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

Abstract

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 (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. The Eint of formamide is −10.0 kcal/mol whereas the Eint 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 Eint are addressed using the MESP parameters ΔVn(NH) and ΔVn(CO) and proposed the hypothesis that a positive ΔVn(NH) enhances NH…Ow interaction while a negative ΔVn(CO) enhances the CO…Hw interaction. The hypothesis is proved by expressing Eint jointly as ΔVn(NH) and ΔVn(CO) and also verified for twenty FDA approved drugs. The predicted Eint for the drugs using ΔVn(NH) and ΔVn(CO) agreed well with the calculated Eint. 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.

Quantifying the hydrogen-bond propensity of drugs and its relationship with Lipinski's rule of five

“…In our prior studies, we successfully forecasted hydrogen bond strengths between water and various chemical motifs, utilizing reference molecules representing each motif, selected for their simplicity and appropriateness. 38,42 Fig. 1 shows twenty ring molecules, each incorporating distinct chemical motifs such as CO — HC, CO — HN, N — HC, CN — HN, F — HC, N — OC, Br — HC, S — HC, etc.…”

“…41 Very recently, Haritha and Suresh have conducted quantification of hydrogen bond strength between water and various chemical motifs (OC–NH, FC–CH, OC–CH, N–CO, N–C–NH, N–CH) frequently encountered in rings in drugs, and the findings indicate that variation in the MESP at the nuclei, Δ V n , of interacting atoms within each motif plays a pivotal role in predicting the strength of these hydrogen bond interactions. 38,42 In the ring molecule, the ordered pairs of (Δ V n of heteroatom, Δ V n of H atom) exhibited variations of (+, +), (+, −), (−, +), and (−, −) compared to a reference molecule. The (−, +) MESP behaviour consistently enhanced the (ring)heteroatom⋯H w and O w ⋯H(ring) interactions, while the (+, −) behaviour weakened these interactions.…”

The fundamental nature and importance of electrostatic potential in hydrogen bond formation: a case study of heterocycles frequently observed in drugs

“…19 Recently, Suresh et al studied heterocycles in drugs which contain CO-HN motifs and proposed a theory for predicting HB bond strength using MESP parameters of interacting atoms of the ring system. 56 Graton et al…”