期刊
FRONTIERS IN PHARMACOLOGY
卷 13, 期 -, 页码 -出版社
FRONTIERS MEDIA SA
DOI: 10.3389/fphar.2022.1012008
关键词
FOF1-ATP synthase inhibition; conformational dynamics; solvent sites; binding free energy; hot spot binding residues; bacterial pathogens
资金
- CONACyT, Mexico [508395]
- Universidad Nacional Autonoma de Mexico (UNAM)
- UNAM-DGAPA PAPIIT [IN206221, IN219022]
In addition to its role in ATP production, FOF1-ATP synthase also plays key regulatory functions in the cell membrane. Its dysfunction is associated with various human diseases and poses a threat to the survival of bacterial pathogens. Therefore, FOF1-ATP synthase has become a potential drug target for treating human diseases and combating antibiotic resistance.
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 F-1 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.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据