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• W2015871138 abstract "Cyclophilins (Cyp) are a family of cellular enzymes possessing peptidyl-prolyl isomerase activity, which catalyze the cis−trans interconversion of proline-containing peptide bonds. The two most abundant family members, CypA and CypB, have been identified as valid drug targets for a wide range of diseases, including HCV, HIV, and multiple cancers. However, the development of small molecule inhibitors that possess nM potency and high specificity for a particular Cyp is difficult given the complete conservation of all active site residues between the enzymes. Monte Carlo statistical sampling coupled to free energy perturbation theory (MC/FEP) calculations have been carried out to elucidate the origin of the experimentally observed nM inhibition of CypA by acylurea-based derivatives and the >200-fold in vitro selectivity between CypA and CypB from aryl 1-indanylketone-based μM inhibitors. The computed free-energies of binding were in close accord with those derived from experiments. Binding affinity values for the inhibitors were determined to be dependent upon the stabilization strength of the nonbonded interactions provided toward two catalytic residues: Arg55 and Asn102 in CypA and the analogous Arg63 and Asn110 residues in CypB. Fine-tuning of the hydrophobic interactions allowed for enhanced potency among derivatives. The aryl 1-indanylketones are predicted to differentiate between the cyclophilins by using distinct binding motifs that exploit subtle differences in the active site arrangements. Ideas for the development of new selective compounds with the potential for advancement to low-nanomolar inhibition are presented." @default.
• W2015871138 created "2016-06-24" @default.
• W2015871138 creator A5053870181 @default.
• W2015871138 creator A5068966234 @default.
• W2015871138 date "2010-12-31" @default.
• W2015871138 modified "2023-10-18" @default.
• W2015871138 title "Computational Insight into Small Molecule Inhibition of Cyclophilins" @default.
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• W2015871138 doi "https://doi.org/10.1021/ci1004114" @default.
• W2015871138 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/21194235" @default.
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