The binding and solution-phase properties of six inhibitors of FK506 binding protein (FKBP12) were investigated using free energy perturbation techniques in Monte Carlo statistical mechanics simulations. These nonimmunosuppressive molecules are of current interest for their neurotrophic activity when bound to FKBP12 as well as for their potential as building blocks for chemical inducers of protein dimerization. Relative binding affinities were computed and analyzed for ligands differing by a phenyl ring, an external phenyl or pyridyl substituent, and a pipecolyl or prolyl ring. Such results are, in general, valuable for inhibitor optimization and, in the present case, bring into question some of the previously reported binding data.
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A comparison between Miertus–Scrocco–Tomasi (MST) SCRF and free energy perturbation (FEP) estimates of the free energy of hydration of eight small neutral molecules is presented. In both cases, the 6‐31G* molecular electrostatic potential is used to describe the electrostatic properties of the molecules. The results demonstrate the ability of both methodologies to provide useful theoretical estimates of the total free energy of hydration; the average errors are only 1.5 kcal/mol (FEP) and 0.8 kcal/mol (MST/SCRF). The largest errors in the FEP and MST/SCRF results are less than 1.5 kcal/mol for all molecules except acetic acid, where the FEP method overestimates the free energy of hydration by 3.3 kcal/mol. © John Wiley & Sons, Inc.
No abstract is provided for this article.
The origins of binding affinity and COX-2/COX-1 selectivity for analogues of celecoxib have been explored using an approach that combines docking with Monte Carlo (MC) simulations. These inhibitors are COX-2-selective nonsteroidal antiinflammatory drugs (NSAIDs) that are of current interest because the gastrointestinal irritation they cause is reduced compared to that caused by traditional NSAIDs. We report a novel docking method, based on a combined Tabu and Monte Carlo protocol, that determines starting conformations for MC simulations. Using the docking-predicted starting conformations, relative changes in binding free energies were computed for methyl, ethyl, hydroxymethyl, hydroxyl, thiomethyl, methoxy, trifluoromethyl, chloro, fluoro, and unsubstituted derivatives with the MC free energy perturbation (FEP) method. The computed free energies are in good accord with IC50 values, and the structural information from the simulations can be used to explain the experimentally observed binding trends. In addition, the docking and FEP results have provided clarification of the binding conformation of the phenylsulfonamide moiety and the origin of COX-2/COX-1 selectivity. Namely, the COX-2 Val → COX-1 Ile subtitution is accompanied by an unfavorable conformational shift of the phenylsulfonamide ring.
The cation-olefin addition of 2-methyl-2-propyl cation and 2-methylpropene has been investigated in the gas phase and in solution with ab initio calculations and Monte Carlo statistical mechanics simulations. The reaction is exothermic by ca. 20 kcal/mol and proceeds without activation energy in the gas phase. However, solvation introduces a 3-4 kcal/mol barrier at a C-C separation near 5 Å in methylene chloride, THF, and methanol. An intermediate in a shallow energy well is found near 3-Å separation. Implications for sterol biosynthesis are discussed.
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTPULSAR: a personalized microcomputer-based system for keyword search and retrieval of literature informationScott F. Smith, William L. Jorgensen, and Philip L. FuchsCite this: J. Chem. Inf. Comput. Sci. 1981, 21, 4, 209–213Publication Date (Print):November 1, 1981Publication History Published online1 May 2002Published inissue 1 November 1981https://doi.org/10.1021/ci00032a006RIGHTS & PERMISSIONSArticle Views38Altmetric-Citations2LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (568 KB) Get e-Alerts
Non-nucleoside reverse transcriptase inhibitors (NNRTIs) that interfere with the replication of human immunodeficiency virus (HIV) are being pursued with guidance from molecular modeling including free-energy perturbation (FEP) calculations for protein-inhibitor binding affinities. The previously reported pyrimidinylphenylamine 1 and its chloro analogue 2 are potent anti-HIV agents; they inhibit replication of wild-type HIV-1 in infected human T-cells with EC(50) values of 2 and 10 nM, respectively. However, they show no activity against viral strains containing the Tyr181Cys (Y181C) mutation in HIV-RT. Modeling indicates that the problem is likely associated with extensive interaction between the dimethylallyloxy substituent and Tyr181. As an alternative, a phenoxy group is computed to be oriented in a manner diminishing the contact with Tyr181. However, this replacement leads to a roughly 1000-fold loss of activity for 3 (2.5 μM). The present report details the efficient, computationally driven evolution of 3 to novel NNRTIs with sub-10 nM potency toward both wild-type HIV-1 and Y181C-containing variants. The critical contributors were FEP substituent scans for the phenoxy and pyrimidine rings and recognition of potential benefits of addition of a cyanovinyl group to the phenoxy ring.
The Thorpe−Ingold hypothesis for the gem-dimethyl effect in the cyclization reactions of 2-chloroethoxide derivatives has been investigated computationally in the gas phase and in aqueous solution. Ab initio MP2/6-311+G(d,p) and CBS-Q calculations reveal little intrinsic difference in reactivity with increasing α-methylation for the series of reactants 1−3. However, inclusion of continuum hydration or of explicit hydration through mixed quantum and statistical mechanics (MC/FEP) simulations does reproduce the substantial, experimentally observed rate increases with increasing α-methylation. Analysis of the MC/FEP results provides clear evidence that the rate increases stem primarily from increased steric hindrance to hydration of the nucleophilic oxygen atom with increasing α-methylation. Thus, the gem-dimethyl acceleration of oxirane formation for 1−3 is found to be predominantly a solvent effect.
No abstract is provided for this article.
Es werden die π‐Orbital‐Wechselwirkungen zwischen den kleinen Ringen und den Äthylen‐ bzw. Butadienbrücken z.B. für Dewarbenzol und Benzvalen bzw. für 2,3‐Dimethylen‐bicyclo[2.
The recently developed Charge Model 5 (CM5) is tested for its utility in condensed-phase simulations. The CM5 approach, which derives partial atomic charges from Hirshfeld population analyses, provides excellent results for gas-phase dipole moments and is applicable to all elements of the periodic table. Herein, the adequacy of scaled CM5 charges for use in modeling aqueous solutions has been evaluated by computing free energies of hydration (Δ
Monte Carlo simulations have been performed on a series of 20 active-site-directed thrombin inhibitors to determine the interactions and energetics associated with the binding of these compounds. Physicochemical descriptors of potential value in the prediction of binding affinities were averaged during simulations of each inhibitor unbound in water and bound to thrombin. Regression equations based on 3-5 descriptors are able to reproduce the experimental binding affinities, which cover a 7 kcal/mol range, with rms errors of 1.0-1.3 kcal/mol, and yield correlation coefficients, r(2), of 0.7-0.8. On the basis of these results, the quantities most important in determining the binding affinities are: (1) the enhancement of van der Waals interactions in going from solution to the bound state, (2) the intramolecular strain induced in the inhibitor upon binding, (3) the number of hydrogen bonds lost in the binding process, and (4) the number of rotatable bonds in the inhibitor. The descriptors are physically reasonable and, in combination with the insights gained from analysis of the simulation structures, suggest directions for the development of improved thrombin inhibitors.
