Computer-Aided Drug Design

1. Advances In Silico Approaches on Data Analysis,
Disease Diagnostics and Dark Proteome.
PRESENT BY- FAIZAN AHMED HILAL

2. Drug Properties
• A Drug should have
1. Activity
2. Selectivity(Single target)
3. Oral absorption
4. Distribution inside
5. Metabolism
6. Excretion
7. Solubility at Ph 2 and 7
8. No side Effects( short & long term)
9. No Toxicity
10. Bioavailability
11. Metabolites also non toxic
12. Stability at ph 2 and 7
13. Blood Brain Barrier(BBB) Penetration

3. Drug should have
14 Pgp(P glycoprotein) efflux
15 shelf life
16 form(oral, IV, IP, nasal, etc)
17 Mechanism of action is known
18 low cost
19 Ease of manufacturing
20 Ease of animal trials/ clinical trials

4. Structural features
1. Molecular Weight
2. Hydrogen bond donors
3. Hydrogen bond acceptors
4. Log P
5. pKa/pKb
6. Polar surface area
7. Hetrocycles
8. Aromatic rings
9. Ketonic groups
10. Rotatable bonds
11. Crystalline nature
12. Ester bonds/ amide bonds
13. Neutral or salt form

5. Absorption
• Some drugs work outside the body(barrier
creams, some laxatives) but most must:
• Enter the body
given by enteral – oral, sublingual, buccal, rectal
Im, iv etc
• Cross lipid barrier/ cell walls:
• Gut wall, capillary wall, cell wall, blood brain
barrier
• Get into the body (after distribution) to reach the
cellular target

6. Factors affecting oral absorption
• Disintegration of tablet
• Dissolution of particles
• Chemical stability of drugs
• Stability of drugs to enzymes
• Motility and mixing in GI tract
• Presence and type of blood
• Passage across GI tract wall
• Blood flow to gi tract
• formulation

7. Distribution
• Volume of distribution
• Plasma protein binding/ tissue sequestration
• Brings drug to target tissue
• Affects concentration at site of action

8. Metabolism
• Drug molecules are transformed by enzymes
• Drug actions may increase or decrease
• Individual variation genetically determined
• May have several routes of metabolism
• May tak place anywhere but liver is the
primary site
• Not comstant- can be changed by other drugs:
drug-drug interactions; drug-food interactions

9. Biotransformation of drugs
• Mutation allowing de-toxification of natural toxic
materials are advantageous
• Drugs are caught up in these de-toxification
processes
• Drugs may be converted to
 less toxic/ effective materials
 more toxic/ effective materials
Materials with different type of effect or toxicity

10. Excretion
• Urine is the main
• Glomerular filteration allows drugs <25K Da to pass
into urine; reduced by plasma protein binding; only a
portion of plasma is filtered.
• Tubular secretion active carreir process for cations and
for anions
• Passive re-absorption of lipid soluble drugs back into
the body across the tubule cells.
• Effects of pH to make more of weak acid drug present
in ionised form in alkaline ph therefore < re-absorbed
and excreted faster; vice-versa for weak bases

11. Lipinski Rule of Five
• Lipinski Rule of Five
Lipinski rule of 5 helps in distinguishing between drug like and non
drug like molecules. It predicts high probability of success or failure
due to drug likeness for molecules complying with 2 or more of the
following rules
1.Molecular mass less than 500 Dalton
2.High lipophilicity (expressed as LogP less than 5)
3.Less than 5 hydrogen bond donors
4.Less than 10 hydrogen bond acceptors
5.Molar refractivity should be between 40-130

12. Ghose Rule
• Ghose et al. suggested a qualifying range that could
be used in the development of druglike chemical
libraries and recommended the following
constraints: molecular weight between 160 and 480;
calculated logP between -0.4 and 5.6; molar
refractivity between 40 and 130 and total number of
atoms between 20 and 7022.

13. The Primary Role of the BBB
• It separates components of the circulating
blood form neurons and so maintains the
chemical composition of the neuronal
microenvironment
• It protects the brain from pathogens and
endows relative immune privilege

14. Rules for preventing BBB permeability
• N+O< 6
• Polar surface area < 60-70 A2
• MW < 450
• Log D = 1-3
• ClogP – (N+O)>0

15. Drugs that cross BBB
• Opiod analgesics – morphine, hydrocodone,
fentanyl, and heroin
• CNS Stimulants – cocaine, amphetamines
• Tranquilizers which binds to GABA receptors,
benzodiazepines, barbiturates, and alcohol etc

16. Toxicity is another important parameter
Toxic mechanism
Reactive Mechanism
Gene induction
Mutagenicity
Oxidative stress
Autoimmune response

17. Substructure that may initiate toxicity
• Aromatic amines
• Hydroxyl amines
• Aromatic nitro
• Nitroso
• Alkyl halide
• Polycyclic aromatic
• A,b – unsaturated aldehydes
• Nitrogen containing aromatic
• Bromine aroamtic
• Thiophenes
• Hydrazine
• Hydroquinone
• azo
• Vinyl
• Phenol
• aliphatic

18. • Acute toxicity from single dose
• Chronic toxicity from long term dosing
• Cytotoxicity, cell death
• Genetoxicity; mutagenic change to DNA
• Immunotoxicity immune response
• Teratogenicity, embryo toxicity

19. Two major computational methods for the calculation
of structure and property
• Quantum Mechanics
 Nuclei and electrons of the molecules are separately
considered
 Two approaches
Ab initio – more rigorous, from first principles(no stored
parameters or data), takes a long time, restricted to
small molecules
Semi-emperical – faster, but less accurate, can be used on
larger molecules
Useful for MO energies partial charges, electrostatic
potential, dipole moments

20. Molecular Mechanics
• Nuclei and electrons are lumped into atom-
like particles
• Interactions are based on spring and classical
potentials
• Calculate structure and dynamics total
energies, entropies free energies and diffusion

21. Component of force filed
• Energy = Stretching Energy + Bending Energy +
Torsion + non bonded interaction energy

22. 3D QSAR analysis of the quantitative relationship between the
biological activity of set of compounds and their three dimensional
properties
• Molecular Shape Analysis
• Molecular topological analysis
• Comparative molecular movement analysis
• Self organizing molecular field analysis
• Comparative molecular field analysis

23. • Pharmacodynamics is the effect that drugs
have on the body
• Pharmacokinetics is the study of the way in
which drugs move through the body during
ADME