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

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.

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Mathematical Analysis of a Series of 4-Acetylamino-2-(3,5-dimethylpyrazol-1-yl)-6-pyridylpyrimidines: A Simple Way to Relate Quantum Similarity to Local Chemical Reactivity Using the Gaussian Orbitals Localized Theory

Journal of Theoretical Chemistry ◽

10.1155/2014/624891 ◽

2014 ◽

Vol 2014 ◽

pp. 1-13 ◽

Cited By ~ 4

Author(s):

Alejandro Morales-Bayuelo ◽

Verónica Valdiris ◽

Ricardo Vivas-Reyes

Keyword(s):

Density Functional ◽

Chemical Reactivity ◽

Point Of View ◽

Quantum Similarity ◽

Electronic Effects ◽

Fukui Functions ◽

Reactivity Descriptors ◽

Bonding Theory ◽

Molecular Quantum Similarity ◽

Gaussian Orbitals

Molecular Quantum Similarity (MQS) descriptors and Density Functional Theory (DFT) based reactivity descriptors were studied for a series of 4-Acetylamino-2-(3,5-dimethylpyrazol-1-yl)-6-pyridylpyrimidines compounds used for Parkinson’s disease (PD) treatment. The quantification of the steric and electronic effects was shown through scales of quantitative convergence; such scales allow us to establish a methodology to quantify the similarity from the local chemical reactivity (Fukui Functions) point of view. This procedure provides new considerations in the local reactivity of the A2A Adenosine receptor antagonists in a disease of difficult control as PD. In addition, we present new considerations to the localized bonding theory and show a new methodology for quantum similarity on the Fukui Functions. Considering that the Fukui functions under a condensation scheme may have ambiguities in the (DFT) context.

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

Journal of Quantum Chemistry ◽

10.1155/2014/239845 ◽

2014 ◽

Vol 2014 ◽

pp. 1-19 ◽

Cited By ~ 2

Author(s):

Alejandro Morales-Bayuelo ◽

Ricardo Vivas-Reyes

Keyword(s):

Chemical Reactivity ◽

Statistical Correlation ◽

Diels Alder ◽

Quantum Similarity ◽

Reactivity Descriptors ◽

Distortion Analysis ◽

Ct Analysis ◽

Chemical Reactivity Descriptors ◽

Molecular Quantum Similarity ◽

Grand Canonical

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.

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