Human glutaminyl cyclase (hQC) appeared as a promising new target with its inhibitors attracted much attention for the treatment of Alzheimer's disease (AD) in recent years. But so far, only a few compounds have been reported as hQC inhibitors. To find novel and potent hQC inhibitors, a high-specificity ZBG (zinc-binding groups)-based pharmacophore model comprising customized ZBG feature was first generated using HipHop algorithm in Discovery Studio software for screening out hQC inhibitors from the SPECS database. After purification by docking studies and drug-like ADMET properties filters, four potential hit compounds were retrieved. Subsequently, these hit compounds were subjected to 30-ns molecular dynamic (MD) simulations to explore their binding modes at the active side of hQC. MD simulations demonstrated that these hit compounds formed a chelating interaction with the zinc ion, which was consistent with the finding that the electrostatic interaction was the major driving force for binding to hQC confirmed with MMPBSA energy decomposition. Higher binding affinities of these compounds were also verified by the binding free energy calculations comparing with the references. Thus, these identified compounds might be potential hQC candidates and could be used for further investigation.

P2Y receptor is an attractive target for the anti-platelet therapies, treating various thrombotic diseases. In this work, a total of 107 6-aminonicotinate-based compounds as potent P2Y antagonists were studies by a molecular modeling study combining three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking and molecular dynamics (MD) simulations to explore the decisive binding conformations of these antagonists with P2Y and the structural features for the activity. The optimum CoMFA and CoMSIA models identified satisfactory robustness and good predictive ability, with R = .983, q = .805, [Formula: see text] = .881 for CoMFA model, and R = .935, q = .762, [Formula: see text] = .690 for CoMSIA model, respectively. The probable binding modes of compounds and key amino acid residues were revealed by molecular docking. MD simulations and MM/GBSA free energy calculations were further performed to validate the rationality of docking results and to compare the binding modes of several compound pairs with different activities, and the key residues (Val102, Tyr105, Tyr109, His187, Val190, Asn191, Phe252, His253, Arg256, Tyr259, Thr260, Val279, and Lys280) for the higher activity were pointed out. The binding energy decomposition indicated that the hydrophobic and hydrogen bond interactions play important roles for the binding of compounds to P2Y. We hope these results could be helpful in design of potent and selective P2Y antagonists.

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An integrated computational study was performed to identify the binding mechanisms of benzamide-based derivatives with Abl_wt/Abl_T315I kinases for designing Abl inhibitors.

We explored the structural features that have an impact on TgCDPK1 activity and TgCDPK1/Src selectivity by multi-computational methods with different statistical models.