4SCan/vADME: intelligent library screening as a shortcut from hits to lead compounds

Abstract

Managing to solve the first step in drug discovery the hit finding can be a quite elaborate task, but it is only the initial step to the final goal; hit-to-lead optimisation still lies ahead and consumes even more time and resources. The solution is rather simple, that is, to take only the most promising compounds into account; but who is going to decide which ones are the most promising among a list of tens of millions of compounds in a virtual combinatorial library? 4SCan/vADME helps by bridging the gap between virtual (combinatorial) libraries designed by chemists and the insilico methods, docking and alignment, for screening databases. After choosing a random starting set, the implemented learning and prediction algorithm iteratively considers only combinations of fragments that have shown to result in more suitable interactions by the chosen method. ADME properties of the final list are then calculated via several insilico methods, resulting in a combined evaluation of the individual compounds target-specific, as well as ADME, properties. Based on the latter list of evaluated compounds, medicinal chemists can then decide which compounds might be the best ones to synthesise first and to serve as possible lead candidates. Following a brief introduction to virtual high-throughput screening techniques, the 4SCan/vADME method is outlined and discussed in this paper, using an example coming out of the 4SC pipeline.

Keywords::

• ADME
• alignment
• docking
• in silico
• virtual high-throughput screening

Acknowledgment

The authors thank M Seifert for his help with ProPose and adjusting parameters, M Busemann for help with the QSAR models and proofreading and D Vitt for discussions and support. The authors also thank F Schmitt of quattro research GmbH for support regarding questions about quattro/DS.