%0 Journal Article
%T A physicochemical descriptor-based scoring scheme for effective and rapid filtering of kinase-like chemical space
%A Narender Singh
%A Hongmao Sun
%A Sidhartha Chaudhury
%A Mohamed AbdulHameed
%A Anders Wallqvist
%A Gregory Tawa
%J Journal of Cheminformatics
%D 2012
%I BioMed Central
%R 10.1186/1758-2946-4-4
%X The method employs a collection of 22,615 known kinase inhibitors from the ChEMBL database. A kinase-likeness score is computed using statistical analysis of nine key physicochemical descriptors for these inhibitors. Based on this score, the kinase-likeness of four publicly and commercially available databases, i.e., National Cancer Institute database (NCI), the Natural Products database (NPD), the National Institute of Health's Molecular Libraries Small Molecule Repository (MLSMR), and the World Drug Index (WDI) database, is analyzed. Three of these databases, i.e., NCI, NPD, and MLSMR are frequently used in the virtual screening of kinase inhibitors, while the fourth WDI database is for comparison since it covers a wide range of known chemical space. Based on the kinase-likeness score, a kinase-focused library is also developed and tested against three different kinase targets selected from three different branches of the human kinome tree.Our proposed methodology is one of the first that explores how the narrow chemical space of kinase inhibitors and its relevant physicochemical information can be utilized to build kinase-focused libraries and prioritize pre-existing compound databases for screening. We have shown that focused libraries generated by filtering compounds using the kinase-likeness score have, on average, better docking scores than an equivalent number of randomly selected compounds. Beyond library design, our findings also impact the broader efforts to identify kinase inhibitors by screening pre-existing compound libraries. Currently, the NCI library is the most commonly used database for screening kinase inhibitors. Our research suggests that other libraries, such as MLSMR, are more kinase-like and should be given priority in kinase screenings.Chemical space can be defined as "the total descriptor space covered by all the known and possible small organic compounds" [1]. Chemical space is thus so vast that it prompted Lipinsky and Hopkins to compare
%U http://www.jcheminf.com/content/4/1/4