The Kemp decarboxylation reaction for benzisoxazole-3-carboxylic acid derivatives has been investigated using QM/MM calculations in protic and dipolar aprotic solvents. Aprotic solvents have been shown to accelerate the rates of reaction by 7−8 orders of magnitude over water; however, the inclusion of an internal hydrogen bond effectively inhibits the reaction with near solvent independence. The effects of solvation and intramolecular hydrogen bonding on the reactants, transition structures, and the rate of reaction are elucidated using two-dimensional potentials of mean force (PMF) derived from free energy perturbation calculations in Monte Carlo simulations (MC/FEP). Free energies of activation in six solvents have been computed to be in close agreement with experiment. Solute−solvent interaction energies show that poorer solvation of the reactant anion in the dipolar aprotic solvents is primarily responsible for the observed rate enhancements over protic media. In addition, a discrepancy for the experimental rate in chloroform has been studied in detail with the conclusion that ion-pairing between the reactant anion and tetramethylguanidinium counterion is responsible for the anomalously slow reaction rate. The overall quantitative success of the computations supports the present QM/MM/MC approach, which features PDDG/PM3 as the QM method.
Extensive testing of the SCC-DFTB method has been performed, permitting direct comparison to data available for NDDO-based semiempirical methods. For 34 diverse isomerizations of neutral molecules containing the elements C, H, N, and O, the mean absolute errors (MAE) for the enthalpy changes are 2.7, 3.2, 5.0, 5.1, and 7.2 kcal/mol from PDDG/PM3, B3LYP/6-31G(d), PM3, SCC-DFTB, and AM1, respectively. A more comprehensive test was then performed by computing heats of formation for 622 neutral, closed-shell H, C, N, and O-containing molecules; the MAE of 5.8 kcal/mol for SCC-DFTB is intermediate between AM1 (6.8 kcal/mol) and PM3 (4.4 kcal/mol) and significantly higher than for PDDG/PM3 (3.2 kcal/mol). Similarly, SCC-DFTB is found to be less accurate for heats of formation of ions and radicals; however, it is more accurate for conformational energetics and intermolecular interaction energies, though none of the methods perform well for hydrogen bonds with strengths under ca. 7 kcal/mol. SCC-DFTB and the NDDO methods all reproduce MP2/cc-pVTZ molecular geometries with average errors for bond lengths, bond angles, and dihedral angles of only ca. 0.01 A, 1.5 degrees , and 3 degrees . Testing was also carried out for sulfur containing molecules; SCC-DFTB currently yields much less accurate heats of formation in this case than the NDDO-based methods due to the over-stabilization of molecules containing an SO bond.
The PDDG/PM3 semiempirical molecular orbital method has been parameterized for molecules, ions, and complexes containing sulfur; the mean absolute error (MAE) for heats of formation, DeltaH(f), of 6.4 kcal/mol is 35 - 40 % smaller than for PM3, AM1, and MNDO/d. For completeness, parameterization was also carried out for silicon and phosphorous. For 144 silicon-containing molecules, the DeltaH(f) MAE for PDDG/PM3, PM3, and AM1 is 11 - 12 kcal/mol, while MNDO/d yields 9.4 kcal/mol. For the limited set of 43 phosphorus-containing molecules, MNDO/d also yields the best results followed by PDDG/PM3, AM1, and PM3. The benefits of the d-orbitals in MNDO/d for hypervalent compounds are apparent for silicon and phosphorous, while they are masked in the larger dataset for sulfur by large errors for branched compounds. Overall, for 1480 molecules, ions, and complexes containing the elements H, C, N, O, F, Si, P, S, Cl, Br, and I, the MAEs in kcal/mol for DeltaH(f) are 6.5 (PDDG/PM3), 8.7 (PM3), 10.3 (MNDO/d), 10.8 (AM1), and 19.8 (MNDO).
ADVERTISEMENT RETURN TO ISSUEEditorialNEXTIntroducing the Journal of Chemical Theory and ComputationWilliam L. JorgensenView Author Information EditorCite this: J. Chem. Theory Comput. 2005, 1, 1, 1Publication Date (Web):October 21, 2004Publication History Published online21 October 2004Published inissue 1 January 2005https://pubs.acs.org/doi/10.1021/ct040003shttps://doi.org/10.1021/ct040003seditorialACS PublicationsCopyright © 2005 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 Views1612Altmetric-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 (8 KB) Get e-AlertscloseSUBJECTS:Ab initio molecular dynamics,Solvation dynamics,Surface science Get e-Alerts
Structure-based (SBDD) and ligand-based (LBDD) drug design are extremely important and active areas of research in both the academic and commercial realms. This book provides a complete snapshot of the field of computer-aided drug design and associated experimental approaches. Topics covered include X-ray crystallography, NMR, fragment-based drug design, free energy methods, docking and scoring, linear-scaling quantum calculations, QSAR, pharmacophore methods, computational ADME-Tox, and drug discovery case studies. A variety of authors from academic and commercial institutions all over the world have contributed to this book, which is illustrated with more than 200 images. This is the only book to cover the subject of structure and ligand-based drug design, and it provides the most up-to-date information on a wide range of topics for the practising computational chemist, medicinal chemist, or structural biologist. Professor Kenneth Merz has been selected as the recipient of the 2010 ACS Award for Computers in Chemical & Pharmaceutical Research that recognizes the advances he has made in the use of quantum mechanics to solve biological and drug discovery problems.
