No abstract

O conceito FERMO foi empregado com sucesso ao princípio ácido-base de dureza e moleza de Pearson para quatro ligantes ambidentados. Usando um postulado intuitivo basedo em argumentos HOMO-LUMO para a dureza e moleza, as diferenças de energia FERMO-LUMO descrevem corretamente os sítios duros e moles para os sistemas estudados. Além disso, os orbitais de Kohn-Sham e Hartree-Fock levam às mesmas conclusões. The FERMO concept was successfully applied to the Pearson´s Hard and Soft acid-base principle for four ambidentate ligands. Using an intuitive statement based on the HOMO-LUMO approach to the hardness and softness, the FERMO-LUMO gaps correctly describe the soft and hard sites in the studied systems. Moreover, Kohn-Sham and Hartree-Fock MOs lead to same conclusions.

Mycobacterium tuberculosis (Mt) is a leading cause of infectious disease in the world today. This outlook is aggravated by a growing number of Mt infections in individuals who are immunocompromised as a result of HIV infections. Thus, new and more potent anti-tuberculosis agents are necessary. Therefore, DNA gyrase was selected as a target enzyme to combat Mt. In this work, the first three-dimensional molecular model of the hypothetical structures for the Mycobacterium tuberculosis DNA gyrase (mtDNAg) was elucidated by a homology modeling method. In addition, the orientations and binding affinities of some gatifloxacin analogs with those new structures were investigated. Our findings could be helpful for the design of new more potent gatifloxacin analogs.

The high frequency of contamination by herbicides suggests the need for more active and selective herbicides. Glyphosate is the active component of one of the top-selling herbicides, which is also a potent EPSP synthase inhibitor. That is a key enzyme in the shikimic acid pathway, which is found only in plants and some microorganisms. Thus, EPSP synthase is regarded as a prime target for herbicides. In this line, molecular modeling studies using molecular dynamics simulations and DFT techniques were performed to understand the interaction of glyphosate and its analogs with the wild type enzyme and Gly96Ala mutant EPSP synthase. In addition, we investigated the reaction mechanism of the natural substrate. Our findings indicate some key points to the design of new selective glyphosate derivates.

No presente trabalho foi aplicada uma metodologia teórica desenvolvida em um trabalho anterior que utiliza os programas Molegro ® e Spartan ® para avaliar as constantes cinéticas de associação e reativação de oximas, em relação a resultados in vitro previamente reportados na literatura. Como observado antes, os resultados mostraram boa correlação entre as energias livres teóricas de ligação das oximas e os dados experimentais, corroborando a metodologia como adequada para a predição de parâmetros cinéticos e termodinâmicos, os quais podem ser úteis para o planejamento e seleção de novas e mais efetivas oximas.In this work we applied a theoretical methodology developed in a former work, using the Molegro ® and Spartan ® softwares, to evaluate the association and kinetic reactivation constants of oximes, facing in vitro data previously reported in the literature. As reported before, results showed a good agreement between the theoretical binding free energies of the oximes and experimental data, corroborating the methodology as suitable for the prediction of kinetic and thermodynamic parameters that might be helpful for the design and selection of new and more effective oximes. Keywords: acetylcholinesterase, QM/MM, chemical mechanism of reactivation, neurotoxic agents IntroductionThe action of the nerve agents 1,2 as inhibitors of the enzyme acetylcholinesterase (AChE) stops the hydrolysis of the neurotransmitter acetylcholine and can lead to an irreversible inhibition of this enzyme (aging) thus triggering the cholinergic syndrome.3 To avoid this it's necessary a nucleophile, like an oxime, whose hydroxyl group is believed to be able to remove the nerve agent from the active site and reactivate AChE (Scheme 1). This reactivation reaction (illustrated in equation 1) involves, first, the association of the oxime to the inhibited enzyme (EIOx) and then the reactivation of the enzyme by the leaving of the oxime complexed to the neurotoxic agent (I-Ox).Where K R and k r are the dissociation constants, which represent the affinity of oximes for the inhibited AChE, and the rate constant for the decomposition of the stable enzyme-inhibitor-reactivator complex, respectively. 4,5The literature reports many structurally different oximes able to perform the reactivation of AChE inhibited by several different nerve agents, but one structure able to act efficiently against all the existing neurotoxic agents has not yet been reported 4,5 and oximes that are efficient against one specific nerve agent can be completely ineffective with another.2-6 Several molecular modelling studies available in literature point out to important features on the oximes structures that could be very useful to guide experimental research on this issue. [7][8][9][10][11][12][13][14][15][16][17][18][19] In a former work 4 we have Methodology Ligands data set and docking energy calculationsThe in vitro data of K R and k r for the oximes studied in this work (Figure 1) regarding AChE inhibited by cyclosarin, were reported by Kassa et al. 5 Crystallogr...