MolTaut: A Tool for the Rapid Generation of Favorable Tautomer in Aqueous Solution

• Published in: Journal of chemical information and modeling Vol. 63; no. 7; pp. 1833 - 1840
• Main Authors: Pan, Xiaolin, Zhao, Fanyu, Zhang, Yueqing, Wang, Xingyu, Xiao, Xudong, Zhang, John Z. H., Ji, Changge
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 10.04.2023
• Subjects: Aqueous solutions; CAD; Computer aided design; Isomerism; Physical properties; Ranking; Solvation; Source code; Tautomers; Water
• ISSN: 1549-9596; 1549-960X
• DOI: 10.1021/acs.jcim.2c01393

Fast and proper treatment of the tautomeric states for drug-like molecules is critical in computer-aided drug discovery since the major tautomer of a molecule determines its pharmacophore features and physical properties. We present MolTaut, a tool for the rapid generation of favorable states of drug-like molecules in water. MolTaut works by enumerating possible tautomeric states with tautomeric transformation rules, ranking tautomers with their relative internal energies and solvation energies calculated by AI-based models, and generating preferred ionization states according to predicted microscopic pK a. Our test shows that the ranking ability of the AI-based tautomer scoring approach is comparable to the DFT method (wB97X/6-31G*//M062X/6-31G*/SMD) from which the AI models try to learn. We find that the substitution effect on tautomeric equilibrium is well predicted by MolTaut, which is helpful in computer-aided ligand design. The source code of MolTaut is freely available to researchers and can be accessed at https://github.com/xundrug/moltaut. To facilitate the usage of MolTaut by medicinal chemists, we made a free web server, which is available at http://moltaut.xundrug.cn. MolTaut is a handy tool for investigating the tautomerization issue in drug discovery.