Intermolecular potential functions have been developed for urea. Ab initio 6–31G(d) calculations were performed on urea‐water complexes to obtain interaction energies and hydrogen‐bond lengths that were used in developing the partial charges for the OPLS model. An important test was made by computing through Monte Carlo simulations the difference in chloroform/water partition coefficients for urea and acetamide, Δ log P. The accord between the computed result from statistical perturbation theory for TIP4P water and OPLS chloroform (2.0 ± 0.1 ) and the experimental value (1.9) is excellent. The computed absolute free energy of hydration of acetamide (‐9.5 ± 0.4 kcal/mol) also matches the experimental data at 25 °C (‐9.68 kcal/mol). These facts provide confidence in the computed value of −13.6 ± 0.4 kcal/mol for the absolute free energy of hydration of urea, an experimentally unavailable result. The water structure around urea and acetamide was also characterized; the average numbers of solute‐water hydrogen bonds are 5 for urea and 3–4 for acetamide.
The complexation of anions by octamethylcalix[4]pyrrole 1 and 2,5-dimethylpyrrole has been investigated by energy minimizations in the gas phase and by Monte Carlo (MC) simulations in dichloromethane using the OPLS force field. In agreement with experiment, the 1,3-alternate conformation of 1, in which adjacent pyrrole rings are pointing in opposite directions, was shown to be the most stable conformation in the absence of a halide anion. The cone conformer of 1, having all pyrrole units in a parallel orientation, is not stable in the absence of a halide anion, but it is the most stable conformation upon anion binding due to the formation of four NH−halide hydrogen bonds. The relative free energies of binding of chloride, bromide, and iodide with the cone of 1 in dichloromethane are calculated with free energy perturbation (FEP) simulations to be in excellent agreement with experiment. However, the calculations predict a far greater affinity for fluoride ion than was measured. This can be explained by the presence of trace amounts of water. For reference, MC/FEP calculations were also carried out for 2,5-dimethylpyrrole, which was predicted to bind only fluoride ion, consistent with NMR experiments. On the technical side, the MC sampling efficiency of alternative internal-coordinate representations of the complexes was also considered.
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Halogen bonding, due to its directionality and tunable strength, is being increasingly utilized in self-assembling materials and crystal engineering. Using density functional theory (DFT) and molecular mechanics (OPLS/CM1Ax) calculations, multiply halogen bonded complexes of brominated imidazole and pyridine are investigated along with their potential in construction of self-assembling architectures. Dimers with 1-10 halogen bonds are considered and reveal maximal binding energies of 3-36 kcal/mol. Cooperative (nonadditive) effects are found in complexes that extend both along and perpendicular to the halogen bonding axes, with interaction energies depending on polarization, secondary interactions, and ring spacers. Four structural motifs were identified to yield optimal halogen bonding. For the largest systems, the excellent agreement found between the DFT and OPLS/CM1Ax results supports the utility of the latter approach for analysis and design of self-assembling supramolecular structures.
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During the 1980s, advances in the abilities to perform computer simulations of chemical and biomolecular systems and to calculate free energy changes led to the expectation that such methodology would soon show great utility for guiding molecular design. Important potential applications included design of selective receptors, catalysts, and regulators of biological function including enzyme inhibitors. This time also saw the rise of high-throughput screening and combinatorial chemistry along with complementary computational methods for de novo design and virtual screening including docking. These technologies appeared poised to deliver diverse lead compounds for any biological target. As with many technological advances, realization of the expectations required significant additional effort and time. However, as summarized here, striking success has now been achieved for computer-aided drug lead generation and optimization. De novo design using both molecular growing and docking are illustrated for lead generation, and lead optimization features free energy perturbation calculations in conjunction with Monte Carlo statistical mechanics simulations for protein−inhibitor complexes in aqueous solution. The specific applications are to the discovery of non-nucleoside inhibitors of HIV reverse transcriptase (HIV-RT) and inhibitors of the binding of the proinflammatory cytokine MIF to its receptor CD74. A standard protocol is presented that includes scans for possible additions of small substituents to a molecular core, interchange of heterocycles, and focused optimization of substituents at one site. Initial leads with activities at low-micromolar concentrations have been advanced rapidly to low-nanomolar inhibitors.
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTComputer Assisted Mechanistic Evaluations of Organic Reactions. 26. Diastereoselective Additions: Cram's RuleJan M. Fleischer, Alan J. Gushurst, and William L. JorgensenCite this: J. Org. Chem. 1995, 60, 3, 490–498Publication Date (Print):February 1, 1995Publication History Published online1 May 2002Published inissue 1 February 1995https://pubs.acs.org/doi/10.1021/jo00108a006https://doi.org/10.1021/jo00108a006research-articleACS PublicationsRequest reuse permissionsArticle Views222Altmetric-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
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTAb initio study of the displacement reactions of chloride ion with formyl and acetyl chlorideJames F. Blake and William L. JorgensenCite this: J. Am. Chem. Soc. 1987, 109, 13, 3856–3861Publication Date (Print):June 1, 1987Publication History Published online1 May 2002Published inissue 1 June 1987https://pubs.acs.org/doi/10.1021/ja00247a007https://doi.org/10.1021/ja00247a007research-articleACS PublicationsRequest reuse permissionsArticle Views146Altmetric-Citations49LEARN 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 (1)»Supporting Information Supporting Information Get e-Alerts
