Bayesian models leveraging bioactivity and cytotoxicity information for drug discovery.

Collaborations in Chemistry, 5616 Hilltop Needmore Road, Fuquay-Varina, NC 27526, USA. Electronic address: .
Chemistry & biology (Impact Factor: 6.52). 03/2013; 20(3):370-8. DOI: 10.1016/j.chembiol.2013.01.011
Source: PubMed

ABSTRACT Identification of unique leads represents a significant challenge in drug discovery. This hurdle is magnified in neglected diseases such as tuberculosis. We have leveraged public high-throughput screening (HTS) data to experimentally validate a virtual screening approach employing Bayesian models built with bioactivity information (single-event model) as well as bioactivity and cytotoxicity information (dual-event model). We virtually screened a commercial library and experimentally confirmed actives with hit rates exceeding typical HTS results by one to two orders of magnitude. This initial dual-event Bayesian model identified compounds with antitubercular whole-cell activity and low mammalian cell cytotoxicity from a published set of antimalarials. The most potent hit exhibits the in vitro activity and in vitro/in vivo safety profile of a drug lead. These Bayesian models offer significant economies in time and cost to drug discovery.