|dc.description.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 M inhibitors. The computed free-energies of binding were in close accord with those derived from experiment. Binding affinity values for the inhibitors were determined to be dependent upon the stabilization strength of the nonbonded interactions provided towards 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.
OPLS-AA force field parameters have been developed and validated for use in the simulation of 68 unique combinations of room temperature ionic liquids featuring 1-alkyl-3-methylimidazolium [RMIM] (R = Me, Et, Bu, Hex, Oct), N-alkylpyridinium [RPyr], and choline cations, along with Cl-, PF6-, BF4-, NO3-, AlCl4-, Al2Cl7-, TfO-, saccharinate, and acesulfamate anions. The new parameters were fit to conformational profiles from gas-phase ab initio calculations at the LMP2/cc-pVTZ(-f)//HF/6-31G(d) theory level and compared to experimental condensed-phase structural and thermodynamic data. Monte Carlo simulations of the ionic liquids gave relative deviations from experimental densities of ca. 1-3% at 25 C for most combinations and also yielded close agreement over a temperature range of 5 to 90 C. Predicted heats of vaporization compared well with available experimental data and estimates. Transferability of the new parameters to multiple alkyl side chain lengths for [RMIM] and [RPyr] was determined to give excellent agreement with charges and torsion potentials developed specific to desired alkyl lengths in 35 separate ionic liquid simulations. As further validation of the newly developed parameters, the Kemp elimination reaction of benzisoxazole via piperidine in 1-butyl-3-methylimidazolium hexafluorophosphate [BMIM][PF6], and β-elimination of 1,1,1-tribromo-2,2-bis(phenyl-substituted)ethanes in 1-butyl-3-methylimidazolium hexafluorophosphate [BMIM][PF6], and 1-butyl-3-methylimidazolium tetrafluoroborate [BMIM][BF4] with piperidine and pyrrolidine as amines were computed using mixed quantum and molecular mechanics (QM/MM) simulations and found to give close agreement with the experimental free energy of activation for the kemp elimination and overestimated free energies of activation with the experiment for the β-elimination.||en_US