Computational insight into small molecule inhibition of cyclophilins

Somisetti V. Sambasivarao, Orlando Acevedo

Research output: Contribution to journalArticle

9 Citations (Scopus)

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-basedμM 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.

Original languageEnglish (US)
Pages (from-to)475-482
Number of pages8
JournalJournal of Chemical Information and Modeling
Volume51
Issue number2
DOIs
StatePublished - Feb 28 2011
Externally publishedYes

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Cyclophilins
Free energy
Enzymes
Derivatives
energy
Molecules
interaction
stabilization
Peptidylprolyl Isomerase
Peptides
family member
Conservation
cancer
Stabilization
Tuning
conservation
Polytetrafluoroethylene
Sampling
drug
Disease

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)
  • Computer Science Applications
  • Library and Information Sciences

Cite this

Computational insight into small molecule inhibition of cyclophilins. / Sambasivarao, Somisetti V.; Acevedo, Orlando.

In: Journal of Chemical Information and Modeling, Vol. 51, No. 2, 28.02.2011, p. 475-482.

Research output: Contribution to journalArticle

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