Introduction to Drug Discovery

What is a Drug?
• A chemical substance that interacts with a biological system to produce a
biological response

Is drug beneficial or detrimental?

• A Double edged sword, depending on dose level.
 Appropriate dose = Medicine to prevent, treat or cure diseases
 Overdose = Poison which may lead to severe side effects or death

• Example –
 Paracetamol & ibuprofen – Pain killer (appropriate) or hepatotoxin (overdose)
 Diamorphine (heroine) – Excellent pain killer but highly addictive
Is drug at beneficial dose safe?
• NO! No drug is completely safe as it intervenes both normal and
abnormal biological process
• Drug safety measurement = Therapeutic Index (TI)
dose that produce toxic effects in 50% of patients
TI = dose that produce the maximum therapeutic effects in 50% of patients

• Higher therapeutic index = safer

Examples
Drug A Condition Drug B Drug C
100 mg/kg Dose that produce toxic effects in 50% of patients 20 mg/kg 2 mg/kg
Dose that produce the maximum
10 mg/kg 10 mg/kg 1 mg/kg
therapeutic effects in 50% of patients
10 Therapeutic Index 2 2
What are the sources of drugs?
• Naturally occurring
 Plants – Paclitaxel, a chemodrug isolated from Taxus brevifolia
 Animals – Captopril, an anti-hypertensive and vasodilator agent isolated from snakes venom
 Microbes – Penicillin, a famous antibiotic isolated from penicillium

• Chemically synthesized
 Semi-synthetic – Irinotecan, a chemodrug modified from natural occurring alkaloid
 Synthetic – Donepezil, a purely synthetic anti-Alzheimer's disease drug

Why synthetic drug ?

NP
 Faster
Synthetic  Cheaper
 More specific

All new approved drugs from 01 JAN 1981 to

30 SEP 2019; n = 1881.
 How drugs are discovered and developed?
Drug Discovery Drug Development
USD~2.6 Billion

4 ~ 8 years 5~7 years 1~2 years

Advantages of CADD
 Less random
 Unbiased and accurate predictions
 High performance with
multitasking capability
Computer Aided
Drug Design (CADD) *Shorten research time, reduce cost,
and increase successful rate
 Specific
CADD Techniques Drug Design

Structure- &
Ligand-based
Drug Design

Molecular
ADMET
docking

1
&
&
Pharmacokinetic and Predictive Protein-ligand
Molecular
Toxicology
Toxicity Predictions Dynamics Interaction
CADD
Techniques

Quantitative
Structure-
Pharmacophore activity
Relationship
(QSAR)

Identify Contribution of Each

Bioactivity-favored Functional Group on
Functional Groups Bioactivity
What are physicochemical properties?
• A term used to describe physical and chemical properties of certain
substance at one go

Are they important in CADD?

• Yes! They are the fundamental elements that measured by CADD software
to corelate compounds’ structure to their respective bioactivity

Types of physicochemical properties

• Hydrophobicity of the molecule
• Hydrophobicity of substituents
Most common
• Electronic effects of substituents
• Steric properties of substituents
Hydrophobicity
• Lacking of affinity for water; tendency of a substance to repel water

Hydrophobicity of molecule: Important for a drug to cross cell membrane

[ Drug in octanol]
Partition Coefficient P = [Drug in water]

High P High hydrophobicity

Hydrophobicity of substituents:
• Crucial for drugs to interact hydrophobically with protein binding sites

Example :

• Positive values imply substituents are more hydrophobic than H

• Negative values imply substituents are less hydrophobic than H
Hydrophobicity of substituents:
Example :

Cl
Log P(theory) = log P(benzene) + πCl + πCONH2
= 2.13 + 0.71 - 1.49
= 1.35
CONH2 Log P(observed) = 1.51
meta -Chlorobenzamide

Is π identical to P ?
• Similar but not identical
 P measures the overall hydrophobicity of the whole molecule which is important in absorption prediction
 π measures the regional hydrophobicity of molecules which is important in ligand-protein interaction.
Electronic effects of substituents
• The effects of substituents on the electron density of the structure
• Obtained by comparing the dissociation constants of substituted benzoic acids
with benzoic acid
• The changes in electron density would alter the ionization or polarity of the
structure, thus affects its binding affinity towards targeted proteins

