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ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXT"Delta plots"—A new way to visualize electronic excitationHarry Morrison , William L. Jorgensen , Bernard Bigot , Daniel Severance , Yldefonso Munoz-Sola , Randy Strommen , and Bipin Pandey Cite this: J. Chem. Educ. 1985, 62, 4, 298Publication Date (Print):April 1, 1985Publication History Received3 August 2009Published online1 April 1985Published inissue 1 April 1985https://doi.org/10.1021/ed062p298RIGHTS & PERMISSIONSArticle Views117Altmetric-Citations4LEARN 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 (2 MB) Get e-Alerts Get e-Alerts
Several enetetrayne containing compounds have been synthesized and their chemistry explored vis-a-vis the Bergman cycloaromatization. With one exceptio
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTTheoretical examination of the SN2 reaction involving chloride ion and methyl chloride in the gas phase and aqueous solutionJayaraman Chandrasekhar, Scott F. Smith, and William L. JorgensenCite this: J. Am. Chem. Soc. 1985, 107, 1, 154–163Publication Date (Print):January 1, 1985Publication History Published online1 May 2002Published inissue 1 January 1985https://pubs.acs.org/doi/10.1021/ja00287a028https://doi.org/10.1021/ja00287a028research-articleACS PublicationsRequest reuse permissionsArticle Views1850Altmetric-Citations354LEARN 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-Alertsclose Get e-Alerts
The Janus kinases (JAKs) are key components of the JAK-STAT signaling pathway and are involved in myriad physiological processes. Though they are the molecular targets of many FDA-approved drugs, these drugs manifest adverse effects due in part to their inhibition of the requisite JAK kinase activity. However, the JAKs uniquely possess an integrated pseudokinase domain (JH2) that regulates the adjacent kinase domain (JH1). The therapeutic targeting of JH2 domains has been less thoroughly explored and may present an avenue to modulate the JAKs without the adverse effects associated with targeting the adjacent JH1 domain. The potential of this strategy was recently demonstrated with the FDA approval of the TYK2 JH2 ligand deucravacitinib for treating plaque psoriasis. In this light, the structure and targetability of the JAK pseudokinases are discussed, in conjunction with the state of development of ligands that bind to these domains.
Monte Carlo (MC) simulations in combination with a linear response approach were used to estimate the free energies of binding for a series of 12 TIBO nonnucleoside inhibitors of HIV-1 reverse transcriptase. Separate correlations were made for the R6 and S6 absolute conformations of the inhibitors, as well as for the analogous N6-monoprotonated species. Models based upon the neutral unbound inhibitors produced overall better fits to experimental values than did those using the protonated unbound inhibitors, with only slight differences between the neutral R6 and S6 cases. The best results were obtained with a three-parameter linear response equation containing van der Waals (α), electrostatic (β), and solvent accessible surface area (SASA, γ) terms. The averaged (R6 and S6) rms error was approximately 0.88 kcal/mol for the observed range of 4.06 kcal/mol in inhibitor activities. The averaged values of α, β, and γ were −0.150, 0.114, and 0.0286, respectively. Omission of the α term gave β 0.152 and γ 0.022 with a rms of 0.92. The unweighted van der Waals components were found to be highly attractive but failed to correlate well across the series of inhibitors. Contrastingly, while the electrostatic components are all repulsive, they show a direct correlation with inhibitor activity as measured by ΔGbinding. The role of γ is primarily to produce an overall negative binding energy, and it can effectively be replaced with a negative constant. During the MC simulations of the unbound solvated inhibitors, the R6 and S6 absolute conformations do not interconvert due to the formation of a favorable hydrogen bond to solvent. In the complex, however, interconversion of these conformations of the inhibitor is observed during the course of the simulations, a phenomenon which is apparently not observed in the crystalline state of the complex. Hydrogen bonding of the inhibitor to the backbone NH of K101 and the lack of such an interaction with the CO of K101 or with solvent correlate with enhanced activity, as does the ability to assume a number of different orientations of the inhibitor dimethylallyl moiety with respect to residues Y181 and Y188 while retaining contact with W229. Overall, the use of a combination of MC simulation with a linear response method shows promise as a relatively rapid means of estimating inhibitor activities. This approach should be useful in the preliminary evaluation of potential modifications to known inhibitors to enhance activity.
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTComputer-assisted mechanistic evaluation of organic reactions. 8. General treatment of periselectivityJulia Schmidt Burnier and William L. JorgensenCite this: J. Org. Chem. 1984, 49, 16, 3001–3020Publication Date (Print):August 1, 1984Publication History Published online1 May 2002Published inissue 1 August 1984https://pubs.acs.org/doi/10.1021/jo00190a029https://doi.org/10.1021/jo00190a029research-articleACS PublicationsRequest reuse permissionsArticle Views113Altmetric-Citations16LEARN 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-Alertsclose Get e-Alerts
DFT calculations have been used to develop improved descriptions of the torsional energetics for nucleosides and nucleotides in the OPLS-AA force field. Scans of nucleotide dihedral angles (γ, χ, and β) and methyl phosphates provided the bases for the new torsional parameters. In addition, the angle-bending parameters of phosphodiesters and ribose were updated, and adjustments were made to existing carbohydrate torsions to better capture the sugar puckering landscape of ribose. MD simulations of nucleosides with the new parameters demonstrate a significant improvement in the ribose sugar puckering and χ angle distributions. Additionally, energy-minimization of protein-nucleotide crystal structures with the new parameters produced accurate poses.
