In-silico Drug Design and In-silico Screening (Track)

POTENTIAL GLYOXALASE-I ENZYME INHIBITORS AS ANTICANCER AGENTS USING “ZINC BINDING FEATURE” AS GUIDED PHARMACOPHORE VIRTUAL SCREENING

Al-Balas Q., Hassan M., Isawi I., Alshari N., Mhaidat N. and Al-Maayta A.

Department of Medicinal Chemistry and Pharmacognosy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan

Abstract

Being the number one killer for humanity , cancer has received unpreceded attention from scientific community worldwide. With WHO estimation of 13 million deaths in 2030, efforts to fight cancer should be the responsibility of the majority of research groups to unravel all the potential agents for its termination. Glyoxalase-I was found to be a pivotal target, its main role is to detoxify harmful metabolites such as methylglyoxal to innocent bystanders, its inhibition will accumulate toxic metabolites inside cancer cell which will lead later to their death. Exploiting the presence of zinc atom inside its active site, our research group has designed a pharmacophore containing “zinc binding feature” which can selectively mine the commercial databases for compounds possessing selective functional groups such as “Ketol” or carboxylic acid that has the possibility to append zinc atom. AldrichCPR commercial database has been dredged and then the candidate compounds were filtered according to Lipiniskis, Vebers and ADMET rules. The candidates were then docked using flexible docking protocol in discovery studio 4.0 from Biovia® which resulted in seven compounds selected with the best ranking and optimum posing. Finally, glyoxalase-I activity was determined in vitro against the enzyme with the best compound scoring 34% of inhibition at 25mM.