Epik: pKa and Protonation State Prediction through Machine Learning.

Epik version 7 is a software program that uses machine learning for predicting the pKa values and protonation state distribution of complex, druglike molecules. Using an ensemble of atomic graph convolutional neural networks (GCNNs) trained on over 42,000 pKa values across broad chemical space from both experimental and computed origins, the model predicts pKa values with 0.42 and 0.72 pKa unit median absolute and root mean square errors, respectively, across seven test sets. Epik version 7 also generates protonation states and recovers 95% of the most populated protonation states compared to previous versions. Requiring on average only 47 ms per ligand, Epik version 7 is rapid and accurate enough to evaluate protonation states for crucial molecules and prepare ultra-large libraries of compounds to explore vast regions of chemical space. The simplicity and time required for the training allow for the generation of highly accurate models customized to a program's specific chemistry.

Potent Antimalarials with Development Potential Identified by Structure-Guided Computational Optimization of a Pyrrole-Based Dihydroorotate Dehydrogenase Inhibitor Series.

Dihydroorotate dehydrogenase (DHODH) has been clinically validated as a target for the development of new antimalarials. Experience with clinical candidate triazolopyrimidine DSM265 (1) suggested that DHODH inhibitors have great potential for use in prophylaxis, which represents an unmet need in the malaria drug discovery portfolio for endemic countries, particularly in areas of high transmission in Africa. We describe a structure-based computationally driven lead optimization program of a pyrrole-based series of DHODH inhibitors, leading to the discovery of two candidates for potential advancement to preclinical development. These compounds have improved physicochemical properties over prior series frontrunners and they show no time-dependent CYP inhibition, characteristic of earlier compounds. Frontrunners have potent antimalarial activity in vitro against blood and liver schizont stages and show good efficacy in Plasmodium falciparum SCID mouse models. They are equally active against P. falciparum and Plasmodium vivax field isolates and are selective for Plasmodium DHODHs versus mammalian enzymes.