Design and screening of dehydrogenated harmine derivatives targeting PI3Kα and their molecular dynamics validation
Using PI3Kα as the target protein,a computer-aided design method is used to optimize the structure of harmine and obtain compounds with high binding power to the target protein.On this basis,molecular docking,three-dimensional quantitative structure-activity relationship(3D-QSAR)and molecular dynamics techniques are used to verify the binding ability and stability of the modified compound to the target protein.Finally,potential harmine derivatives with better binding ability to the target are screened.Using ACD/Percepta software,structural modifications are performed on the mother nucleus of harmine,resulting in a compound library of 136 745 compounds.Schrödinger software is used to screen the compounds with MM/GBSA(Molecular mechanics generalized born surface area)binding energy ranking in the top three from the compound library,and 3D-QSAR is used to verify them.Finally,three structural derivatives are verified by molecular dynamics method,and the ADMET properties are predicted.Through a series of computer-aided design methods,including software design,3D-QSAR,virtual screening and molecular dynamics simulation,136 745 new derivatives of norharmaline are obtained,and the stability of the protein structure complex is evaluated,and finally 3 compounds with high binding energy are obtained.Among them,derivative No.37971 is found to have better 3D-QSAR model activity prediction value,TPSA(topologically polar surface area)value(87.84)and bioavailability(33.21%).This study provides design ideas for the structural modification of norharmaline,which is obtained theoretically with PI3Kα Compounds with better target binding ability,the obtained molecules are expected to be potential candidate compounds through molecular docking and molecular dynamics validation,and lay the foundation for further experimental validation.
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