Hydrogen bonds ofOCNHmotif in rings in drugs: A molecular electrostatic potential analysis

Abstract

AbstractThe OCNH unit is one of the most frequently encountered structural motifs in rings in drugs which serves dual role as the proton donor through NH bond and proton acceptor through the CO bond. Here, we predicted the HB strength (Eint) of OCNH motif with H2O for commonly observed 37 rings in drugs with DFT method M06L/6‐311++G(d,p). The HB strength is rationalized in terms of molecular electrostatic potential (MESP) topology parameters ΔVn(NH)and ΔVn(CO)which describe the relative electron deficient/rich nature of NH and CO, respectively, with respect to the reference formamide. TheEintof formamide is −10.0 kcal/mol whereas theEintof ring systems is in the range −8.6 to −12.7 kcal/mol—a minor increase/decrease compared to the formamide. The variations inEintare addressed using the MESP parameters ΔVn(NH)and ΔVn(CO)and proposed the hypothesis that a positive ΔVn(NH)enhances NH…Owinteraction while a negative ΔVn(CO)enhances the CO…Hwinteraction. The hypothesis is proved by expressingEintjointly as ΔVn(NH)and ΔVn(CO)and also verified for twenty FDA approved drugs. The predictedEintfor the drugs using ΔVn(NH)and ΔVn(CO)agreed well with the calculatedEint. The study confirms that even delicate variations in the electronic feature of a molecule can be quantified in terms of MESP parameters and they provide a priori prediction of the HB strength. The MESP topology analysis is recommended to understand the tunability of HB strength in drug motifs.