Research Journal of Pharmacy and Technology

R. Sudha ¹, P. Brindha Devi ², G. Nithya ¹

Affiliations
1 Department of Chemistry, School of Basic Sciences, Vels Institute of Science, Technology and Advanced Studies, IN
2 Department of Bio-Engineering, B.Tech Biotechnology, Vels Institute of Science, Technology and Advanced Studies, IN

Abstract

Cyclooxygenases (COX-1 and COX-2) catalyze the rate-limiting step in the biosynthesis of prostaglandins, prostacyclins, and thromboxanes. Ibuprofen has classically fallen into the time-dependant class of COX inhibitors as it binds rapidly and reversibly to Cox and acts as a competitive inhibitor of arachidonic acid oxygenation.The discovery of new and novel anti-inflammatory drugs is an area of intense interest in both pharmaceutical industry and academic laboratories. Significant advances have been made in the treatment of inflammatory diseases such as rheumatoid arthritis and multiple sclerosis, but most dramatically with new biologic agents. Perhaps due in part to the mixed experiences with COX-2 inhibitors, very few small molecule anti-inflammatory drugs with novel modes of action have made it to the market in the last decade.The various benzilic acid compounds synthesized have taken for in-silico analysis to study the structure activity relationship using crystal structure co-crystallized with 2-(4-isobtyl phenyl) propionic acid (PDB ID: 4PH9).The synthesized ligands were docked using three different docking strategies; High throughput virtual screening, Standard Precision and Extra Precision docking strategies. After three different analyses, the docking scores of the synthesized compounds were found to be in the range of -8.221 to –6.342 Kcal mol^-1. Finally the compounds are shortlisted based on the visual inspection of the amino acids interaction.

Keywords

Cyclooxygenases, Docking, Benzilic Acid and Inflammatory Diseases.

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R. Sudha ¹, P. Brindha Devi ², G. Nithya ¹

Affiliations
1 Department of Chemistry, School of Basic Sciences, Vels Institute of Science, Technology and Advanced Studies, IN
2 Department of Bio-Engineering, B. Tech Biotechnology, Vels Institute of Science, Technology and Advanced Studies, IN

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.

Keywords

SIRT3, Benzilic Acid, Docking, Toxicity.

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