Hydrogen bonds of OC-NH motif in rings in drugs: A molecular electrostatic potential analysis

The 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 (E-int) 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 ?V-n(NH) and Delta V-n(CO) which describe the relative electron deficient/rich nature of -NH and -CO, respectively, with respect to the reference formamide. The E-int of formamide is -10.0 kcal/mol whereas the E-int of ring systems is in the range -8.6 to -12.7 kcal/mol-a minor increase/decrease compared to the formamide. The variations in E-int are addressed using the MESP parameters?V-n(NH) and ?V-n(CO) and proposed the hypothesis that a positive ?V-n(NH) enhances NH horizontal ellipsis O-w interaction while a negative ?V-n(CO) enhances the CO horizontal ellipsis H-w interaction. The hypothesis is proved by expressing E-int jointly as ?V-n(NH) and ?V-n(CO) and also verified for twenty FDA approved drugs. The predicted E-int for the drugs using ?V-n(NH) and ?V-n(CO) agreed well with the calculated E-int. 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.