MakeIntern IIT Delhi CADD Presentation.pdf
0 likes126 views
The document presents an overview of drug discovery processes, with a focus on computer-aided drug design (CADD) and its applications in creating inhibitors for benign prostatic hyperplasia (BPH). It discusses the role of 5-alpha reductase and presents docking scores for various synthesized compounds, indicating that nd-3 exhibited the highest binding affinity. The conclusion emphasizes the benefits of CADD in terms of cost-effectiveness, efficiency, and reducing failure rates in drug development.
MakeIntern IIT Delhi CADD Presentation.pdf
- 1. SURVIVAL OF THE FITTEST HYGIA COLLEGE OF PHARMACY, LUCKNOW,UP Presented by:
- 2. CONTENT • Drug Discovery Process • Trajectory of Computer Aided Drug Design • Data Source • Drug Design for Benign Prostatic Hyperplasia • Target Identification (Structure Based Drug Design) • Ligand Design • Docking Score • Result & Conclusion
- 3. Process of Drug Discovery & Development - Failure Rate at each Step Reference: U. Nielsch, U. Fuhrmann, S. Jaroch New approaches to drug discovery Springer Nature, New York (2016). Duxin Sun, We Gao,” Why 90% of clinical drug development fails and how to improve it? “Acta Pharmaceutica Sinica B,Volume 12, Issue 7, July 2022, Pages 3049-3062.
- 4. TRAJECTORY OF COMPUTER AIDED DRUG DESIGN
- 5. LIGAND BASED DRUG DESIGN Provides crucial insights into the nature of drug-target interactions and predictive models suitable for lead compound optimization in the absence of 3D structures of potential drug targets. Structure-based drug design is the design and optimization of a chemical structure, based on available protein target information, with the goal of identifying a compounds suitable for biological testing, leading to a drug candidate.. STRUCTURE BASED DRUG DESIGN
- 6. Data Source Chemical Databases Website link Protein Databases Website link Zinc https://zinc.docking.org/ PDB https://www.rcsb.org/ PubChem https://pubchem.ncbi.nlm.nih.gov/ PIR https://proteininformationresource.or g/ DrugBank https://go.drugbank.com/ Swiss-Prot https://www.ebi.ac.uk/uniprot/ ChemBank https://pubchem.ncbi.nlm.nih.gov/so urce/ChemBank SCOP https://scop.mrc-lmb.cam.ac.uk/ eMolecules https://www.emolecules.com/ Reference: https://canterbury.libguides.com/chem/journal-articles
- 8. Drug Design for Benign Prostatic Hyperplasia Dihydrotestosterone (DTH) is causative factor in progression of BENIGN PROSTATIC HYPERPLASIA (BHP). Inhibition of 5AR is the treatment for controlling the BPH by diminishing the concentration of DHT in the prostate and is expected to improve the pathology of disease. Action of 5-alpha reductase a membrane bound NADPH dependant enzyme Benign prostatic hyperplasia (BPH), a common condition of males over the age of 50 is characterized by enlargement of the prostate and results in urinary obstructions.
- 9. PDB ID: 7BW1 Leu16, Leu19, Ala20, Val23, Lys25, Pro26, Ser27, Tyr29, Gly30, Lys31, Ala40, Trp44, Gln47, Glu48, His81, Tyr82, Arg85, Tyr89, Asn93, Arg94, Gly95, Arg96, Tyr98, Leu102, Arg105, Gly106, Phe109, Cys110, Asn151, Asp155, Leu158, Arg159, Leu161, Arg162, Ser168, Tyr169, Arg170, Pro172, Phe177, Ser181, Gly182, Asn184, Phe185, Glu188, Trp192, Phe207, Ser211, Phe214, Leu215, Leu217, Arg218, His221, His222, Tyr226. Active Pocket of 5αR-2 Residues present in the Pocket Pocket Surface area (Å2 ) Volume (Å3 ) 1 829.083 648.171 In-silico 5-Alpha reductase activity prediction using SBDD Reference: www.rcsb.org
- 10. Treatment ejaculatory dysfunction, breast enlargement, insulin resistance kidney dysfunction and other metabolic dysfunctions. FINASTERIDE 5-alpha reductase inhibitor (5ARI) DUTASTERIDE DESIGN of 5-Alpha reductase Inhibitors ND-1 to ND-6 Clinically Approved Reference: Dhingra N,”Computer-Aided Drug Design and Development: An Integrated Approach”, 1-15. http://dx.doi.org/10.5772/intechopen.105003
- 11. Docking Score of Novel 5ARIs S. No. Compounds D-score 1. ND-1 −66.23 2. ND-2 −62.87 3. ND-3 −74.91 4. ND-4 −60.68 5. ND-5 −59.75 6. ND-6 −62.79 7. FN (Finasteride) −57.09 Order of Docking Score ND3 > ND1 > ND2 > ND6 > ND4 and ND5 ND-3 Highest D-score of −74.91 than FN Reference drug finasteride (FN) known to possess an affinity for the 5AR receptor is included in the docking studies for comparing the docking results. Reference: Dhingra N,”Computer-Aided Drug Design and Development: An Integrated Approach”, 1-15. http://dx.doi.org/10.5772/intechopen.105003
- 12. Result The docking score has been observed in order ND3 > ND1 > ND2 > ND6 > ND4 and ND5. Similar docking behavior has been observed among all the synthesized compounds in comparison to FN, by interacting hydrophobically with common amino acid residues THR175A, ALA59A, ALA63A, SER471A, and ALA264A. Additional aromatic interactions have also been observed only in ND-6 for amino acid HIS268A. Among all the newly synthesized derivatives ND-1 to ND-6, ND-3 has been found to bound best with the 5AR receptor affording the highest D-score of −74.91 than FN. This high score of −74.91 can be attributed to its strong hydrogen bonds between NO2 at the p-position of the benzene ring with amino acid residue GLY241A and GLY245A.
- 13. CADD CONCLUSION • Cost Effective • Less Time Consuming • Accelerate therapeutic Development • ADMET determination decreases the chances of failure. • Avoid High Failure Rates.
- 14. Thank you