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 H₂ O 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 ΔV_n(NH) and ΔV_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 ΔV_n(NH) and ΔV_n(CO) and proposed the hypothesis that a positive ΔV_n(NH) enhances NH…O_w interaction while a negative ΔV_n(CO) enhances the CO…H_w interaction. The hypothesis is proved by expressing E_int jointly as ΔV_n(NH) and ΔV_n(CO) and also verified for twenty FDA approved drugs. The predicted E_int for the drugs using ΔV_n(NH) and ΔV_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.