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

Abstract

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 H2O molecule. Further, the global minimum of ring…H2O 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.

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

“…In our previous study, we have introduced the notations 5r, 6r, 65r, 56r, 66r, 665r, 5r-6r, 5r ^À5r, 65r ^66r, 5r$56r, 5r-566r, 6r-66r, and 6r ^66r for a better understanding of the common structural moieties and ring-linker patterns present in drug molecules. 56 Here, 5r and 6r represent 5-membered and 6-membered rings, respectively.…”

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

“…54,55 MESP has previously been used in our work to determine the precise sites of maximal HB energies and to establish a relationship between the lipophilicity and HB interaction energies of ring⋯H 2 O complexes. 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 theoretically studied the HB accepting properties of new heteroaromatic ring chemical motifs and established a relation between the HB accepting ability p K BHX and monomer based quantum descriptor, and the local minimum in the electrostatic potential on the H-bond accepting site, V min .…”

“…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 theoretically studied the HB accepting properties of new heteroaromatic ring chemical motifs and established a relation between the HB accepting ability p K BHX and monomer based quantum descriptor, and the local minimum in the electrostatic potential on the H-bond accepting site, V min . 57 Kenny derived an electrostatic descriptor V α ( r ), defined as an electrostatic potential at a distance r from the donor hydrogen on an axis defined by the nuclei of the hydrogen atom and the atom to which it is bonded, which is capable of predicting the HB acidity.…”

Molecular electrostatic potential and volume-aided drug design based on the isoindolinone-containing cyclopeptide S-PK6

“…Molecular electrostatic potentials have been extensively used in pharmacology to identify characteristic patterns of positive and negative potentials that affect particular types of biological activities. [1][2][3] Electrostatic complementarity and shape complementarity have been recognized as important tools for improving the affinity of molecules against a specific target due to their important role in protein-protein interactions (PPIs). 4,5 Generally, PPI involves two or more proteins binding together to carry out their biological functions.…”