Conformational flexibility, internal hydrogen bonding, and passive membrane permeability: Successful in silico prediction of the relative permeabilities of cyclic peptides

Department of Chemistry and Biochemistry, University of California at Santa Cruz, Santa Cruz, CA 95064, USA.
Journal of the American Chemical Society (Impact Factor: 11.44). 12/2006; 128(43):14073-80. DOI: 10.1021/ja063076p
Source: PubMed

ABSTRACT We report an atomistic physical model for the passive membrane permeability of cyclic peptides. The computational modeling was performed in advance of the experiments and did not involve the use of "training data". The model explicitly treats the conformational flexibility of the peptides by extensive conformational sampling in low (membrane) and high (water) dielectric environments. The passive membrane permeabilities of 11 cyclic peptides were obtained experimentally using a parallel artificial membrane permeability assay (PAMPA) and showed a linear correlation with the computational results with R(2) = 0.96. In general, the results support the hypothesis, already well established in the literature, that the ability to form internal hydrogen bonds is critical for passive membrane permeability and can be the distinguishing factor among closely related compounds, such as those studied here. However, we have found that the number of internal hydrogen bonds that can form in the membrane and the solvent-exposed polar surface area correlate more poorly with PAMPA permeability than our model, which quantitatively estimates the solvation free energy losses upon moving from high-dielectric water to the low-dielectric interior of a membrane.

1 Follower
  • [Show abstract] [Hide abstract]
    ABSTRACT: Rapid advancements in genomics have brought a better understanding of molecular mechanisms for various pathologies and identified a number of highly attractive target classes. Some of these targets include intracellular protein-protein interactions (PPIs), which control many essential biological pathways. Their surfaces are part of a diverse and unexplored biological space, where traditional small molecule scaffolds are not always successful. While large biologics can effectively modulate PPIs in the extracellular region, their limitation in crossing the cellular membrane leaves intracellular protein targets outside of their reach. There is a growing need in the pharmaceutical field to push the boundaries of traditional drug design and discover innovative molecules that are able to modulate key biological pathways by inhibiting intracellular PPIs. Peptides are one of the most promising classes of molecules that could deliver such therapeutics in the near future. In this review, we describe technological advancements and emerging chemical approaches for stabilizing active peptide conformations, including stapling, hydrogen bond surrogates, beta-hairpin mimetics, grafting on stable scaffolds, and macrocyclization. These design strategies carry the promise of opening the doors for peptide therapeutics to reach the currently "undruggable" space. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
    European Journal of Medicinal Chemistry 01/2015; 94. DOI:10.1016/j.ejmech.2015.01.014 · 3.43 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In the modern age of proteomics, vast numbers of protein-protein interactions (PPIs) are being identified as causative agents in pathogenesis, and are thus attractive therapeutic targets for intervention. Although traditionally regarded unfavorably as druggable agents relative to small molecules, peptides in recent years have gained considerable attention. Their previous dismissal had been largely due to the susceptibility of unmodified peptides to the barriers and pressures exerted by the circulation, immune system, proteases, membranes and other stresses. However, recent advances in high-throughput peptide isolation techniques, as well as a huge variety of direct modification options and approaches to allow targeted delivery, mean that peptides and their mimetics can now be designed to circumvent many of these traditional barriers. As a result, an increasing number of peptide-based drugs are reaching clinical trials and patients beyond.
    Future medicinal chemistry 12/2014; 6(18):2073-2092. DOI:10.4155/fmc.14.134 · 4.00 Impact Factor
  • [Show abstract] [Hide abstract]
    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

Full-text (2 Sources)

Available from
Jun 3, 2014