In Silico Design and Analysis of a Kinase-Focused Combinatorial Library Considering Diversity and Quality

A structurally diverse, high-quality, and kinase-focused database plays a critical role in finding hits or leads in kinase drug discovery. Here, we propose a workflow for designing a virtual kinase-focused combinatorial library using existing structures. Based on the analysis of known protein kinase inhibitors (PKIs), detailed fragment optimization, fragment selection, fragment linking, and a molecular filtering scheme were defined. Quick recognition of core fragments that can possibly form dual hydrogen bonds with the hinge region of the ATP-pocket was proposed. Furthermore, three diversity and four quality metrics were chosen for compound library analysis, which can be applied to databases with over 30 million structures. Compared with 13 commercial libraries, our protocol demonstrates a special advantage in terms of good skeleton diversity, acceptable fingerprint diversity, balanced scaffold distribution, and high quality, which can work well not only on existing PKIs, but also on four chosen commercial libraries. Overall, the strategy can greatly facilitate the expansion of a desirable chemical space for kinase drug discovery.