Back to the Future: Can physical models of passive membrane permeability help reduce drug candidate attrition and move us beyond QSPR?
ABSTRACT It is widely recognized that ADMET (Adsorption, Distribution, Metabolism, Excretion - Toxicology) liabilities kill the majority of drug candidates that progress to clinical trials. The development of computational models to predict small molecule membrane permeability is therefore of considerable scientific and public health interest. Empirical qualitative structure permeability relationship (QSPR) models of permeability have been a mainstay in industrial applications, but lack a deep understanding of the underlying biological physics. Others and we have shown that implicit solvent models to predict passive permeability for small molecules exhibit mediocre predictive performance when validated across experimental test sets. Given the vast increase in computer power, more efficient parallelization schemes, and extension of current atomistic simulation codes to general use graphical processing units (GPUs), the development and application of physical models based on all-atom simulations may now be feasible. Preliminary results from rigorous free energy calculations using all-atom simulations indicate that performance relative to implicit solvent models may be improved, but many outstanding questions remain. Here we review the current state of the art physical models for passive membrane permeability prediction, and present a prospective look at promising new directions for all-atom approaches. © 2012 John Wiley & Sons A/S.
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ABSTRACT: Transient receptor potential vanilloid subtype 1 (TRPV1) is a heat-sensitive ion channel also involved in pain sensation, and is the receptor for capsaicin, the active ingredient of hot chili peppers. The recent structures of TRPV1 revealed putative ligand density within the S1 to S4 voltage-sensor-like domain of the protein. However, questions remain regarding the dynamic role of the lipid bilayer in ligand binding to TRPV1. Molecular dynamics simulations were used to explore behavior of capsaicin in a 1-palmitoyl-2-oleoyl phosphatidylcholine bilayer and with the target S1-S4 transmembrane helices of TRPV1. Equilibrium simulations reveal a preferred interfacial localization for capsaicin. We also observed a capsaicin molecule flipping from the extracellular to the intracellular leaflet, and subsequently able to access the intracellular TRPV1 binding site. Calculation of the potential of mean force (i.e., free energy profile) of capsaicin along the bilayer normal confirms that it prefers an interfacial localization. The free energy profile indicates that there is a nontrivial but surmountable barrier to the flipping of capsaicin between opposing leaflets of the bilayer. Molecular dynamics of the S1-S4 transmembrane helices of the TRPV1 in a lipid bilayer confirm that Y511, known to be crucial to capsaicin binding, has a distribution along the bilayer normal similar to that of the aromatic group of capsaicin. Simulations were conducted of the TRPV1 S1-S4 transmembrane helices in the presence of capsaicin placed in the aqueous phase, in the lipid, or docked to the protein. No stable interaction between ligand and protein was seen for simulations initiated with capsaicin in the bilayer. However, interactions were seen between TRPV1 and capsaicin starting from the cytosolic aqueous phase, and capsaicin remained stable in the majority of simulations from the docked pose. We discuss the significance of capsaicin flipping from the extracellular to the intracellular leaflet and mechanisms of binding site access by capsaicin. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.Biophysical Journal 03/2015; 108(6):1425-34. DOI:10.1016/j.bpj.2015.02.013 · 3.83 Impact Factor
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ABSTRACT: When a range of lipid bilayers are melted to the disordered fluid phase from the (much less permeable) ordered gel phase, their permeability to a variety of permeants shows a peak at the transition temperature and drops off with increasing temperature, rather than just rising as melting proceeds. To explore this anomalous behavior, a simulated coarse-grained lipid membrane model that exhibits a phase transition upon expansion or compression was studied to determine how the permeation rate of a simple particle depends on the phase composition in the two-phase region and on particle size. The permeation rate and each phase's area fraction and area density could be directly calculated, along with the probability that the permeant would cross in either phase or at interfacial regions. For large permeants and system sizes, conditions could be found where permeability increases upon compression of the bilayer. Permeation was negligible in the gel phase and, in contrast to the predictions of the "leaky interface" hypothesis, was not enriched in interfacial regions. The anomalous effect could instead be attributed to an increase in the area per lipid of fluid phase domains. This result motivated a model for the decrease in effective permeability barrier through fluid phase domains arising from a decrease in the length of the gel/fluid interface at the midpoint of a permeation event.Langmuir 01/2015; DOI:10.1021/la504269t · 4.38 Impact Factor
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ABSTRACT: Drug design efforts are turning to a new generation of therapeutic targets, such as protein-protein interactions (PPIs), that had previously been considered "undruggable" by typical small molecules. There is an emerging view that accessing these targets will require molecules that are larger and more complex than typical small molecule drugs. Here, we present a methodology for the discovery of geometrically diverse, membrane permeable cyclic peptide scaffolds based on the synthesis and permeability screening of a combinatorial library, followed by deconvolution of membrane-permeable scaffolds to identify cyclic peptides with good to excellent passive cell permeabilities. We use a combination of experi-mental and computational approaches to investigate structure-permeability relationships in one of these scaffolds, and un-cover structural and conformational factors that govern passive membrane diffusion in a related set of cyclic peptide dia-stereomers. Further, we investigate the dependency of permeability on side chain identity of one of these scaffolds through single-point diversifications to show the adaptability of these scaffolds towards development of permeability-biased librar-ies suitable for bioactivity screens. Overall, our results demonstrate that many novel, cell permeable scaffolds exist beyond those found in extant natural products, and that such scaffolds can be rapidly identified using a combination of synthesis and deconvolution which can, in principle, be applied to any type of macrocyclic template.Journal of the American Chemical Society 12/2014; DOI:10.1021/ja508766b · 11.44 Impact Factor