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1.
Sci Rep ; 14(1): 9392, 2024 04 24.
Article in English | MEDLINE | ID: mdl-38658769

ABSTRACT

A series of arecoline derivatives with amino acid moieties were designed and synthesised using an acylamide condensation strategy, taking arecoline as the foundational structure. The insecticidal efficacy of these compounds against Aphis craccivora and Tetranychus cinnabarinus was evaluated. Notably, derivatives 3h and 3i demonstrated superior insecticidal activity compared with arecoline. Additionally, 3h and 3i showed good fungicidal effectiveness against two types of plant fungi. Moreover, molecular docking analyses suggested that 3h and 3i could affect the nervous systems of A. craccivora and T. cinnabarinus by binding to neuronal nicotinic acetylcholine receptors. These findings suggest that compounds 3h and 3i represent promising leads for further development in insecticide and fungicide research.


Subject(s)
Amino Acids , Antifungal Agents , Drug Design , Insecticides , Molecular Docking Simulation , Insecticides/pharmacology , Insecticides/chemical synthesis , Insecticides/chemistry , Animals , Antifungal Agents/pharmacology , Antifungal Agents/chemical synthesis , Antifungal Agents/chemistry , Amino Acids/chemistry , Aphids/drug effects , Tetranychidae/drug effects , Structure-Activity Relationship , Receptors, Nicotinic/metabolism , Receptors, Nicotinic/chemistry , Microbial Sensitivity Tests
2.
Appl Biochem Biotechnol ; 187(4): 1173-1192, 2019 Apr.
Article in English | MEDLINE | ID: mdl-30187344

ABSTRACT

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.


Subject(s)
Alzheimer Disease/drug therapy , Aminoacyltransferases/antagonists & inhibitors , Aminoacyltransferases/metabolism , Enzyme Inhibitors/metabolism , Enzyme Inhibitors/pharmacology , Molecular Dynamics Simulation , Alzheimer Disease/enzymology , Aminoacyltransferases/chemistry , Drug Evaluation, Preclinical , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/therapeutic use , Humans , Molecular Docking Simulation , Protein Binding , Protein Conformation , Thermodynamics , User-Computer Interface
3.
J Biomol Struct Dyn ; 35(13): 2938-2965, 2017 Oct.
Article in English | MEDLINE | ID: mdl-27634290

ABSTRACT

P2Y12 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 P2Y12 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 P2Y12 and the structural features for the activity. The optimum CoMFA and CoMSIA models identified satisfactory robustness and good predictive ability, with R2 = .983, q2 = .805, [Formula: see text] = .881 for CoMFA model, and R2 = .935, q2 = .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 P2Y12. We hope these results could be helpful in design of potent and selective P2Y12 antagonists.


Subject(s)
Niacin/analogs & derivatives , Purinergic P2Y Receptor Antagonists/chemistry , Receptors, Purinergic P2Y12/metabolism , Amino Acids/chemistry , Amino Acids/metabolism , Hydrogen Bonding , Molecular Docking Simulation , Molecular Dynamics Simulation , Niacin/chemistry , Protein Binding , Quantitative Structure-Activity Relationship , Receptors, Purinergic P2Y12/chemistry
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