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 (Eint ) 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 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.

Quantum chemical studies on the binding domain of SARS-CoV-2 S-protein: human ACE2 interface complex.

A two-layer ONIOM(B3LYP/6-31G*:PM7) method is used to model the binding of several drug/drug-like molecules (L) at the SARS-CoV-2 S-protein: human ACE2 protein interface cavity. The selected molecules include a set of thirty-five ligands from the study of Smith and Smith which showed a high docking score in the range of -7.0 to -7.7 kcal/mol and another set of seven repurposing drugs, viz. favipiravir, remdesivir, EIDD, galidesivir, triazavirin, ruxolitinib, and baricitinib. The ONIOM model of the cavity (M) showed a highly polarized electron distribution along its top-to-bottom direction while Ls with lengths in the range 1.0 - 1.5 nm fitted well inside the cavity in a head-to-tail fashion to yield ML complexes. The ligands showed a large variation in the ONIOM-level binding energy (Eb), in the range -2.7 to -85.4 kcal/mol. The Eb of ML complexes better than -40.0 kcal/mol is observed for myricetin, fidarestat, protirelin, m-digallic acid, glucogallin, benserazide hydrochlorideseradie, remdesivir, tazobactum, sapropterin, nitrofurantoin, quinonoid, pyruvic acid calcium isoniazid, and aspartame, and among them the highest Eb -85.4 kcal/mol is observed for myricetin. A hydroxy substitution is suggested for the phenyl ring of aspartame to improve its binding behavior at the cavity, and the resulting ligand 43 showed the best Eb -84.5 kcal/mol. The ONIOM-level study is found to be effective for the interpretation of the noncovalent interactions resulting from residues such as arginine, histidine, tyrosine, lysine, carboxylate, and amide moieties in the active site and suggests rational design strategies for COVID-19 drug development.Communicated by Ramaswamy H. Sarma.

Hydration patterns of rings in drugs and relationship to lipophilicity: A DFT study.

Rings are one of the major scaffold components of drugs in medicinal chemistry, due to their unique electronic distribution, scaffold rigidity, and three-dimensionality while lipophilicity is considered as a vital parameter of rings that can influence the reactivity, metabolic stability, and toxicity. We have analyzed the electronic features, hydration patterns, solvation effect and lipophilicity data for 51 most widely used ring systems in drugs. Molecular electrostatic potential (MESP) topology analysis has been used to assess the electronic distribution in rings which provided an easy interpretation of the most suitable hydration patterns of the ring with H2 O molecule. Further, the global minimum of ring…H2 O complex has been utilized to predict lipophilicity (logP) with the incorporation of implicit solvation effect. Classification of ring systems based on their molecular weight into four categories, viz. small ring 'sr', medium ring 'mr', large ring 'lr' and extra large ring 'xlr' systems has led to the finding of strong correlations between logP and hydration energy with R = 0.942, 0.933, 0.968 and 0.933, respectively. The micro solvation model is found to be useful for locating the hydrophobic-hydrophilic border for each category of rings in terms of hydration energy whereas the implicit solvation model used for two solvents, n-octanol and water on the most stable hydrated structure led to a global correlation between logP and solvation energy ratio. This correlation predicts a limiting logP value -7.03 for the most hydrophilic ring system and also suggests a clear partitioning of the ring molecules into hydrophobic and hydrophilic classes. The MESP topology-guided approach to understand the electronic features and hydration patterns of rings in drugs lead to powerful predictions on their lipophilicity behavior.