PR-Set7 is the monomethyltransferase of H4Lys20 of chromatin.  The lack of it in the human myelogenous leukemia line was associated with spontaneous megakaryotic differentiation.  It was shown to potentially have physiological importance in cancer progression.  There are several known inhibitors of PR-Set7.  We would have the possibility of lots of remedies with variety of potent inhibitors.  On the other hand, there has been remarkable improvement of chemoinfomatics, molecular modeling tools and computational environment for this decade.  It becomes drug discovery with such computational tools easy to approach.  Our purpose of this research is to find effective PR-Set7 inhibitors with some virtual screening software.  We selected Bromo-methoxy-phenyl derivatives Compd-5 of the paper by Valente et al (Biochime 94, (2012) 2308) as a known lead compound on our virtual screening.  The whole process of this research is as follows: 1) docking pose prediction of Compd-5 using the X-ray structure of PR-Set7 (PDBID: 1ZKK) with a docking tool FRED6 from OpenEye Scientific.  Since the co-crystal of PR-Set7 and Compd-5 has not been reported yet, 2) 300ns molecular dynamic (MD) simulations of the system started from the docking pose in order to obtain the equilibrated structure with the solvent and ions.  3) Structure-base virtual screening of potentially active compounds against the equilibrated protein with HYBRID program from six and half million compounds in Namiki Database.  4) Calculation of ligand-protein interactions and ligand binding entropy for each screened molecule by using SZYBKI program, and 5) further molecular filtering with FILTER program.  Then, we investigated the binding affinities of the compounds both numerically and experimentally: the massively parallel computation of absolute binding free energy with a well-equilibrated system (MP-CAFEE) and measurements of the half maximal inhibitory concentration (IC50) using Matrix Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry (MALDI-TOFMS) for the purpose to confirm the validity our screening.  Each compound had affinity of several dozens of μM by both methods and they are adequate affinities for lead compounds.  This means our screening method is helpful for drug discovery.<br/>

Virtual screening for inhibitor to monomethyltransferase PR-Set7

251st National Meeting (2016)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.