Virtual screening and alchemical free-energy calculations

Benefiting from the resolution in revolution in single-particle cryo-electron microscopy and structure prediction advancements from AlphaFold, virtual screening has become an increasingly popular method for identifying hit compounds for specific targets. At FMP, we have developed a highly parallelized and efficient computational framework for structure-based virtual screening. Using this framework, we can rapidly screen large compound libraries comprising millions of compounds to identify promising hits. Furthermore, we have implemented various types of libraries, including target-focused libraries, on-demand libraries, and bioactive libraries and also developed several filtering strategies after the screening process.

Accurately predicting protein–ligand binding affinity is one of the central goals in computer-based drug design. Molecular dynamics (MD)-based free energy calculations have gained popularity due to their accuracy and solid theoretical foundation. Recently, we presented a combined study that integrates experimental and computational approaches on two series of factor Xa ligands, encompassing a broad chemical space with significant modifications to the central scaffold (Figure 4) [18]. Through this integrated approach, we identified several new ligands with heterocyclic scaffolds different from the previously identified indole-2-carboxamides, exhibiting superior or comparable affinity. Additionally, the previously underexplored terminal alkyne moiety proved to be a suitable non-classical bioisosteric replacement for higher halogen−π aryl interactions. In addition, we used a similar approach to elucidate substrate binding of a phosphor-lysine phosphatase [19].

[18] Fernández-Bachiller, M. I.; Hwang, S.; Schembri, M. E.; Lindemann, P.; Guberman, M.; Herziger, S.; Specker, E.; Matter, Will, D. W.;  Czech, J.; Wagner, M.; Bauer, A.; Schreuder, H.; Ritter, K.; Urmann, M.; Wehner, V.; Sun, H.*, Nazaré, M.* Probing factor Xa protein-ligand interactions: accurate free energy calculations and experimental validations of two series of high-affinity ligands J. Med. Chem. 2022, 65(19), 13013-13028. doi: 10.1021/acs.jmedchem.2c00865

[19] Hauser, A.; Hwang, S.; Sun, H.*; Hackenberger, C.* Combining free energy calculations with tailored enzyme activity assays to elucidate substrate binding of a phospho-lysine phosphatase, Chem. Sci. 2020, 11(47), 12655-12661. doi:10.1039/D0SC03930F