Aromatic system: Hammett Substituent Constant (σ)

σ X = log K X = logK X - logK H

KH

H H X X
CO2H CO2 + H CO2H CO2 + H

[PhCO2-] [xPhCO2-]
KH = Dissociation constant = KX = Dissociation constant =
[PhCO2H] [xPhCO2H]

X = Electron withdrawing group (EWG) or

Electron donating group (EDG)
Effects of EWG and EDG on Hammett Substituent Constant (σ)

EWG EDG
EWG EWG EDG EDG
CO2 H CO2 + H CO2 H CO2 + H

Charge is stabilized, Equilibrium shifts to right, Charge is Destabilized, Equilibrium shifts to left,
KX > KH KX < KH
Effects of substitution positions on Hammett Substituent Constant (σ)

EWG EDG

nitro group; σ p = 0.78 and σ m = 0.71. hydroxyl group; σ p = −0.37 and σ m = 0.12

-
Aliphatic system: σI
• Purely inductive effects
• Obtained experimentally by measuring the rates of hydrolyses of
aliphatic esters
• Hydrolysis rates measured under basic and acidic conditions

X= EDG; Rate σI = Negative

X= EWG; Rate σI = Positive

Basic conditions: Rate affected by steric + electronic factors

Gives σI after correction for steric effect
Acidic conditions: Rate affected by steric factors only (see Es)
Steric effects of substituents
• Effects of bulkiness, size and shape of drugs on bioactivity.
• Can either enhance or reduce the bioactivity of drugs.

Protein + parental ligand

Protein + sterically modified ligand Protein + sterically modified ligand

(appropriate) (excessive)

+ +

Improve binding & activity Reduce binding & activity

Steric effects of substituents
• Taft’s Steric Factor (Es)
• Molar Refractivity (MR)
• Verloop Steric Parameter

Taft’s Steric Factor (Es)：

 Measured by comparing the rates of hydrolysis of substituted aliphatic esters
against a standard ester under acidic conditions

Es = log kx - log ko
kx = rate of hydrolysis of a substituted ester
ko = rate of hydrolysis of the parent ester

 Size of X , steric effects , hydrolysis , kx<ko, Es = negative

 Limitations
 Limited to substituents that interact sterically with the tetrahedral transition
state of the reaction
 Not applicable for substituents that interact with the transition state by
resonance or hydrogen bonding
 May undervalue the steric effect of groups in an intermolecular process (i.e. a
drug binding to a receptor)
Molar Refractivity (MR)
 Quantify steric effects by measuring substituent’s volume

(n2 -1) mol. wt.

MR = 2
x
(n -2) density
Correction factor for Defines volume
polarisation
(n=index of refraction)

Verloop Steric Parameter

 Values are calculated by STERIMOL software based on standard bond
angles, van der Waals radii, bond lengths, and possible conformations of
the substituent
Isosteres
• Isosteres are atoms or groups of atoms which share the same valency (valence
electrons) and similar in chemical or physical properties.
 Classical – Similar in steric or electronic effects
 Non-classical – Do not obey the steric and electronic rules but similar in physical
and chemical properties

*They are all planar groups

of similar size and basicity

Non-Classical Isosteres

Classical Isosteres
Functional group CH3 NH2 OH SH Cl
= C + H+ H + H =N+H+H =O+H =S+H = Cl
Valency calculation
=4+1+1+1 =5+1+1 =6+1 =6+1 =7
(total valence electrons)
=7 =7 = 7 =7
Isosteres modification
• Replacement of certain functional group with its isosteres
• To study the importance of physicochemical properties in bioactivity. (important
in hit-to-lead stage)
Targeted Example of Functional
Strategy Outcome
Effects Groups Replacement
Activity increased, steric is desired;
fix electronic, Smaller to larger
Steric Activity reduced, steric is undesired;
alter steric (OH to SH)
Similar activity, steric is not an issue
Activity increased, low polarity is desired;
fix steric, more polar to less polar
Electronic Activity reduced, high polarity is desired;
alter electronic (OH to CH3)
Similar activity, polarity is not an issue

• To fix problematic structure of bioactive compounds (lead optimization stage)

Example 1: Example 2:
Bioisosteres
A chemical group which can
replace another chemical group
without adversely affecting the
desired activity of a drug