Development of a machine learning‐based target‐specific scoring function for structure‐based binding affinity prediction for human dihydroorotate dehydrogenase inhibitors

Abstract Human dihydroorotate dehydrogenase (hDHODH) is a flavin mononucleotide‐dependent enzyme that can limit de novo pyrimidine synthesis, making it a therapeutic target for diseases such as autoimmune disorders and cancer. In this study, using the docking structures of complexes generated by AutoDock Vina, we integrate interaction features and ligand features, and employ support vector regression to develop a target‐specific scoring function for hDHODH (TSSF‐hDHODH). The Pearson correlation coefficient values of TSSF‐hDHODH in the cross‐validation and external validation are 0.86 and 0.74, respectively, both of which are far superior to those of classic scoring function AutoDock Vina and random forest (RF) based generic scoring function RF‐Score. TSSF‐hDHODH is further used for the virtual screening of potential inhibitors in the FDA‐Approved & Pharmacopeia Drug Library. In conjunction with the results from molecular dynamics simulations, crizotinib is identified as a candidate for subsequent structural optimization. This study can be useful for the discovery of hDHODH inhibitors and the development of scoring functions for additional targets.