Estudo da computação de descritores de reatividade de um sistema polipeptídico usando hamiltonianos semi-empírico

Reactivity descriptors are theoretical quantities retrieved from the molecular electronic structure, convenient to preliminary reactions study and/or their rationalization. A class of these reactivity descriptors, based on the electronic density response variables, have being largely employed to the theoretical study of chemical reactions involving organic molecules. Due to the lower computational cost, compared to the a entire reaction simulation, these descriptors become an attractive alternative to preliminary reactivity studies of macromolecules relevant to drug development. Still,the computational cost using ab-initio/DFT methods to calculate macromolecules make the calculations impractical. Approximated methods, such semiempirical Hamiltonians, may be the way to turn these reactivity descriptors calculations possible. These methods are not well explored to get such quantities, and therefore in this study we propose the comparison of reactivity descriptors from Conceptual Density Functional Theory between an often used DFT calculation protocol and semiempirical Hamiltonians for a protein-like structure. A systematic comparison was conducted exploring well established global and local reactivity descriptors with different approximations and representation types found in literature which are successfully applied for small molecules. We showed that it is possible to use semiempirical Hamiltonians as electronic structure method to calculate reactivity descriptors for macromolecules. The best performance was achieved using frontier orbital energies and densities combined with the Localized Molecular Orbital scheme MOZYME.Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPqDescritores de Reatividade são quantidades obtidas teoricamente a partir da estrutura eletrônica de um sistema molecular, convenientes para o estudo preliminar de reações e/ou sua racionalização. Uma classe desses descritores, baseados em variáveis de resposta da densidade eletrônica, vem sendo empregada largamente para o estudo teórico de reações envolvendo moléculas comuns à química orgânica. Devido ao seu menor custo computacional, comparado com a simulação de uma reação inteira, esses descritores se tornam um alternativa atrativa para o estudo preliminar de macromoléculas com grande apelo no campo do desenvolvimento de drogas. Ainda assim, o custo computacional para obter essas quantidades usando métodos ab-inito/DFT ainda é muito grande para proteínas inteiras. O uso de métodos quânticos com maior nível de aproximações, como os semi-empíricos, pode ser uma via de obter essas informações de reatividade de forma prática. Esses métodos foram pouco explorados para essa questão especifica, e, por isso, no presente estudo foi testada sua utilização realizando uma comparação dos descritores de reatividade da Conceptual Density Functional Theory entre um frequente protocolo de cálculo do DFT e Hamiltonianos Semi-empíricos de um polipeptídeo. Uma comparação sistemática foi conduzida explorando descritores de reatividade globais e locais bem estabelecidos para pequenas moléculas, usando diferentes métodos de aproximação e representação encontradas na literatura. Foi demonstrado que é possível usar Hamiltonianos semi-empíricos como método de estrutura eletrônica no cálculo dos descritores de reatividade para macromoléculas. O melhor desempenho foi obtido usando as energias e densidade dos orbitais de fronteira como aproximação combinados com a técnica de escalonamento linear de Orbitais Moleculares Localizados MOZYME

Synthesis, spectroscopic characterization, DFT calculations, and molecular docking studies of new unsymmetric bishydrazone derivatives

Three new unsymmetric isatin bishydrazone compounds; Comp. I, II, III, were synthesized by the condensation of 3,5-dichloro-salicylaldehyde, 3-bromo-5-chloro-salicylaldehyde, and 3,5-dibromo-salicylaldehyde with isatin monohydrazone, respectively. The synthesized compounds were characterized by elemental analysis, H-1-NMR, FT-IR, UV-Vis spectroscopy, and mass spectrometry technique. For studied molecules, chemical parameters like frontier orbital energies, energy gap, electronegativity, chemical potential, chemical hardness, softness, electrophilicity, nucleophilicity, electrodonating power, electroaccepting power, polarizability, and dipole moment were calculated and discussed. Investigating the validity of well-known electronic structure principles like Maximum Hardness, Minimum Polarizability, and Minimum Electrophilicity Principles in the study, it was determined which compound is more stable compared to others. In recent days, a new software having PRIMorDIA name was developed to explore reactivity and electronic structure in large biomolecules by some of the authors of this paper. Molecular docking studies for these newly synthesized molecules were performed using PRIMorDIA software. Considering the intramolecular interactions, NBO analyzes of three bishydrazone derivatives were conducted to evaluate the chemical behavior. (C) 2021 Elsevier B.V. All rights reserved

Theoretical characterization of the shikimate 5-dehydrogenase reaction fromMycobacterium tuberculosisby hybrid QC/MM simulations and quantum chemical descriptors

International audienceIn this study, we have investigated the enzyme shikimate 5-dehydrogenase from the causative agent of tuberculosis,Mycobacterium tuberculosis. We have employed a mixture of computational techniques, including molecular dynamics, hybrid quantum chemical/molecular mechanical potentials, relaxed surface scans, quantum chemical descriptors and free-energy simulations, to elucidate the enzyme's reaction pathway. Overall, we find a two-step mechanism, with a single transition state, that proceeds by an energetically uphill hydride transfer, followed by an energetically downhill proton transfer. Our mechanism and calculated free energy barrier for the reaction, 64.9 kJ mol(- 1), are in good agreement with those predicted from experiment. An analysis of quantum chemical descriptors along the reaction pathway indicated a possibly important, yet currently unreported, role of the active site threonine residue, Thr65