New insights about the serine/threonine protein kinase substrates from Mycobacterium tuberculosis using molecular docking, quantum similarity analysis and DFT calculations

Background: The protein kinases present in the human body have received a lot of attention because of the interest in their use as therapeutic targets. However, little is known about the protein kinases associated with tuberculosis. For these reasons, this research investigates a new point of view regarding the crystallized serine/threonine protein kinases Pkn A, B and G of Mycobacterium tuberculosis. Methods: The conformational analysis shows a DFG-in motif in Pkn B and G and a DFG-out motif in Pkn A. For all the protein kinases that have been studied, the gatekeeper residue is methionine. A study of the protein kinases with their ligands was also conducted to find new insights on the binding site with a series of ligands associated to protein kinases Pkn A, B and G through molecular docking. The residues with hydrogen bonds on the hinge zone of Pkn A are GLU96 and VAL 98, of Pkn B are GLU 93 and VAL 95 and of Pkn G are GLU233 and VAL235. Results: The results show the H-bond acceptor and H-bond donor sites on the hinge zone to all ligands, establishing a structural model of the ligands on the active site with two or three interactions in this zone. This interaction model was validated using density functional theory calculations (by means of net charges and images of the electrostatic potential) and molecular quantum similarity analysis, showing a high correlation between the electronic and steric effects in each ATP complex studied. Conclusions: In this work we can see that the interactions of the hinge zone are characterized by the key factor of one or two H-bonds acceptors and one H-bond donor in the ligands of this zone. The quantum similarity analysis shows good correlation between the steric and electronic effects in each ATP complex. © 2021. Morales-Bayuelo A and Sánchez-Márquez

Synthesis of Pyrazolo-Fused 4-Azafluorenones in an Ionic Liquid. Mechanistic Insights by Joint Studies Using DFT Analysis and Mass Spectrometry

A series of pyrazolo-fused 4-azafluorenones (indeno[1,2-b]pyrazolo[4,3-e]pyridines, IPP) were synthesized via the three-component reaction between arylaldehydes, 3-methyl-1H-pyrazol- 5-amine and 1,3-indanedione in an ionic liquid as a catalyst at room temperature. The applied synthetic route has the advantages of easy work-up under mild reaction conditions presenting moderate yields and an environmentally benign procedure. A theoretical study based on conceptual-density functional theory has been done, bond reactivity indices have been calculated and an electrophilic and nucleophilic character of localized orbitals has been determined to analyze the possible electronic mechanisms

Molecular Quantum Similarity, Chemical Reactivity and Database Screening of 3D Pharmacophores of the Protein Kinases A, B and G from Mycobacterium tuberculosis

Mycobacterium tuberculosis remains one of the world’s most devastating pathogens. For this reason, we developed a study involving 3D pharmacophore searching, selectivity analysis and database screening for a series of anti-tuberculosis compounds, associated with the protein kinases A, B, and G. This theoretical study is expected to shed some light onto some molecular aspects that could contribute to the knowledge of the molecular mechanics behind interactions of these compounds, with anti-tuberculosis activity. Using the Molecular Quantum Similarity field and reactivity descriptors supported in the Density Functional Theory, it was possible to measure the quantification of the steric and electrostatic effects through the Overlap and Coulomb quantitative convergence (alpha and beta) scales. In addition, an analysis of reactivity indices using global and local descriptors was developed, identifying the binding sites and selectivity on these anti-tuberculosis compounds in the active sites. Finally, the reported pharmacophores to PKn A, B and G, were used to carry out database screening, using a database with anti-tuberculosis drugs from the Kelly Chibale research group (http://www.kellychibaleresearch.uct.ac.za/), to find the compounds with affinity for the specific protein targets associated with PKn A, B and G. In this regard, this hybrid methodology (Molecular Mechanic/Quantum Chemistry) shows new insights into drug design that may be useful in the tuberculosis treatment today

Understanding the comparative molecular field analysis (CoMFA) in terms of molecular quantum similarity and DFT-based reactivity descriptors

Artículo de publicación ISIThe three-dimensional quantitative structure-activity relationship (3D QSAR) models have many applications, although the inherent complexity to understand the results coming from 3D-QSAR arises the necessity of new insights in the interpretation of them. Hence, the quantum similarity field as well as reactivity descriptors based on the density functional theory were used in this work as a consistent approach to better understand the 3D-QSAR studies in drug design. For this purpose, the quantification of steric and electrostatic effects on a series of bicycle [4.1.0] heptane derivatives as melanin-concentrating hormone receptor 1 antagonists were performed on the basis of molecular quantum similarity measures. The maximum similarity superposition and the topo-geometrical superposition algorithms were used as molecular alignment methods to deal with the problem of relative molecular orientation in quantum similarity. In addition, a chemical reactivity analysis using global and local descriptors such as chemical hardness, softness, electrophilicity, and Fukui functions, was developed. Overall, our results suggest that the application of this methodology in drug design can be useful when the receptor is known or even unknown.FONDECYT, CHILE 315003

Understanding the Polar Character Trend in a Series of Diels-Alder Reactions Using Molecular Quantum Similarity and Chemical Reactivity Descriptors

