Journal ArticleDOI
Testing the conformational hypothesis of passive membrane permeability using synthetic cyclic peptide diastereomers.
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TLDR
Results of solution NMR studies and hydrogen/deuterium (H/D) exchange experiments showed that membrane diffusion rates correlated with the degree of intramolecular hydrogen bonding and H/D exchange rates.Abstract:
Little is known about the effect of conformation on passive membrane diffusion rates in small molecules. Evidence suggests that intramolecular hydrogen bonding may play a role by reducing the energetic cost of desolvating hydrogen bond donors, especially amide N−H groups. We set out to test this hypothesis by investigating the passive membrane diffusion characteristics of a series of cyclic peptide diastereomers based on the sequence cyclo[Leu-Leu-Leu-Leu-Pro-Tyr]. We identified two cyclic hexapeptide diastereomers based on this sequence, whose membrane diffusion rates differed by nearly two log units. Results of solution NMR studies and hydrogen/deuterium (H/D) exchange experiments showed that membrane diffusion rates correlated with the degree of intramolecular hydrogen bonding and H/D exchange rates. The most permeable diastereomer, cyclo[d-Leu-d-Leu-Leu-d-Leu-Pro-Tyr] (1), exhibited a passive membrane diffusion rate comparable to that of the orally available drug cyclosporine A.read more
Citations
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The exploration of macrocycles for drug discovery--an underexploited structural class.
TL;DR: This Review describes the growing body of data in favour of macrocyclic therapeutics, and demonstrates that this class of compounds can be both fully drug-like in its properties and readily prepared owing to recent advances in synthetic medicinal chemistry.
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Oral Druggable Space beyond the Rule of 5: Insights from Drugs and Clinical Candidates
TL;DR: This work comprehensively analyzed drugs and clinical candidates with molecular weight (MW) > 500 Da and concluded that oral drugs are found far from the Ro5 and properties such as intramolecular hydrogen bonding, macrocyclization, dosage, and formulations can be used to improve bRo5 bioavailability.
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Multifaceted roles of disulfide bonds. Peptides as therapeutics.
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Concepts of Artificial Intelligence for Computer-Assisted Drug Discovery
TL;DR: The current state-of-the art of AI-assisted pharmaceutical discovery is discussed, including applications in structure- and ligand-based virtual screening, de novo drug design, physicochemical and pharmacokinetic property prediction, drug repurposing, and related aspects.
Journal ArticleDOI
Strategic approaches to optimizing peptide ADME properties.
TL;DR: In vivo, in vitro, and in silico tools are available to evaluate ADME properties of peptides, and structural modification strategies are in place to improve peptide developability.
References
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Journal ArticleDOI
Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings
TL;DR: Experimental and computational approaches to estimate solubility and permeability in discovery and development settings are described in this article, where the rule of 5 is used to predict poor absorption or permeability when there are more than 5 H-bond donors, 10 Hbond acceptors, and the calculated Log P (CLogP) is greater than 5 (or MlogP > 415).
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The mechanism of action of cyclosporin A and FK506
TL;DR: Recent findings that indicate CsA and FK506 operate as prodrugs are reviewed: they bind endogenous intracellular receptors, the immunophilins, and the resulting complex targets the protein phosphatase, calcineurin, to exert the immunosuppressive effect.
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Physicochemical high throughput screening : parallel artificial membrane permeation assay in the description of passive absorption processes
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Emerging approaches in the molecular design of receptor-selective peptide ligands: conformational, topographical and dynamic considerations.
TL;DR: Some of the more useful approaches to the design of peptide ligands with highly potent and specific biological and conformational properties are summarized, and the future development in this area is assessed.
Journal ArticleDOI
Conformation of β-hairpins in protein structures: A systematic classification with applications to modelling by homology, electron density fitting and protein engineering
TL;DR: A systematic classification of beta-hairpin structures which takes into account the polypeptide chain length and hydrogen bonding between the two antiparallel beta-strands is described and can be applied to comparative model building, modelling into electron density and in the prediction of conformation of Beta-hairpins to aid protein engineering.
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