LEADOPT: an automatic tool for structure-based lead optimization, and its application in structural optimizations of...

Lead optimization is one of the key steps in drug discovery, and currently it is carried out mostly based on experiences of medicinal chemists, which often suffers from low efficiency. In silico methods are thought to be useful in improving the efficiency of lead optimization. Here we describe a new in silico automatic tool for structure-based lead optimization, termed LEADOPT. The structural modifications in LEADOPT mainly include two operations: fragment growing and fragment replacing, which are restricted to carry out in the active pocket of target protein with the core scaffold structure of ligand kept unchanged. The bioactivity of the newly generated molecules is estimated by ligand efficiency rather than a commonly used scoring function. Twelve important pharmacokinetic and toxic properties are evaluated using SCADMET, a program for the prediction of pharmacokinetic and toxic properties. LEADOPT was first evaluated using two retrospective cases, in which it showed a very good performance. LEADOPT was then applied to the structural optimizations of the VEGFR2 inhibitor, sorafenib, and the SYK inhibitor, R406. Though just several compounds were synthesized, we have obtained some compounds that are more potent than sorafenib and R406 in enzymatic and functional assays. All of these have validated, at least to some extent, the effectiveness of LEADOPT.