In molecular similarity there is a premise “similar molecules tend to behave similarly”; however in the actual quantum similarity field there is no clear methodology to describe the similarity in chemical reactivity, and with this end an analysis of charge-transfer (CT) processes in a series of Diels-Alder (DA) reactions between cyclopentadiene (Cp) and cyano substitutions on ethylene has been studied. The CT analysis is performed in the reagent assuming a grand canonical ensemble and the considerations for an electrophilic system using B3LYP/6-31G(d) and M06-2X/6-311 + G(d,p) methods. An analysis for CT was performed in agreement with the experimental results with a good statistical correlation (R2=0.9118) relating the polar character to the bond force constants in DA reactions. The quantum distortion analysis on the transition states (TS) was performed using molecular quantum similarity indexes of overlap and coulomb showing good correlation (R2=0.8330) between the rate constants and quantum similarity indexes. In this sense, an electronic reorganization based on molecular polarization in terms of CT is proposed; therefore, new interpretations on the electronic systematization of the DA reactions are presented, taking into account that today such electronic systematization is an open problem in organic physical chemistry. Additionally, one way to quantify the similarity in chemical reactivity was shown, taking into account the dependence of the molecular alignment on properties when their position changes; in this sense a possible way to quantify the similarity of the CT in systematic form on these DA cycloadditions was shown

Discerning torquoselectivity in a series of cyclobutene ring-opening reactions using quantum theory of atoms in molecules and stress tensor

National Key Research and DevelopmentProgram of China, Grant/Award Number:2019YFC1907805 The file attached to this record is the author's final peer reviewed version. The Publisher's final version can be found by following the DOI link.This study aims to investigate the phenomenon of torquoselectivity through four thermal cyclobutenes ring-opening reactions including 1-chlorocyclobut-1-ene (Reaction 1), 3-chloro-4-methylcyclobut-1-ene (Reaction 2), 3-methoxy-4-methylcyclobut-1-ene (Reaction 3), and finally 3-chloro-4-methoxycyclobut-1-ene (Reaction 4). Despite the limitation of conventional methods in which just considers activation energies within transition state theory, this research focuses on the nature of the chemical bond, electronic reorganization, and predicting either non-competitive or competitive reactions within quantum theory of atoms in molecules (QTAIM) and stress tensor frameworks. Various theoretical analyses for these reactions such as metallicity ξ(rb), ellipticity ε, total local energy density H(rb), stress tensor polarizability ℙσ, stress tensor eigenvalue λ3σ, bond-path length, and path lengths H display differently for non-competitive and competitive reactions as well as for the conrotatory preferences either it is the transition state outward conrotatory (TSOC) or transition state inward conrotatory (TSIC) directions by presenting degeneracy or non-degeneracy in their results. Results illustrate that the preference of TSOC or TSIC of these thermal ring-opening reactions could obtain from path lengths H of the ring-opening bonds, where the longer one apparently predicts the preference. In addition, examinations indicate that Reaction 1 is competitive and Reactions (2–4) are non-competitive reactions with TSOC, TSOC, and TSIC preference directions respectively. The concordant results of stress tensor and QTAIM scalar and vectors with experimental results provide a better understanding of all reactions mechanism

New insights of QTAIM and stress tensor to finding non-competitive/competitive torquoselectivity of cyclobutene

The file attached to this record is the Publisher's final version.This study aims to investigate the phenomenon of torquoselectivity through three thermal cyclobutene ring-opening reactions (N1–N3). This research focuses on the nature of the chemical bond, electronic reorganization, predicting non-competitive or competitive reactions, and torquoselectivity preference within Quantum Theory of Atoms in Molecules (QTAIM) and stress tensor frameworks. Various theoretical analyses for these reactions, such as metallicity ξ(rb), ellipticity ε, total local energy density H(rb), stress tensor polarizability Pσ , stress tensor eigenvalue λ3σ , and bond-path length, display differently for non-competitive and competitive reactions as well as for the conrotatory preferences either it is the transition state outward conrotatory (TSout) or transition state inward conrotatory (TSin) directions by presenting degeneracy or non-degeneracy in their results. The ellipticity profile provides the motion of the bond critical point locations due to the different substituents of cyclobutene. In agreement with experimental results, examinations demonstrated that N1 is a competitive reaction and N2–N3 are non-competitive reactions with TSout and TSin preference directions, respectively. The concordant results of QTAIM and stress tensor scalar and vectors with experimental results provide a better understanding of reaction mechanism

Ultrasound-assisted synthesis of novel chalcone, heterochalcone and bis-chalcone derivatives and the evaluation of their antioxidant properties and as acetylcholinesterase inhibitors

The chalcone and bis-chalcone derivatives have been synthesized under sonication conditions via Claisen-Schmidt condensation with KOH in ethanol at room temperature (20–89%). The structures were established on the basis of NMR, IR, Single-crystal XRD, and MS. The best compound 3u had inhibitory activity (IC50 = 7.50 µM). The synthesis, the antioxidative properties, chemical reactivity descriptors supported in Density Functional Theory (DFT), acetylcholinesterase (AChE) inhibition and their potential binding modes, and affinity were predicted by molecular docking of a number of morpholine-chalcones and quinoline-chalcone. A series of bis-chalcones are also reported. Molecular docking and an enzyme kinetic study on compound 3u suggested that it simultaneously binds to the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE. Moreover, the pharmacokinetic profile of these compounds was investigated using a computational method