Docking Analysis of various synthesised Benzilic acid derivatives towards Sirutin protein and toxicity studies

Abstract

SIRT3 is one of the major mitochondrial deacetylase and has been shown to regulate the activity of many mitochondrial proteins. The sirt3 gene is observed in various human cancers. Sirutin gene family is hypothesized to regulate the aging process and plays a role in cellular repair. Expression of a single oncogene in sirt3 mouse embryonic fibroblasts results in in vitro transformation and altered intracellular metabolism. The crystal structure of SIRT3 with acetylated Acetyl CoA Synthatase2 peptide has been obtained to show that SIRT3 can form a stable complex with the substrate peptide in the absence of NAD+. Virtual screening of the compound was carried out by using Glide module of Schrodinger, LLC. Final shortlisting of hit molecules were performed based on visual inspection of important amino acid interactions in the active site cavity, docking scores and the hydrogen bonds involved in binding. The active site of the protein was validated and the Grid was generated with the active site of the protein. The docking score of the protein with the original ligand was found to be -9.836 kcal mol -1 . The compounds were sent for three rounds of docking strategies from HTVS with the criteria of docking score were further docked using Glide SP (Standard precision) docking module and Filtered ligands were subjected to Glide XP docking analysis. The resulted compounds with docking scores were found to be in the range of -8.970 to -4.292 kcal mol -1 . Compound Benzilic acid possessed good docking score with related to the reference ligand and it also possess the cancer cell toxic nature with the inhibition of 64.18% at 50 μg/ml concentration.