#197 Design and discovery of benzamide derivatives as a selective CYP1B1 inhibitor; in-silico & in-vitro approach

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Mohd Siddique, M. U.; Ansari, A. Z. .; Patil, M. .; Goyal, S. N. . #197 Design and Discovery of Benzamide Derivatives As a Selective CYP1B1 Inhibitor; in-Silico & In-Vitro Approach. J Pharm Chem 2022, 8.

Abstract

The aim of this work was to design a small molecule inhibitor of CYP1B1 enzyme by computational approach and performing synthesis and biological evaluation of a small library of synthesized molecules. Selective inhibitors of CYP isoforms are important in the treatment of cancers caused by hormonal imbalance. This could avoid the severe mechanism-based toxicities or off-target effect as CYP1B1 expresses in cancerous tissues, not in a healthy one. Metabolites of estradiol and polyaromatic hydrocarbons generated due to CYP1B1 activity were reported to be oncogenic. Here, we used the combined comparative shape and electrostatic and molecular docking approach towards the design of selective CYP1B1 inhibitors. The designed benzamide derivative displayed Tanimoto shape 0.847 and Tanimoto electrostatic 0.882, respectively, with known CYP1B1 inhibitor. The molecular docking studies also showed the identical pattern of binding as that of reference molecules. Encouraged by these results we synthesized the eight benzamide derivatives that will be screened against various isoforms of CYPs in SacchrosomesTM, ‘Live Yeast cells’ and ‘Live human cells.’ The small molecule benzamide derivative as a selective CYP1B1 inhibitor has been designed by a combined approach of shape and electrostatic based comparative study of reported potent inhibitor with a small library of designed benzamide derivatives followed by molecular modeling studies. The top HIT molecule was then synthesized, and their different derivatives were also made. Further, all molecules will be screened for their potent and selective CYP1B1 inhibitory activity using various isoforms of the CYP1B1 enzyme.

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