“Virtual Screening of Pyrazoloquinolinones into ATP and Allosteric binding site of ChK-1 Kinase”

LIC. IVANA MALVACIO, DRA. MALAKHAT TRUABEKOVA, DRA. DANUTA LESZCZYNSKA, DRA. E. LAURA MOYANO, DR. D. MARIANO VERA

Jackson, Mississippi

Congreso; 11th Southern School on Computational Chemistry and Materials Science; 2011

Interdisciplinary Center for Nanotoxicity, Jackson State University

Checkpoint Kinase 1 (ChK-1) is a key element in the DNA damage response pathway and plays an important role in the S-G2 phase checkpoint. Inhibiting ChK-1 is a therapeutic strategy involving abrogation of the G2-M mitotic checkpoint defense tumor cells toward lethal damage induced by DNA-directed chemotherapeutic agents.Here we report results of molecular docking studies performed for the series of pyrazoloquinolinones aiming to prioritize some of these compounds for experimental assays.In this approach, pyrazoloquinolinones were docked into three-dimensional structure of ChK-1 both ATP-binding site4 and an allosteric binding site1. The overall orientation of the small molecule and its conformations within considered receptor sites were explored. We were able to identify the main protein residues involved in the interactions between ChK-1 receptor sites and the ligand molecules as well as type of interactions involved.Overall, this work illustrates the ability of virtual screening to identify diverse set of ligands which bind to the targeted site. The structural models for these ligands in the ChK-1 binding site will facilitate further medicinal chemistry efforts targeting this kinase.