Discovery of Novel Mammalian target of rapamycin (mTOR) Inhibitors by Support Vector Machine

Abstract Mammalian target of rapamycin (mTOR) is a protein serine/threonine kinase playing the central downstream role in multiple mitogenic signalling pathways. As a c entral regulator of cell growth, proliferation, differentiation and survival, mTOR has b een reported to modulate proliferation and angiogenesis in neoplastic processes. Curre ntly, sirolimus and its analogues the only five mTOR inhibitors approved for clinical u se, which shows a great capacity in anticancer therapy. However, endocrine resistance in cancer therapy has been observed in sirolimus analogues, and the unavailability of n ew mTOR inhibitor besides similar structure of sirolimus analogues makes the resistan ce even worse. It is urgent to discovery new mTOR inhibitors as candidates for develo pment of effective anticancer drugs. In this study, support vector machine (SVM) as a virtual screening strategy was proposed. SVM models of mTOR inhibitors were constr ucted by training data published before 2012, and the ones published after 2012 as test set were used to verify according to cross validation. The selected model performed thi n false hit rates of 0.12% and 0.46% by screening PubChem and MDDR chemical libr aries respectively. As results, 9 novel novel scaffolds for mTOR were identified, and 6 of them have been reported their anticancer-related therapeutic capacity. In summary, SVM performed its ability to identify novel mTOR inhibitors, which can supply some candidates for mTOR anticancer drugs, and supply effective method for anticancer dru g discovery in future.