The Experts below are selected from a list of 141 Experts worldwide ranked by ideXlab platform
Andreas Goller - One of the best experts on this subject based on the ideXlab platform.
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cypscore quantitative prediction of reactivity toward cytochromes p450 based on semiempirical Molecular Orbital Theory
ChemMedChem, 2009Co-Authors: Matthias Hennemann, Arno Friedl, Mario Lobell, Jorg Keldenich, Alexander Hillisch, Timothy Clark, Andreas GollerAbstract:CypScore is an in silico approach for predicting the likely sites of cytochrome P450-mediated metabolism of druglike organic molecules. It consists of multiple models for the most important P450 oxidation reactions such as aliphatic hydroxylation, N-dealkylation, O-dealkylation, aromatic hydroxylation, double-bond oxidation, N-oxidation, and S-oxidation. Each of these models is based on atomic reactivity descriptors derived from surface-based properties calculated with ParaSurf and based on AM1 semiempirical Molecular Orbital Theory. The models were trained with data derived from Bayer Schering Pharma's in-house MajorMetabolite Database with more than 2300 transformations and more than 800 molecules collected from the primary literature. The models have been balanced to allow the treatment of relative intraMolecular, intra-chemotype, and inter-chemotype reactivities of the labile sites toward oxidation. The models were evaluated with promising hit rates on three public datasets of varying quality in the annotation of the experimental positions. For 39 well-characterized compounds from 14 in-house lead optimization programs, we could detect at least one major metabolite for the three highest-ranked positions in 87 % of the compounds and overall more than 62 % of all major metabolites, with promising true- to false-positive ratios of 0.9.
Matthias F Bickelhaupt - One of the best experts on this subject based on the ideXlab platform.
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the nature of nonclassical carbonyl ligands explained by kohn sham Molecular Orbital Theory
Chemistry: A European Journal, 2020Co-Authors: Stephanie C. C. Van Der Lubbe, Matthias F Bickelhaupt, Célia Fonseca Guerra, Pascal VermeerenAbstract:When carbonyl ligands coordinate to transition metals, their bond distance either increases (classical) or decreases (nonclassical) with respect to the bond length in the isolated CO molecule. C-O expansion can easily be understood by π-back-donation, which results in a population of the CO's π*-antibonding Orbital and hence a weakening of its bond. Nonclassical carbonyl ligands are less straightforward to explain, and their nature is still subject of an ongoing debate. In this work, we studied five isoelectronic octahedral complexes, namely Fe(CO)62+ , Mn(CO)6+ , Cr(CO)6 , V(CO)6- and Ti(CO)62- , at the ZORA-BLYP/TZ2P level of Theory to explain this nonclassical behavior in the framework of Kohn-Sham Molecular Orbital Theory. We show that there are two competing forces that affect the C-O bond length, namely electrostatic interactions (favoring C-O contraction) and π-back-donation (favoring C-O expansion). It is a balance between those two terms that determines whether the carbonyl is classical or nonclassical. By further decomposing the electrostatic interaction ΔVelstat into four fundamental terms, we are able to rationalize why ΔVelstat gives rise to the nonclassical behavior, leading to new insights into the driving forces behind C-O contraction.
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the activation strain model and Molecular Orbital Theory
Wiley Interdisciplinary Reviews: Computational Molecular Science, 2015Co-Authors: Lando P Wolters, Matthias F BickelhauptAbstract:The activation strain model is a powerful tool for understanding reactivity, or inertness, of Molecular species. This is done by relating the relative energy of a Molecular complex along the reaction energy profile to the structural rigidity of the reactants and the strength of their mutual interactions: ΔE(ζ) = ΔEstrain(ζ) + ΔEint(ζ). We provide a detailed discussion of the model, and elaborate on its strong connection with Molecular Orbital Theory. Using these approaches, a causal relationship is revealed between the properties of the reactants and their reactivity, e.g., reaction barriers and plausible reaction mechanisms. This methodology may reveal intriguing parallels between completely different types of chemical transformations. Thus, the activation strain model constitutes a unifying framework that furthers the development of cross-disciplinary concepts throughout various fields of chemistry. We illustrate the activation strain model in action with selected examples from literature. These examples demonstrate how the methodology is applied to different research questions, how results are interpreted, and how insights into one chemical phenomenon can lead to an improved understanding of another, seemingly completely different chemical process. WIREs Comput Mol Sci 2015, 5:324–343. doi: 10.1002/wcms.1221 For further resources related to this article, please visit the WIREs website. Conflict of interest: The authors have declared no conflicts of interest for this article.
Matthias Hennemann - One of the best experts on this subject based on the ideXlab platform.
