Changes in free energy, enthalpy, and entropy for transfer of a solute from the gas phase into solution are computed using Monte Carlo simulations in direct and van't Hoff approaches.
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Fatty acid amide hydrolase (FAAH) is a serine hydrolase responsible for the degradation of anandamide, an endogenous cannabinoid agonist, and oleamide, a sleep-inducing lipid. Recently, Boger and co-workers reported a potent, selective, and efficacious class of reversible α-ketoheterocycle inhibitors of FAAH that produce analgesia in animal models (J. Med. Chem. 2005, 48, 1849−1856; Bioorg. Med. Chem. Lett. 2005, 15, 1423−1428). Key aspects of the structure−activity data are addressed here through computational analysis of FAAH inhibition using Monte Carlo (MC) simulations in conjunction with free energy perturbation (FEP) calculations. The MC/FEP simulations demonstrate that incorporation of pyridine at the C5 position of the 2-keto-oxazole and 2-keto-1,3,4-oxadiazole derivatives significantly enhances binding affinity by formation of a hydrogen-bonded array between the pyridyl nitrogen and Lys142 and Thr236. The results also attribute the activity boost upon substitution of oxazole by oxadiazole to reduced steric interactions in the active site and a lower torsional energy penalty upon binding.
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The semi-empirical molecular orbital method MINDO/3 was used to investigate the potential energy surface describing the loss of H2 from the allyl cation C3H5 +. The two lowest energy processes found are the 1,2- and 1,3-eliminations and they commence by 2 → 1 and 3 → 1 hydrogen atom migrations, respectively. In the 1,2-elimination this involves isomerization to the 2-propenyl ion while in the 1,3-elimination, isomerization is to an intermediate corner-protonated cyclopropene. The reactions then proceed by H2 elimination from the 2-propenyl ion and from protonated cyclopropene to yield the propargyl and cyclopropenyl ions, respectively. The results of the calculations are compared to previous experimental studies on metastable ions to examine the partitioning of reverse activation energy between kinetic energy of separation, and internal vibrational energy. In making such a comparison, the limitations of MINDO/3, in particular the overestimation of the stability of small ring compounds, are recognized. It is found that the reverse activation energy appears predominantly in the released kinetic energy, for both reactions. Such findings are in accord with qualitative expectations based on reaction dynamics and are discussed in relation to them. In particular, the activated complexes for both the 1,2- and 1,3-eliminations are “tight” and the potential energy surfaces are of the “repulsive” type for which it is predicted that a high percentage of the reverse activation energy will be partitioned as kinetic energy. The activated complexes are well described as species in which the daughter ion is solvated by the H2 leaving. The incipient products are close to their equilibrium geometries, which is in accord with the observation that energy is partitioned predominantly into translation.
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTComputer-assisted mechanistic evaluation of organic reactions. 20. Ene and retro-ene chemistryGenevieve D. Paderes and William L. JorgensenCite this: J. Org. Chem. 1992, 57, 6, 1904–1916Publication Date (Print):March 1, 1992Publication History Published online1 May 2002Published inissue 1 March 1992https://doi.org/10.1021/jo00032a054Request reuse permissionsArticle Views601Altmetric-Citations42LEARN 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 (1 MB) Get e-Alertsclose Get e-Alerts
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ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTStructure and Binding for Complexes of Rebek's Acridine Diacid with Pyrazine, Quinoxaline, and Pyridine from Monte Carlo Simulations with an All-Atom Force FieldErin M. Duffy and William L. JorgensenCite this: J. Am. Chem. Soc. 1994, 116, 14, 6337–6343Publication Date (Print):July 1, 1994Publication History Published online1 May 2002Published inissue 1 July 1994https://pubs.acs.org/doi/10.1021/ja00093a038https://doi.org/10.1021/ja00093a038research-articleACS PublicationsRequest reuse permissionsArticle Views198Altmetric-Citations18LEARN 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 InRedditEmail Other access optionsGet e-AlertscloseSupporting Info (2)»Supporting Information Supporting Information Get e-Alerts
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ADVERTISEMENT RETURN TO ISSUEEditorialNEXTA Reflection on Paul von Ragué SchleyerWilliam L. Jorgensen*View Author Information Department of Chemistry, Yale University, New Haven, Connecticut 06520-8107, United States*E-mail: [email protected]Cite this: J. Chem. Theory Comput. 2015, 11, 1, 1Publication Date (Web):December 8, 2014Publication History Published online11 December 2014Published inissue 13 January 2015https://pubs.acs.org/doi/10.1021/ct501095whttps://doi.org/10.1021/ct501095weditorialACS PublicationsCopyright © 2014 American Chemical Society. This publication is available under these Terms of Use. Request reuse permissions This publication is free to access through this site. Learn MoreArticle Views890Altmetric-Citations1LEARN 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 InRedditEmail PDF (112 KB) Get e-AlertscloseSUBJECTS:Aromatic compounds,Cations,Computational chemistry,Hydrocarbons,Rearrangement Get e-Alerts
