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TL;DR: In this paper, the authors showed that aqueous non-covalent barriers arise from solute-induced perturbation of the H-bond network of solvating water relative to bulk solvent.
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.
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TL;DR: In this article, the structural dynamics of the COVID main protease were derived from the surface composition/topology and solvation field properties for both high and low molecular weight (HMW and LMW) solutes.
Abstract: Cellular functions are executed via a form of analog computing that is based on the switchable covalent and non-covalent states of multi-molecular fluxes (i.e., time-dependent species/state concentrations) operating in the non-linear dynamics regime. We and others have proposed that the non-covalent states and state transitions of aqueous fluxes are powered principally by the storage and release of potential energy to/from the anisotropic H-bond network of solvating water (which we refer to as the "solvation field"), which is a key tenet of a first principles theory on cellular structure and function (called Biodynamics) that we outlined previously. This energy is reflected in water occupancy as a function of solute surface position, which can be probed computationally using WATMD software. In our previous work, we used this approach to deduce the structural dynamics of the COVID main protease, including substrate binding-induced enzyme activation and dimerization, and product release-induced dimer dissociation. Here, we examine: 1) The general relationships between surface composition/topology and solvation field properties for both high and low molecular weight (HMW and LMW) solutes. 2) The general means by which structural dynamics are powered by solvation free energy, which we exemplify via binding between the E3 ligase CUL4A/RBX1/DDB1/CRBN, LMW degraders, and substrates. We propose that degraders organize the substrate binding surface of cereblon toward complementarity with native and neo substrates, thereby speeding the association rate constant and incrementally slowing the dissociation rate constant. 3) Structure-activity relationships (SAR) based on complementarity between the solvation fields of cognate protein-ligand partners exemplified via LMW degraders.
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TL;DR: In this paper , the authors argue that the limit of understanding of cellular function/dysfunction and pharmacology based on empirical principles (observation/inference) has been reached, and that further progress depends on understanding these phenomena at the first principles theoretical level.
Abstract: The poor preclinical and clinical success rates of low molecular weight (LMW) compounds can be partially attributed to the inherent trial-and-error nature of pharmaceutical research, which is limited largely to retrospective data-driven, rather than prospective prediction-driven human relevant workflows stemming from: 1) inadequate scientific understanding of structure-activity, structure-property, and structure-free energy relationships; 2) disconnects between empirical models derived from in vitro equilibrium data (e.g., Hill and Michaelis-Menten models) vis-à-vis the native non-equilibrium cellular setting (where the pertinent metrics consist of rates, rather than equilibrium state distributions); and 3) inadequate understanding of the non-linear dynamic (NLD) basis of cellular function and disease. We argue that the limit of understanding of cellular function/dysfunction and pharmacology based on empirical principles (observation/inference) has been reached, and that further progress depends on understanding these phenomena at the first principles theoretical level. Toward that end, we have been developing and applying a theory (called “Biodynamics”) on the general mechanisms by which: 1) cellular functions are conveyed by dynamic multi-molecular/-ionic (multi-flux) systems operating in the NLD regime; 2) cellular dysfunction results from molecular dysfunction; 3) molecular structure and function are powered by covalent/non-covalent forms of free energy; and 4) cellular dysfunction is corrected pharmacologically. Biodynamics represents a radical departure from the status quo empirical science and reduction to practice thereof, replacing: 1) the interatomic contact model of structure-free energy and structure-property relationships with a solvation free energy model; 2) equilibrium drug-target occupancy models with dynamic models accounting for time-dependent drug and target/off-target binding site buildup and decay; and 3) linear models of molecular structure-function and multi-molecular/-ionic systems conveying cellular function and dysfunction with NLD models that more realistically capture the emergent non-linear behaviors of such systems. Here, we apply our theory to COVID Mpro inhibition and overview its implications for a holistic, in vivo relevant approach to drug design.