Instructor:

Asst. Prof. Karthi Shanmugam

Bioinformatics Division
SASTRA University

Drug Discovery Process

Karthi Shanmugam, Bioinformatics Division, SASTRA Univeristy

Pharmaceuticals
How do they find these things………..?

• Lipitor
• Gleevec

Karthi Shanmugam, Bioinformatics Division, SASTRA Univeristy

Modern drug discovery
Target to human Disease

↓ •Target Discovery

$ 500 – 1000M
10-15 years
↓ •Lead Discovery
•Drug
↓
Development
Drug

Karthi Shanmugam, Bioinformatics Division, SASTRA Univeristy

Classes of drug molecules
• Small organic molecules
– (<500 MW, oral)
• Proteins
– (>10,000 MW, injectable)
• Vaccines

Karthi Shanmugam, Bioinformatics Division, SASTRA Univeristy

9 steps from target to pill
Disease target
Target ID
Protein
Hit ID
Cell
Hit to Lead
Animal efficacy
Lead opt
Animal Toxicity
IND enable
Human Safety
PI
rial
lT

Efficacy
PII
a
nic i
Cl

PIII Registration
FDA NDA filing

Karthi Shanmugam, Bioinformatics Division, SASTRA Univeristy

Target Identification:
What’s causing the disease?

Target ID

Karthi Shanmugam, Bioinformatics Division, SASTRA Univeristy

Target Validation:
What’s causing the disease?
• Infectious agent or host imbalance?
• Molecular target leading to disease
– Bacteria: find target not in humans
– Host imbalance:
• Replace underactive protein (insulin)
• Inhibit overacting protein (kinase)

Karthi Shanmugam, Bioinformatics Division, SASTRA Univeristy

Drug discovery
• The genome (genetic space) is huge and lots to
search
– Approximately 20,000 human genes that code for proteins
– Which one is causing the disease…?

Karthi Shanmugam, Bioinformatics Division, SASTRA Univeristy

Target validation
Is the target “druggable”?
• Are there known small molecules that bind the
target or a homolog?
• Does the target have a site that looks like it will
bind a small molecule (cavity, energetic hot-
spot)?

Karthi Shanmugam, Bioinformatics Division, SASTRA Univeristy

The chemome (chemical space) is vast

• ~ 1062 drug sized molecules (<500 MW)

• Not enough particles, not enough time

Karthi Shanmugam, Bioinformatics Division, SASTRA Univeristy

Hit identification: Getting on the board

Hit ID

Karthi Shanmugam, Bioinformatics Division, SASTRA Univeristy

You have to test a lot of compounds
to find a drug
0
100,000 -1,000,000 Screening

500-5,000 Hit

100-500 Lead
INDE
10
Years

Phase-I
5
Phase-II
2-3
2 Phase-III

1
15

Karthi Shanmugam, Bioinformatics Division, SASTRA Univeristy

Ways to identify a hit

• Start with a natural substrate and make durg-like

• Start with someone else’s hit (“patent bust”)
• Design a de novo hit by Structure based design
• Screening (HTS or Fragment methods)

Karthi Shanmugam, Bioinformatics Division, SASTRA Univeristy

Start with libraries of drug-like molecules

Karthi Shanmugam, Bioinformatics Division, SASTRA Univeristy

How to handle that many compounds

• Miniaturization (1-100 UL)

• Automation
• Parallel pipetting
• Robotics
• Plate readers

Karthi Shanmugam, Bioinformatics Division, SASTRA Univeristy

Assay formats: Biochemical

• Use a purified protein and an activity you can

visualize

• Use when
• You know what protein you want to inhibit
• You can express and purify the protein
• Selectivity among similar proteins is important

Karthi Shanmugam, Bioinformatics Division, SASTRA Univeristy

Assay formats: Cell based

• Screen in whole cells

• Use when
• Molecular target is known, but not isolable from cell
• Goal is to alter a cellular phenotype
• Pathway is known, best target is not known

Karthi Shanmugam, Bioinformatics Division, SASTRA Univeristy

Assay formats: Cell based

• Results read out by whole cell fluorescent /

luminescence
• Cell-by-cell properties

Karthi Shanmugam, Bioinformatics Division, SASTRA Univeristy

A hit is just the first step of discovering
a drug
0
100,000 -1,000,000 Screening

500-5,000 Hit

100-500 Lead
INDE
10
Years

Phase-I
5
Phase-II
2-3
2 Phase-III

1
15

Karthi Shanmugam, Bioinformatics Division, SASTRA Univeristy

Drug discovery from HIT to Pill

Karthi Shanmugam, Bioinformatics Division, SASTRA Univeristy

Hit-to-Lead: Cell activity / selectivity

Hit to Lead

Karthi Shanmugam, Bioinformatics Division, SASTRA Univeristy

Hit-to-Lead: Cell activity / selectivity

Biochemic
Medicinal al Screen
Chemistry (selectivit
y)

Cell-based
assay

Karthi Shanmugam, Bioinformatics Division, SASTRA Univeristy

More goals to finish HTL

• Potency at least 10X weaker on related target

• Distinct SAR (chemical analogs)
• Known molecular target (preferred)
• Solubility > 100 µM

Karthi Shanmugam, Bioinformatics Division, SASTRA Univeristy

Lead optimization
Animal efficacy

Lead opt

Karthi Shanmugam, Bioinformatics Division, SASTRA Univeristy

What happens when we swallow pill

Karthi Shanmugam, Bioinformatics Division, SASTRA Univeristy

Lead optimization

Medicinal
Pharmacokinetics
Chemistry

Pharmacodynami
cs

Karthi Shanmugam, Bioinformatics Division, SASTRA Univeristy

From clinical candidate to pill

Target ID
Hit ID Drug Discovery
Hit to Lead 3-4 Years

Lead opt
IND enable
PI
PII Drug Development
4-8 Years
PIII
FD
A

Karthi Shanmugam, Bioinformatics Division, SASTRA Univeristy

Clinical Trials

Karthi Shanmugam, Bioinformatics Division, SASTRA Univeristy