Modus Operandi: An Universitäten und in anderen gemeinnützigen Organisationen sind das Interesse an und Aktivitäten in der Wirkstoff-Forschung deutlich gewachsen. Dieser Essay befasst sich mit den Herausforderungen, denen man sich bei Fortschritten in diesem Bereich gegenübersieht. Leitstrukturoptimierung und präklinische Tests werden als wichtige Engpässe identifiziert.
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An efficient procedure is noted for computing absolute free energies of binding for complexes in solution. Two series of computer simulations are required in which the substrate is annihilated in the solvent by itself and in the solvated complex. For illustration, the free energy of binding for two methane-like particles at their contact separation of 4 Å has been computed in TIP4P water. Though several alternatives are possible, in this case, Monte Carlo simulations were employed with statistical perturbation theory in the NPT ensemble at 25 °C and 1 atm. The results for the free energy of binding as well as for the potential of mean force are consistent with prior findings from the integral equation theory of Pratt and Chandler.
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTTheoretical studies of medium effects on conformational equilibriaWilliam L. JorgensenCite this: J. Phys. Chem. 1983, 87, 26, 5304–5314Publication Date (Print):December 1, 1983Publication History Published online1 May 2002Published inissue 1 December 1983https://pubs.acs.org/doi/10.1021/j150644a002https://doi.org/10.1021/j150644a002research-articleACS PublicationsRequest reuse permissionsArticle Views684Altmetric-Citations209LEARN 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 options Get e-Alerts
Monte Carlo statistical mechanics simulations have been carried out for dilute solutions of Na+ in water and tetrahydrofuran (THF) at 25 °C and 1 atm. The intermolecular interactions were described by Lennard-Jones and Coulomb terms in the TIPS format including the TIPS2 parameters for water–water interactions. In conjunction with previous simulation results for Na+ in methanol, the present study provides detailed insights into the nature of ionic solvation by dipolar protic and aprotic solvents. In agreement with x-ray data, the coordination number of Na+ in water is six, identical to the value obtained for Na+ in methanol. However, the coordination number of Na+ in THF fluctuates between five and six. Consistently, the ion–solvent interaction is less exothermic in THF compared to the other two solvents. However, the heat of solution which is the sum of two large opposing contributions, viz., the ion–solvent energy and the solvent reorganization energy, does not differ much for the three solvents. In all three cases, the formation of the first solvation shell accounts for all the solvent structure breaking. In particular, the number of hydrogen bonds formed by water and by methanol beyond the first shell rapidly attains the value in the pure solvent. The computed radial distribution functions and bonding and dimerization energy distributions provide additional support for this analysis.
An empirical modified boundary potential has been derived to correct the structural perturbations arising from the presence of the vacuum boundary in the simulation of spherical TIP4P water systems. The potential is parameterized for a 12.0‐Å sphere of TIP4P water and gives improved number density and orientational sampling behavior. It is also transferable to both larger and smaller simulation systems with only a moderate degradation in performance. Free‐energy calculations have been conducted for the perturbation of a TIP4P water molecule to methane under aqueous conditions, and the modified boundary potential gives results consistent with those from simulations using periodic boundary conditions. However, simple half‐harmonic boundary potentials give unsatisfactory number density, orientational sampling, and free‐energy results. Moreover, use of the modified boundary potential results in a negligible increase in simulation time. It is envisaged that the modified boundary potential will find use in free‐energy perturbation calculations on proteins with a solvent sphere centered on the active site. © 1995 by John Wiley & Sons, Inc.
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ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTQuantum and statistical mechanical studies of liquids. 3. Deriving intermolecular potential functions for the water dimer from ab initio calculationsWilliam L. JorgensenCite this: J. Am. Chem. Soc. 1979, 101, 8, 2011–2016Publication Date (Print):April 1, 1979Publication History Published online1 May 2002Published inissue 1 April 1979https://pubs.acs.org/doi/10.1021/ja00502a014https://doi.org/10.1021/ja00502a014research-articleACS PublicationsRequest reuse permissionsArticle Views303Altmetric-Citations62LEARN 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
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ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTQuantum and statistical mechanical studies of liquids. 10. Transferable intermolecular potential functions for water, alcohols, and ethers. Application to liquid waterWilliam L. JorgensenCite this: J. Am. Chem. Soc. 1981, 103, 2, 335–340Publication Date (Print):January 1, 1981Publication History Published online1 May 2002Published inissue 1 January 1981https://pubs.acs.org/doi/10.1021/ja00392a016https://doi.org/10.1021/ja00392a016research-articleACS PublicationsRequest reuse permissionsArticle Views3920Altmetric-Citations1079LEARN 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
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTEnergy Difference between the Classical and the Nonclassical 2-Norbornyl Cation in Solution. A Combined ab Initio-Monte Carlo Aqueous Solution StudyPeter R. Schreiner, Daniel L. Severance, William L. Jorgensen, Paul von Schleyer, and Henry F. Schaefer IIICite this: J. Am. Chem. Soc. 1995, 117, 9, 2663–2664Publication Date (Print):March 1, 1995Publication History Published online1 May 2002Published inissue 1 March 1995https://pubs.acs.org/doi/10.1021/ja00114a037https://doi.org/10.1021/ja00114a037research-articleACS PublicationsRequest reuse permissionsArticle Views203Altmetric-Citations44LEARN 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
Modus operandi: There is increased interest and activity in drug discovery at universities and other non-profit organizations. The essay addresses challenges associated with progress in this area. Lead optimization and preclinical testing are identified as key bottlenecks.
