In- Silico Drug Design and Molecular Docking Studies of Poly ADP-Ribose Polymerase (PARP-1) Inhibitors as Anticancer Agents

Abstract

Background of the Topic: Drug discovery employs bioinformatics and computational biology (CADD) approaches for the identification and optimization of lead compounds. The PARP-1 is the member of the PARP family. PARP-1 is the enzyme that repairs the DNA damage in cancer cell hence it is selected as the target for the study. PARP inhibitors were shown the prominent results in the treatment of different kinds of malignancies due to loss of function of BRCA1/2 genes.
 Methodology: Based on literature review, database search, ADME and MD simulation, top 10 selected ligands were screened and tested against PARP-1 (4R6E) protein using molecular docking (Glide and Gold software), protein ligand interaction by LIGPLOT analysis. Molecular simulation studies were performed using DESMOND software afterwards on the top compound (CHEMBL378794).
 Results: All top 10 compounds showed binding affinity based inhibitory potential against the PARP-1 protein. The highest binding affinities from top 10 compounds towards anticancer targets were exhibited by CHEMBL378794 and CHEMBL245559. 
 Discussion: The comparative analysis of 4R6E and the identified hits using MD simulation exhibited better stability of the binding domain with these molecules suggesting their strong interaction and selectivity towards PARP-1. 
 Conclusion: This study showed the significant results in cancer treatment and their strong interaction with PARP-1 binding BRCT domain. Hence, these molecules could further be carried forward to explore their potency against PARP-1 sensitive cancer.