Drug design is the inventive process of finding new medications based on the knowledge of a biological target.

1. Strategies in Drug Design
Dr. Ashwani Dhingra
Associate Professor
GGSCOP, YNR.

2. If Drug (Imported Binding gp)

5. Evaluating a
Structure
for SBDD
• 3 methods are X-ray crystallography, NMR and
Homology modelling.
• Crystal Structures should be evaluated for (i)
Resolution, (ii) Reliability (or) R-factors, (iii)
Coordinate error.
• Crystal structures determined with data
extending beyond 2.5Å ® are acceptable for
drug design purpose.
• 'R' factor ¾¾®and Rfree of a model are a
measure of correlation between model and
experimental data (i.e.) Rfree value
[ideally (Rfree < 25%)] < 28%.

6. Denovo-Drug Design
• Involves the design of Novel drug structure based on the knowledge of binding
site alone.
• This can lead to a novel lead compound successfully, which can then be a start
point of structure based drug.
• Position of atoms in crystal structure is accurate to 0.2–0.4Å.
• Flexible molecules are better than rigid as they find alternative binding
conformation
• Hit and trial.
• Chances of hitting ideal structure are poor.
• Denovo does not identify whether the structures identified will have favourable
pharmacokinetics/safety.

7. Scheme

8. Analogue Based
Drug Design

9. Examples

10. Structural analogues
(e.g) Opioid agonist and antagonist
Morphine (N–methyl subst)
(Proto type opiate agonist)
Nalorphine (N–allyl normorphine)
(Morphine antagonist)

11. Pharmacological
analogues
• Different pharmacophores exist to explain the same
pharmacological activity of structurally different
drugs.

12. Analogue
based Drug
Design
Advantage
• The development of a pioneer drug is
extraordinarily uncertain because it’s
therapeutic use has not been validated
clinically. On the other hand, preparing an
analogue has the advantage that the
predicted therapeutic use of the analogue
has already been proved.
Disadvantage
• Many hurdles to overcome with regard of
pharmacokinetic behavior and safety. The
analogue products are often regarded as
"me-too" compounds.

13. Classification of Analogue Drugs
Structural and pharmacological analogues
• Drugs which have similar chemical structures and with a similar main pharmacological
activity.
Structural analogues
• Drugs which have a similar chemical structure but have quite different
pharmacological properties.
Pharmacological analogues
• Drugs which have a similar pharmacological activity without having any discernible
chemical or structural relationship

14. • .

16. Several examples of Analogue Based Drug Design
¯
1. Levo dopa (Lead Source)
Melevodopa (Natural product/Pro drug analogue)
2. Omeprazole (Lead Source)
Esomeprazole (Drug enantiomer analogue)
3. Captopril (Lead Source)
Zofenopril (Drug analogue)
4. Cetrizine (Lead source)
Levocetrizine (Drug enantiomer analogue)

17. 5. Losartan (Lead source)
Olmesartan (Drug analogue/Prodrug)
6. Celecoxib (Lead source)
Valdecoxib (Drug analogue)
7. Fluvastatin (Lead source)
Rosuvastatin (Drug analogue)
8. GABA (Lead source)
Pregabalin (natural product analogue)

18. Evaluating a Structure for
SBDD
• Low coordinate error is crucial in crystal structure. [Narrow
tolerance for both angle and distance 0.2Å].
• Coordinate error measured by 2 methods.
• 1. Luzzati method
• Based on averaging coordinate error as a function of 'R'
factors that vary with expected errors are calculated based on
the temperature factor (or) 'B' factor of an atom and the
atom: reflection ratios.
• Luzzati co-ordinate error is in the range of 0.2 – 0.3 Å.
• Ideal Bond lengths should be no greater than 0.15 Å (or) 3°
for bond angles.
• At least 90% of the backbone f and Y angles should fall into
the most favoured
• regions of Ramachandran plot.

19. 2. 'B' factor and atom: reflection ratio (atom/refl) as in stroud and
fauman method.
Expected error=0.642 + 0.00852 e(B/7.88)–0.687–0.00223e(B/6.16).
e(–2) (atoms/refl)

21. Example for
Structure
based Drug
Design
• COMT–Catechol 0–methyl transferase enzyme
• Ado Met: Coenzyme S–Ademosyl L–methionine.
• Ado Hcy: S–Ademosyl Homocysteine
• If R = CH2 CH2 NH 2 ® Dopamine
• If R = CH2 CH–COOH ® L–Dopa.
• |
• NH2

22. 2 distinct forms of COMT:
• ® Soluble COMT (S–COMT) 221 A. Acids.
• Membrane bound COMT (MB–COMT) 50 Human
residues.
• Physiological substrate of COMT:
• Catecholamine neurotransmitters
• Dopamine
• Nor-adrenaline
• Adrenaline & some of their metabolites

23. Structure
based Drug
Design
Strategy

24. • Nitrocatechol derivative (e.g) Entacapone
Acts Peripherally
• Tolcapone®
acts both peripherally & centrally
Second Generation COMT Inhibitors

25. Experimental
driven drug
design
strategies
Library based drug design
Ligand based drug design
Structure based drug design
Site directed Mutagenesis (SMD)/
Reverse SAR

26. Library based
drug design
(Includes 2D
QSAR, 3D
QSAR)
Random Library
Directed Library
Fragment Library

27. Ligand
based drug
design
Endogenous based design
Prototype based design
Analogue based design

28. Structure
based drug
design
Receptor/ Active site hypothetical
picture
Receptor/ Active site prototype
picture
Receptor/ Active site actual picture
Receptor/ Active site actual picture
with and without ligands present

29. Thank You
Dr. Ashwani Dhingra
Associate Professor
GGSCOP, YNR.