Exploring the druggability of the binding site of aurovertin, an exogenous allosteric inhibitor of FOF1-ATP synthase
In addition to playing a central role in the mitochondria as the main producer of ATP, FOF1-ATP synthase performs diverse key regulatory functions in the cell membrane. Its malfunction has been linked to a growing number of human diseases, including hypertension, atherosclerosis, cancer, and some ne...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-10-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.1012008/full |
| _version_ | 1798019994180648960 |
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| author | Luis Fernando Cofas-Vargas Paola Mendoza-Espinosa Paola Mendoza-Espinosa Luis Pablo Avila-Barrientos Diego Prada-Gracia Héctor Riveros-Rosas Enrique García-Hernández |
| author_facet | Luis Fernando Cofas-Vargas Paola Mendoza-Espinosa Paola Mendoza-Espinosa Luis Pablo Avila-Barrientos Diego Prada-Gracia Héctor Riveros-Rosas Enrique García-Hernández |
| author_sort | Luis Fernando Cofas-Vargas |
| collection | DOAJ |
| description | In addition to playing a central role in the mitochondria as the main producer of ATP, FOF1-ATP synthase performs diverse key regulatory functions in the cell membrane. Its malfunction has been linked to a growing number of human diseases, including hypertension, atherosclerosis, cancer, and some neurodegenerative, autoimmune, and aging diseases. Furthermore, inhibition of this enzyme jeopardizes the survival of several bacterial pathogens of public health concern. Therefore, FOF1-ATP synthase has emerged as a novel drug target both to treat human diseases and to combat antibiotic resistance. In this work, we carried out a computational characterization of the binding sites of the fungal antibiotic aurovertin in the bovine F1 subcomplex, which shares a large identity with the human enzyme. Molecular dynamics simulations showed that although the binding sites can be described as preformed, the inhibitor hinders inter-subunit communications and exerts long-range effects on the dynamics of the catalytic site residues. End-point binding free energy calculations revealed hot spot residues for aurovertin recognition. These residues were also relevant to stabilize solvent sites determined from mixed-solvent molecular dynamics, which mimic the interaction between aurovertin and the enzyme, and could be used as pharmacophore constraints in virtual screening campaigns. To explore the possibility of finding species-specific inhibitors targeting the aurovertin binding site, we performed free energy calculations for two bacterial enzymes with experimentally solved 3D structures. Finally, an analysis of bacterial sequences was carried out to determine conservation of the aurovertin binding site. Taken together, our results constitute a first step in paving the way for structure-based development of new allosteric drugs targeting FOF1-ATP synthase sites of exogenous inhibitors. |
| first_indexed | 2024-04-11T16:49:34Z |
| format | Article |
| id | doaj.art-17d8a8ce8039438493a490a74edf5cf5 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-04-11T16:49:34Z |
| publishDate | 2022-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-17d8a8ce8039438493a490a74edf5cf52022-12-22T04:13:28ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-10-011310.3389/fphar.2022.10120081012008Exploring the druggability of the binding site of aurovertin, an exogenous allosteric inhibitor of FOF1-ATP synthaseLuis Fernando Cofas-Vargas0Paola Mendoza-Espinosa1Paola Mendoza-Espinosa2Luis Pablo Avila-Barrientos3Diego Prada-Gracia4Héctor Riveros-Rosas5Enrique García-Hernández6Universidad Nacional Autónoma de México, Instituto de Química, Ciudad Universitaria, Mexico City, MexicoUniversidad Nacional Autónoma de México, Instituto de Química, Ciudad Universitaria, Mexico City, MexicoTecnologico de Monterrey, The Institute for Obesity Research, Monterrey, MexicoUniversidad Nacional Autónoma de México, Instituto de Química, Ciudad Universitaria, Mexico City, MexicoUnidad de Investigación en Biología Computacional y Diseño de Fármacos, Hospital Infantil de México Federico Gómez, Mexico City, MexicoDepartamento de Bioquímica, Facultad de Medicina, Universidad Nacional Autónoma de México, Avenida Universidad 3000, Cd. Universitaria, Mexico City, MexicoUniversidad Nacional Autónoma de México, Instituto de Química, Ciudad Universitaria, Mexico City, MexicoIn addition to playing a central role in the mitochondria as the main producer of ATP, FOF1-ATP synthase performs diverse key regulatory functions in the cell membrane. Its malfunction has been linked to a growing number of human diseases, including hypertension, atherosclerosis, cancer, and some neurodegenerative, autoimmune, and aging diseases. Furthermore, inhibition of this enzyme jeopardizes the survival of several bacterial pathogens of public health concern. Therefore, FOF1-ATP synthase has emerged as a novel drug target both to treat human diseases and to combat antibiotic resistance. In this work, we carried out a computational characterization of the binding sites of the fungal antibiotic aurovertin in the bovine F1 subcomplex, which shares a large identity with the human enzyme. Molecular dynamics simulations showed that although the binding sites can be described as preformed, the inhibitor hinders inter-subunit communications and exerts long-range effects on the dynamics of the catalytic site residues. End-point binding free energy calculations revealed hot spot residues for aurovertin recognition. These residues were also relevant to stabilize solvent sites determined from mixed-solvent molecular dynamics, which mimic the interaction between aurovertin and the enzyme, and could be used as pharmacophore constraints in virtual screening campaigns. To explore the possibility of finding species-specific inhibitors targeting the aurovertin binding site, we performed free energy calculations for two bacterial enzymes with experimentally solved 3D structures. Finally, an analysis of bacterial sequences was carried out to determine conservation of the aurovertin binding site. Taken together, our results constitute a first step in paving the way for structure-based development of new allosteric drugs targeting FOF1-ATP synthase sites of exogenous inhibitors.https://www.frontiersin.org/articles/10.3389/fphar.2022.1012008/fullFOF1-ATP synthase inhibitionconformational dynamicssolvent sitesbinding free energyhot spot binding residuesbacterial pathogens |
| spellingShingle | Luis Fernando Cofas-Vargas Paola Mendoza-Espinosa Paola Mendoza-Espinosa Luis Pablo Avila-Barrientos Diego Prada-Gracia Héctor Riveros-Rosas Enrique García-Hernández Exploring the druggability of the binding site of aurovertin, an exogenous allosteric inhibitor of FOF1-ATP synthase Frontiers in Pharmacology FOF1-ATP synthase inhibition conformational dynamics solvent sites binding free energy hot spot binding residues bacterial pathogens |
| title | Exploring the druggability of the binding site of aurovertin, an exogenous allosteric inhibitor of FOF1-ATP synthase |
| title_full | Exploring the druggability of the binding site of aurovertin, an exogenous allosteric inhibitor of FOF1-ATP synthase |
| title_fullStr | Exploring the druggability of the binding site of aurovertin, an exogenous allosteric inhibitor of FOF1-ATP synthase |
| title_full_unstemmed | Exploring the druggability of the binding site of aurovertin, an exogenous allosteric inhibitor of FOF1-ATP synthase |
| title_short | Exploring the druggability of the binding site of aurovertin, an exogenous allosteric inhibitor of FOF1-ATP synthase |
| title_sort | exploring the druggability of the binding site of aurovertin an exogenous allosteric inhibitor of fof1 atp synthase |
| topic | FOF1-ATP synthase inhibition conformational dynamics solvent sites binding free energy hot spot binding residues bacterial pathogens |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.1012008/full |
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