Various atomic charge calculation schemes of CoMFA on HIF‐1 inhibitors of moracin analogs

Selection of appropriate partial charges in a molecule is crucial to derive good quantitative structure–activity relationship models. In this work, several partial atomic charges were assigned and tested in a comparative molecular field analysis (CoMFA) models. Many CoMFA models were generated for a series of hypoxia inducible factor 1 (HIF‐1) inhibitors using various partial atomic charges including charge equalization, Mülliken population analysis (MPA), natural population analysis, and electrostatic potential (ESP)‐derived charges. These atomic charges were investigated at various theoretical levels such as empirical, semiempirical, Hartree–Fock (HF), and density functional theory (DFT). Among them, Merz‐Singh‐Kollman (MK) ESP‐derived charges at the level of HF/6‐31G* gave the highest predictive q² with experimental pIC₅₀ values. With this charge scheme, a detailed analysis of CoMFA model was performed to understand the electrostatic interactions between ligand and receptor. More elaborate charge calculation schemes such as HF and DFT correlated more strongly with activity than empirical or semiempirical schemes. The choice of optimization methods was important. As geometries were fully optimized at the given levels of theory, the aligned structures were different. They differed considerably, especially for the flexible parts. This was likely the source of the substantial variation of q² values, even when the same steric factor was considered without electrostatic parameters. ESP‐derived charges were most appropriate to describe CoMFA electrostatic interactions among MPA, NBA, and ESP charges. Overall q² values vary considerably (0.8–0.5) depending on the charge schemes applied. The results demonstrate the need to consider more appropriate atomic charges rather than default CoMFA charges. © 2011 Wiley Periodicals, Inc. Int J Quantum Chem, 2012