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cypscore quantitative prediction of reactivity toward cytochromes p450 based on semiempirical Molecular Orbital Theory
ChemMedChem, 2009Co-Authors: Matthias Hennemann, Arno Friedl, Mario Lobell, Jorg Keldenich, Alexander Hillisch, Timothy Clark, Andreas GollerAbstract:CypScore is an in silico approach for predicting the likely sites of cytochrome P450-mediated metabolism of druglike organic molecules. It consists of multiple models for the most important P450 oxidation reactions such as aliphatic hydroxylation, N-dealkylation, O-dealkylation, aromatic hydroxylation, double-bond oxidation, N-oxidation, and S-oxidation. Each of these models is based on atomic reactivity descriptors derived from surface-based properties calculated with ParaSurf and based on AM1 semiempirical Molecular Orbital Theory. The models were trained with data derived from Bayer Schering Pharma's in-house MajorMetabolite Database with more than 2300 transformations and more than 800 molecules collected from the primary literature. The models have been balanced to allow the treatment of relative intraMolecular, intra-chemotype, and inter-chemotype reactivities of the labile sites toward oxidation. The models were evaluated with promising hit rates on three public datasets of varying quality in the annotation of the experimental positions. For 39 well-characterized compounds from 14 in-house lead optimization programs, we could detect at least one major metabolite for the three highest-ranked positions in 87 % of the compounds and overall more than 62 % of all major metabolites, with promising true- to false-positive ratios of 0.9.
Célia Fonseca Guerra - One of the best experts on this subject based on the ideXlab platform.
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the nature of nonclassical carbonyl ligands explained by kohn sham Molecular Orbital Theory
Chemistry: A European Journal, 2020Co-Authors: Stephanie C. C. Van Der Lubbe, Matthias F Bickelhaupt, Célia Fonseca Guerra, Pascal VermeerenAbstract:When carbonyl ligands coordinate to transition metals, their bond distance either increases (classical) or decreases (nonclassical) with respect to the bond length in the isolated CO molecule. C-O expansion can easily be understood by π-back-donation, which results in a population of the CO's π*-antibonding Orbital and hence a weakening of its bond. Nonclassical carbonyl ligands are less straightforward to explain, and their nature is still subject of an ongoing debate. In this work, we studied five isoelectronic octahedral complexes, namely Fe(CO)62+ , Mn(CO)6+ , Cr(CO)6 , V(CO)6- and Ti(CO)62- , at the ZORA-BLYP/TZ2P level of Theory to explain this nonclassical behavior in the framework of Kohn-Sham Molecular Orbital Theory. We show that there are two competing forces that affect the C-O bond length, namely electrostatic interactions (favoring C-O contraction) and π-back-donation (favoring C-O expansion). It is a balance between those two terms that determines whether the carbonyl is classical or nonclassical. By further decomposing the electrostatic interaction ΔVelstat into four fundamental terms, we are able to rationalize why ΔVelstat gives rise to the nonclassical behavior, leading to new insights into the driving forces behind C-O contraction.
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Halogen Bonds in Ligand-Protein Systems: Molecular Orbital Theory for Drug Design.
Journal of chemical information and modeling, 2020Co-Authors: Enrico Margiotta, Stephanie C. C. Van Der Lubbe, Lucas De Azevedo Santos, Gábor Paragi, Stefano Moro, F. Matthias Bickelhaupt, Célia Fonseca GuerraAbstract:Halogen bonds are highly important in medicinal chemistry as halogenation of drugs, generally, improves both selectivity and efficacy toward protein active sites. However, accurate modeling of halogen bond interactions remains a challenge, since a thorough theoretical investigation of the bonding mechanism, focusing on the realistic complexity of drug-receptor systems, is lacking. Our systematic quantum-chemical study on ligand/peptide-like systems reveals that halogen bonding is driven by the same bonding interactions as hydrogen bonding. Besides the electrostatic and the dispersion interactions, our bonding analyses, based on quantitative Kohn-Sham Molecular Orbital Theory together with energy decomposition analysis, reveal that donor-acceptor interactions and steric repulsion between the occupied Orbitals of the halogenated ligand and the protein need to be considered more carefully within the drug design process.
E. M. Dianov - One of the best experts on this subject based on the ideXlab platform.
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Crystal field and Molecular Orbital Theory of MBm centres in glasses
Journal of Physics B: Atomic Molecular and Optical Physics, 2010Co-Authors: E. F. Kustov, L. I. Bulatov, Vladislav Dvoyrin, Valery M. Mashinsky, E. M. DianovAbstract:The spectral phenomena in optical fibres with bismuth-doped aluminosilicate glass core are explicated on the basis of a Molecular Orbital Theory and of a Schrodinger equation solution, taking into account the exchange, spin–orbit and crystal field interactions of s, p and d electrons of M atoms (M signifies Bi, Sb, Pb, Sn, In, Te, etc) with ligand orbits of environmental B atoms (B signifies O, S, Se, etc). Energy level diagrams and selection rules of transitions between Molecular Orbital states of s and p electrons of MBm molecule permit us to determine the energies of the main spectral transitions of absorption and luminescent spectra and their correspondence with experimental spectra of different types of optical fibres is obtained.