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Title: | Computational Design of Inhibitors Targeting the Catalytic β Subunit of Escherichia coli FOF1-ATP Synthase |
Author: | Avila-Barrientos, Luis Pablo Cofas-Vargas, Luis Fernando Agüero-Chapin, Guillermin Hernández-García, Enrique Ruiz-Carmona, Sergio Valdez-Cruz, Norma A. Trujillo-Roldán, Mauricio Weber, Joachim Ruiz-Blanco, asser B. Barril Alonso, Xavier García-Hernández, Enrique |
Keywords: | Escheríchia coli Inhibidors enzimàtics Disseny de medicaments Escherichia coli Enzyme inhibitors Drug design |
Issue Date: | 22-Apr-2022 |
Publisher: | MDPI |
Abstract: | With the uncontrolled growth of multidrug-resistant bacteria, there is an urgent need to search for new therapeutic targets, to develop drugs with novel modes of bactericidal action. FoF1-ATP synthase plays a crucial role in bacterial bioenergetic processes, and it has emerged as an attractive antimicrobial target, validated by the pharmaceutical approval of an inhibitor to treat multidrug-resistant tuberculosis. In this work, we aimed to design, through two types of in silico strategies, new allosteric inhibitors of the ATP synthase, by targeting the catalytic β subunit, a centerpiece in communication between rotor subunits and catalytic sites, to drive the rotary mechanism. As a model system, we used the F1 sector of Escherichia coli, a bacterium included in the priority list of multidrug-resistant pathogens. Drug-like molecules and an IF1-derived peptide, designed through molecular dynamics simulations and sequence mining approaches, respectively, exhibited in vitro micromolar inhibitor potency against F1. An analysis of bacterial and Mammalia sequences of the key structural helix-turn-turn motif of the C-terminal domain of the β subunit revealed highly and moderately conserved positions that could be exploited for the development of new species-specific allosteric inhibitors. To our knowledge, these inhibitors are the first binders computationally designed against the catalytic subunit of FOF1-ATP synthase. Keywords: FOF1-ATP synthase; allosteric inhibition; evolutionary and PPI algorithms; peptide design; structure-based drug design. |
Note: | Reproducció del document publicat a: https://doi.org/10.3390/antibiotics11050557 |
It is part of: | Antibiotics, 2022, vol. 11, num. 5, p. 557 |
URI: | http://hdl.handle.net/2445/191530 |
Related resource: | https://doi.org/10.3390/antibiotics11050557 |
ISSN: | 2079-6382 |
Appears in Collections: | Articles publicats en revistes (Farmàcia, Tecnologia Farmacèutica i Fisicoquímica) |
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