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

Abstract

We define V_n as the molecular electrostatic potential (MESP) at the nucleus of a free atom, calculated excluding the contribution of that nucleus charge. The V_n value at the nucleus of a free atom and that within the atom-in-molecule state show substantial difference (ΔV_n) due to alterations in the electronic configuration of the atom resulting from molecular bonding. Thus, variations in molecular structure and bonding lead to differing ΔV_n values for the same type of atoms in molecules. The V_n analysis focuses on frequently occurring ring structures in drugs and several drug molecules using density functional theory (DFT) at the M06L/6-311++G(d,p) level. The summation of ΔV_n for all heteroatoms acting as hydrogen bond acceptors (HBA) yields ΣΔV_n(A), while ΣΔV_n(H) represents the cumulative sum of ΔV_n for hydrogen atoms participating in hydrogen bond donors (HBD) and those in C–H bonds near heteroatoms. The total hydrogen bond propensity of a drug molecule (E_HBP) is predicted by E_HBP = 0.05 (ΣΔV_n(A) − ΣΔV_n(H)) − 7.68n. This equation is derived using interaction energy (ΣE_int) calculations for ‘n’ configurations of twenty ring molecule⋯H₂O complexes. The E_HBP and ΣE_int showed a strong linear relationship with R = 0.974. Further, the E_HBP equation is validated using the ΣE_int data of FDA-approved oral drugs. The E_HBP prediction, solely based on MESP data, ranges from −2.3 to −131.5 kcal mol⁻¹ for 193 FDA-approved oral drugs. Most orally administered drugs adhering to Lipinski's rule of five criteria typically fall within the E_HBP range of −16.0 to −84.0 kcal mol⁻¹. The study also derived a relationship between E_HBP and Lipinski's rule of five (Ro5) parameters by incorporating a new parameter that accounts for hydrogen atoms participating in O_w⋯H interactions from CH groups. This research presents a robust MESP-based approach for predicting hydrogen bond propensity in drug molecules, complementing drug design and optimization efforts. The correlation with Lipinski's rule of five parameters underscores the importance of hydrogen bond interactions in drug-likeness.