General structure-free energy relationships of hERG blocker binding under native cellular conditions

Abstract

We proposed previously that aqueous non-covalent barriers arise from solute-induced perturbation of the H-bond network of solvating water ('the solvation field') relative to bulk solvent, where the association barrier equates to enthalpic losses incurred from incomplete replacement of the H-bonds of expelled H-bond enriched solvation by inter-partner H-bonds, and the dissociation barrier equates to enthalpic + entropic losses incurred during dissociation-induced resolvation of H-bond depleted positions of the free partners (where dynamic occupancy is powered largely by the expulsion of such solvation to bulk solvent during association). We analyzed blockade of the ether-a-go-go-related gene potassium channel (hERG) based on these principles, the results of which suggest that blockers: 1) project a single rod-shaped R-group (denoted as 'BP') into the pore at a rate proportional to the desolvation cost of BP, with the largely solvated remainder (denoted as 'BC') occupying the cytoplasmic 'antechamber' of hERG; and 2) undergo second-order entry to the antechamber, followed by first-order association of BP to the pore. In this work, we used WATMD to qualitatively survey the solvation fields of the pore and a representative set of 16 blockers sampled from the Redfern dataset of marketed drugs spanning a range of pro-arrhythmicity. We show that the highly non-polar pore is solvated principally by H-bond depleted and bulk-like water (incurring zero desolvation cost), whereas blocker BP moieties are solvated by variable combinations of H-bond enriched and depleted water. With a few explainable exceptions, the blocker solvation fields (and implied desolvation/resolvation costs) are qualitatively well-correlated with blocker potency and Redfern safety classification.

Solvation dynamics-powered structure and function of multi-molecular cellular systems exemplified by non-equilibrium cereblon-degrader-CK1α ternary complex formation

“…Here, we summarize the general learnings from our previous WATMD calculations on COVID M pro4 and LMW hERG blockers, 5 together with cereblon and the degrader drugs studied in this work. Preferences among the sterically-accessible conformational states of a given solute are determined principally by solvation H-bond free energy (versus interatomic energy contributions), which varies spatially across solute surfaces, as follows:…”

“…We have extended our previous work on molecular fluxes, 1,4,5 focusing on the general means by which:…”

“…In our previous work, we applied Biodynamics principles and WATMD software (a first principles method for probing water occupancy across solute surfaces) to qualitatively deduce the solvation free energy-powered non-covalent non-equilibrium intra-and intermolecular state transitions of the COVID main protease (M pro ) and dynamic blockade of the human ether-a-go-go related gene potassium channel (hERG). 4,5 In this work, we:…”

Improving the preclinical and clinical success rates of LMW drugs depends on radical revisions to the status quo scientific foundations of medicinal chemistry: a case study on COVID Mproinhibition

“…The total non-covalent binding free energy can be derived as follows: Gbinding = Ginteratomic solute contacts + (Gsolute H-bond + Gdesolvation) [10] where Gbinding is the total free energy gain, Ginteratomic solute contacts is the interatomic contact free energy contribution, Gdesolvation is the water transfer free energy contribution, and Gsolute H-bond is the intra-or inter-solute H-bond free energy contribution. Caveat 2: Interpretation of structure-activity relationships (the currency of medicinal chemistry) in terms of interatomic contact free energy contributions, the prediction of non-covalent free energy and structure-free energy relationships using force-field based approaches (e.g., molecular dynamics, free energy perturbation, conformational searching, energy minimization), and data modeling approaches (e.g., quantitative structure-activity relationship (QSAR) analysis, docking/scoring, pharmacophore analysis) are subject to grossly overestimated solute and grossly underestimated solvation contributions.…”

“…We proposed that such barriers consist principally of molecular desolvation and resolvation costs, 5,[7][8][9][10][12][13][14][15][16] which was inspired by the pioneering work of McKay and Kurtzman on the microscopic behaviors of solvating water. 3 Our work has led to novel insights about the general mechanisms by which:…”