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

Abstract

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.