Comparative Computational Studies on Selective CytochromeP450 1B1 Inhibitors

Abstract

Selective inhibitors of CYP isoforms gaining importance in the treatment of cancers caused by hormonal imbalance. Metabolites of estradiol and polyaromatic hydrocarbons generated due to CYP1B1 activity were reported to be oncogenic. The selective CYP1B1 inhibitors could have the potential therapeutic utility in controlling the cancer due to these oncogens. Due to the CYP isoforms high sequence similarity the design of selective CYP inhibitor is difficult. Recently our group has reported two novel chemical classes (scaffolds) that are specific towards CYP1B1. The chemical architecture of these compounds should give valuable information for its selectivity and potency against CYP1B1. Overlay of our compounds and ANF by Shape and electrostatic based similarity and molecular docking displayed different orientations. Moreover the study has shown the overlay of three atom bridge of selective inhibitor superimposed on -O-CH- linking aryl groups rather than -CO-CH=CH- of ANF. Molecular docking simulation revealed that the selective inhibitors are either establishing H-bonding interaction with Asp333 or π-π staking interaction Phe231 and Phe268. Molecular docking simulation has provided much more information rather than simple shape and electrostatic based similarity study. Crucial H-bonding interactions and π-π staking interactions responsible for selectivity towards CYP1B1 were identified. Two atom linker between the aryl groups matter, cyclization simply ensures the planarity of ANF and quinazolines.

Keywords

• cyp1b1
• selective inhibitors
• similarity search
• docking
• druggability
• adme