EXPRORER: Rational Cosolvent Set Construction Method for Cosolvent Molecular Dynamics Using Large-Scale Computation

Cosolvent molecular dynamics (CMD) simulations involve an MD simulation of a protein in the presence of explicit water molecules mixed with cosolvent molecules to perform hotspot detection, binding site identification, and binding energy estimation, while other existing methods (e.g., MixMD, SILCS, and MDmix) utilize small molecules that represent functional groups of compounds. However, the cosolvent selections employed in these methods differ and there are only a few cosolvents that are commonly used in these methods. In this study, we proposed a systematic method for constructing a set of cosolvents for drug discovery, termed the EXtended PRObes set construction by REpresentative Retrieval (EXPRORER). First, we extracted typical substructures from FDA-approved drugs, generated 138 cosolvent structures, and for each cosolvent molecule, we conducted CMD simulations to generate a spatial probability distribution map of cosolvent atoms (PMAP). Analyses of PMAP similarity revealed that a cosolvent pair with a PMAP similarity greater than 0.70–0.75 shared similar structural features. We present a method for the construction of a cosolvent subset that satisfies a similarity threshold for all cosolvents, and we tested the constructed sets for four proteins. To our knowledge, this is the first study to include a systematic proposal for cosolvent set construction, and thus, the EXPRORER cosolvents will provide deeper insights into ligand binding sites of various proteins.