Abstract
Tuberculosis is an ancient and current disease. Resistance to the prodrug pyrazinamide (PZA), one of the most important antituberculosis drug, is often associated with various mutations in the pncA gene that expresses the metalloenzyme pyrazinamidase (PZase). Some hard and intermediate acids, such as Co(II), Mn(II), and Zn(II), showed the ability to partially recover the susceptibility to PZA in resistant strains. In this work, we investigate the affinity that zinc complexes can achieve in the PZase protein with a low affinity for pyrazinamide. First, we select the PZase mutant with the best resistance profile to PZA using the web-server SUSPECT-PZA and a home-made script. Then we use the tmQM database, which contains 86,665 metal complexes with crystallographic structures and quantum descriptors, to search for zinc complexes with high affinity for PZase. Out of 5867 Zn complexes, 100 with lower dipole moment, higher hardness and lower HOMO energy were selected. Molecular docking studies using (a) empirical scoring functions (SF) and (b) SF based on machine learning, allowed us to find complexes such as BUXZUQ, FEQTUS or DOSQUA that have higher affinity for PZase than PZA. These Zn complexes not only exhibit higher global reactivity compared to PZA, but are also very similar to each other, and to a lesser degree their organic part is also similar to that of PZA. The compounds we have reported can serve as a basis for the design of new antituberculosis metallodrugs.
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Acknowledgments
The team thanks Dr. Ataualpa Carmo Braga, from the Institute of Chemistry of the University of Sao Paulo, for the support in the use of Gaussian09. JAAH thanks the financial support of the Management Agreement No. 237-2015-FONDECYT to the Vice-Rectorate for Research of the Universidad Nacional de Ingeniería of Peru. KSM, AVW, OEAA and MDCB thank the Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) [process number 439582/2018-0], Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) [Finance Code 001] and Fundação de Amparo a Pesquisa do Rio Grande do Sul (FAPERGS) [process number 22/2551-0000385-0].
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Alvarado-Huayhuaz, J.A. et al. (2022). Search for Zinc Complexes with High Affinity in Pyrazinamidase from Mycobacterium Tuberculosis Resistant to Pyrazinamide. In: Scherer, N.M., de Melo-Minardi, R.C. (eds) Advances in Bioinformatics and Computational Biology. BSB 2022. Lecture Notes in Computer Science(), vol 13523. Springer, Cham. https://doi.org/10.1007/978-3-031-21175-1_12
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