Molecular Modeling Of Novel Selective Estrogen Receptor Down-regulators And Virtual Screening Of Novel D₂ And 5-HT_2ADual Antagonists

In the first section,selective estrogen receptor degraders(SERDs)for the treatment of positive breast cancer can act both as estrogen alpha receptor(ER?)antagonists and degraders.In this study,the optimal antagonist models(CoMFA-A,q2=0.660,r2=0.996;CoMSIA-A,q2=0.728,r2=0.992)and degrader models(CoMFA-D,q2=0.850,r2=0.996;CoMSIA-D,q2=0.719,r2=0.995)of a series of potent benzothiophene-containing SERDs were constructed to explore the three-dimensional quantitative structure activity relationship.Internal and external validation indicated that all models exhibited good applicability,high predictive ability and robustness.Contour maps revealed the relationships between the essential structural features and antagonistic and degradation activities.Additionally,molecular docking,molecular dynamics and free energy calculation studies were further performed to investigate the detailed binding mode.Finally,ten novel compounds were designed based on above findings,where the predicted activity of compound D8 was equivalent to that of the compound LSZ102.3D-QSAR,ADMET and bioavailability predictions indicated that all designed compounds with good biological activity,good physicochemical and bioavailability could be potential candidates for SERDs.These results and combinations of computational methods provided guidance for the rational drug design of novel potential SERDs.In the second section,the extrapyramidal side effects of schizophrenia treatment can be significantly reduced by simultaneously targeting dopamine D2 and serotonin 5-HT2A receptors.In this study,based on tetrahydropyridopyrimidone derivatives,pharmacophore models of the D2 and 5-HT2A receptors dual antagonists were successfully constructed,and then verified by the Decoy test method.Moreover,based on the best pharmacophore model,virtual screening was performed on ZINC database.In addition,ADMET,molecular docking and molecular dynamics studies were applied in the virtual screening process to improve the reliability of screening results.Finally,four compounds(Z1,Z2,Z3 and Z4)with new skeletons were obtained through virtual screening.Overall,this study could provide theoretical guidance for the structural optimization,design and synthesis of novel D2 and 5-HT2A receptors dual antagonists.