Rational drug design involves developing compounds that target specific biomolecules involved in disease processes through protein-protein or protein-nucleic acid interactions. Protein targets can be identified through techniques like X-ray crystallography and NMR. Computational tools and global gene expression analysis help increase the efficiency and cost-effectiveness of the drug design process by aiding in structure-guided approaches and target identification. Drug design can involve developing ligands for targets with known structures or developing ligands with predefined properties for unknown targets identified through gene expression data. Combination therapies and overcoming toxic side effects are important challenges in developing improved anti-cancer drugs.

1. Rational Drug Design
Seema Bansal

2. Introduction
• Drug: Compounds used for the prevention and treatment of diseases like
cancer, etc.
• Ideal drug:
1) target: bio-molecule ,involved in signaling or metabolic pathways, that are
specific to disease process by either protein-protein or protein-nucleic acid
interactions.
2)antagonist action-inhibiting functions of the disease causing proteins.
3) Inhibiting interactions of the proteins.
4) Activates other proteins, that are deregulated in such disease like cancer.

3. Drug Discovery
Protein targets for drugs can be known by 3D X-ray crystallography, NMR,
docking tools, Computer aided drug designing.
PDB: 71550 proteins structure available.
X-ray crystallography: 63124
NMR: 7985
Cryoelectron microscopy: 266
Hybrid: 42
Other: 133
Still, insignificant so many lead drugs are unknown.

4. Drug designing is:
1)challenging
2)Expensive
3)Time consuming
So, Multidisciplinary approach:
Computational tools, methodologies for structure guided approach + Global
gene expression data analysis by softwares.
Hence,
1) Efficiency increased
2) Cost effectiveness
3) Time saved
4) Strategies to overcome toxic side effects

5. Drug Design
2 ways:
A) Development of ligands with desired properties for targets having known
structure and functions.
B) Development of ligands with predefined properties for targets whose
structural information may be or may not be known.
This, unknown target information can be found by global gene expression data.

6. Figure 1: Possible steps in drug designing for known target

7. Figure 2: Possible steps in drug designing for unknown target

8. Figure 3: Additional properties towards the improvement of
drug like properties

9. Figure 4: Structure of few anti-cancer drugs

10. Figure 5: BCR-ABL kinase domain: showing the binding pocket
of nilotinib (purple) bound to the active site of the target BCR-
ABL in Chain C. In this figure, BCR-ABL is the cluster of four
chains (chain A , chain B [purple], chain C [blue], and chain D
[red]).

11. Figure 6: Adjacent surface for nilotinib: shows the adjacent
surface pocket that is the surface within 3 Å of the drug to the
active site of the target (BCR-ABL). This surface provides
guidance in the process of drug development.

12. - This adjacent surface provides information necessary for modification of
bound drug.
- Red= where protein needs H-acceptors
- Cream= Hydrophobic surface
- Pocket surface= active site
Ligands that bind well, should have H-bond acceptor groups touching red
surface.
Reactivity: Nucleophilic, electrophilic or radical frontier density measures
susceptibility of substrate by attack.
-It reveals reactive sites based on electron configuration.

13. Known targets for Cancer therapy:
• EGFR shows aberrant expression in cancers like lung cancer, breast cancer.
• It interacts with other 151 proteins.
• It is involved in 19 signaling pathways.
• EGF is a natural ligand and binds to EGFR and mediates signaling events.
• Another drug with the EGFR as a target is gefitinib.
• It attaches to protein kinase domain in EGFR, which is an important target
involved in many malignancy promoting processes.

14. Mutation in EGFR
Figure 7: Types of mutation of EGF receptor: shows the different types of
mutation and their position in the EGF receptor.

15. Figure 8: The tyrosine kinase domain of the EGF receptor:
showing the binding of gefitinib.

16. Figure 8: Protein–protein interaction network for EGF receptor- shows the
interacting network between EGF receptor and other proteins.
Up, down and unchanged regulation could be studied by gene expression
levels.

17. Drug Designing Methods:
• Databases:
PDB: Experimentally determined structures.
NCI: National Cancer Institute.
Pubchem: Bulk data available for QSAR for lead discovery.
3D MIND: Information about cytotoxic potency for 60 human cancer cell lines.
OSIRIS: To draw chemical structures and predict drug like properties like
absorption in body etc.
Links at the bottom of the paper.
Autodock and Dock6 for docking

18. Currents drugs:
1) Safety concerns
2) Adverse toxic side effects
3) Cardiac Toxicity
4) Devlopment of drug resistance.
So, the maximum docking score doesn’t necessarily mean it’s a potent drug.
Hence, current drugs need to overcome this hurdle of toxicity.

19. Combination Therapy
• Ancient Asian herbal medicine with combination of many herbs
produces no side effects
• Same approach is applied to modern medicine
• We can use combination of different drugs to combat a specific
disease like cancer.

20. Multidisciplinary Approach
A) Global gene expression profiling
- It reveals insights into pathogenosis of diseases including cancer.
- Methods such as SAGE or Microarray analysis(MA) are used.
- To access SAGE or MA, bioinformatics tools are used.
B) Global Gene Expression Analysis
• Databases like GEO (for microarray data) or SAGE data depository, Stanford
MA Database etc. are available.
• We can ‘group the genes’ based on the data from above mentioned tools for gene
annotation.
• DAVID tool- gene annotation, gene ontology, protein pathways and protein
domains finding.
• GSEA (Gene Set Enrichment Analysis)- defines whether set of genes shows
difference between normal and abnormal states of the genes or not.

21. • All these tools are free tools but many commercial tools are available to
carry out specific experiments.
• Gene up/down/unchanged expression is required for target finding for lead
molecules.
• Modification of the drug itself or applying different strategies is necessary
for combination therapy.

22. Conclusion
• Cancer is common in all the ages and it shows metastasis, angiogenesis and
cell death, etc.
• So, drugs to cure cancer are necessary.
• Except toxicity, drugs are quite tolerable so they are combined with other
drugs.
• Comparative analysis of gene expression levels between drug treated and
non-treated condition should be studied.
• If getting superior quality drug than the available ones, clinical trial phases
can be performed on them.

23. • QUESTIONS???