Design And Synthesis Of Human Voltage Gated Proton Channel Hv1 Inhibitors

Objective: Voltage-gated proton channels are expressed in a variety of cell types and tissues.The voltage-gated proton channel Hv1 plays important roles in proton extrusion,p H homeostasis,and production of reactive oxygen species in a variety of cell types,for example,acid extrusion in lung epithelial cells and sperm,and regulation of p H homeostasis in phytoplankton.It was found that the p H of most tumor cells is opposite to that of normal cells.The extracellular p H of tumor cells is acidic,and the intracellular p H is alkaline.This acidic microenvironment of tumors is related to the malignant biological behavior of tumor cells,such as promoting invasion and metastasis,escaping immune attack,etc.These behaviors suggest that Hv1 voltage-gated proton channels may play an important role in the occurrence and metastasis of tumors..A large number of studies have shown that Hv1 voltage-gated proton channels are highly expressed in invasive breast cancer,and in malignant tumors such as colorectal adenocarcinoma and glioma,the expression of Hv1 voltage-gated proton channels is also significantly higher than that of normal tissues.In immune cells,voltage-gated proton channels are involved in charge compensation during production of reactive oxygen species by the NADPH oxidase complex.Excessive Hv1 activity increases proliferation and invasiveness in cancer cells and worsens brain damage in ischemic stroke.It has now been found that the compound 2-guanidinobenzimidazole(2GBI)inhibits Hv1 proton conduction from the inside of the cell by binding to the voltage-sensitive domain(VSD),but does not completely block Hv1.So we need to develop better structural inhibitors that bind to the human voltage-gated proton channel Hv1.Methods: Using computer-aided drug design method,Mainly used in the Discovery Studio 4.0 and Schrodinger 2015 software to simulate the protein model of the voltage-gated proton channel Hv1 and screen out small molecule compounds with good conformational stability.3WKV protein was used as a homologous template and Hv1 receptor was obtained by homology modeling.Through molecular docking by Schr?-dinger suite2009,nine compounds with the highest scores were selected,and ADMET was predicted..Through a series of comparison to select the most stable structure and interaction of one of the best compounds Zinc91852157 molecular dynamics simulation experiment.Finally compare docking scores,spatial conformations,and laboratory conditions for these compounds,eventually choose only one of the compounds Zinc76005320 synthesized.Results: Through homology modeling,we obtained a more stable structure of Hv1 voltage-gated proton channels protein receptor,and then through the high-throughput virtual screening obtained Zinc91852157,Zinc92715249,Zinc62116375,Zinc83544056,Zinc76005263,Zinc83456223,Zinc39952440,Zinc91852158,Zinc76005320 highest score of nine Compounds.Comparing the kinetic simulation of the compound Zinc91852157 with 2 GBI,we found that the stability of the compound Zinc91852157 is higher than 2 GBI.The compound Zinc76005320 was synthesized by consulting the literature and formulating a synthetic route.Conclusion: In this paper,we use computer-aided drug design methods such as homology modeling and virtual screening to screen out compounds that bind better to Hv1 receptors.ADMET was then used to predict the resulting compounds to determine their drug-producing properties and toxic side effects.Finally,molecular dynamics simulations were performed on compounds that were relatively well-established in all respects and 2 GBI.One of the compounds was synthesized by comparing the synthesis conditions and the structure of the compound,which laid a good foundation for the further study of human voltage gated proton channel Hv1 inhibitors.