Relationships (QSAR) techniques

• QSAR is based on the fact that: Biological properties are a function of the physicochemical parameters including: P, , Es, π, MR etc.

(𝑙𝑜𝑔1

𝐶) = 𝑘1𝜋2 + 𝑘2𝜋 + 𝑘3𝜎 + 𝑘4

i.e. Biological activity

or potency,

Where, k1-k4 are regression coefficients

Accuracy of a Hansch equation will depend on: 1. the number of analogues (n) used 2. the choice of parameters 3. the accuracy of the biological data: determined by

standard deviation (s) and the regression coefficient (r) (r should be 0.9)

Hansch equation

P = lipophilicity = electronic effects or Hammett constant, Es = Taft steric parameter π = lipophilic substitution coefficients, MR = molar refractivity

Hansch analysis - example

• Hansch equation log1

𝐶= 1.05𝜎 − 1.28

was developed to relate inhibition of bacterial growth by a series of sulfonamides analogs.

– inhibition is favored by EWG

Craig plots • These are two dimensional plots used in conjunction with established

Hansch equation to select the aromatic substituents that are likely to produce highly active analogues.

a Craig plot of para against para π values

If a Hansch equation: Log1/C = 2.67π – 2.56 + 3.92 has been developed for a lead compound, How will the potency of the lead be increased using Craig plot?

QSAR methods

• QSAR methods are categorized based on the structural representation when the descriptor values are derived

Method Structure representation

1D-QSAR Molecular/structural formula

2D-QSAR Molecular connectivity/topology

3D-QSAR Molecular geometry/stereochemistry