title: Investigating the binding mechanism of novel 6-aminonicotinate-based antagonists with P2Y12by 3D-QSAR, docking and molecular dynamics simulations.
abstract: P2Y12receptor 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 P2Y12antagonists 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 P2Y12and 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 P2Y12antagonists.
authors.affiliation: a Department of Physical Chemistry , College of Pharmacy, Guangdong Pharmaceutical University , Guangzhou 510006 , China.
authors.forename: Shengfu
authors.identifier: http://orcid.org/0000-0003-1493-1474
authors.initials: S
authors.lastname: Zhou
authors.affiliation: b Department of Cardiothoracic Surgery , Affiliated Second Hospital of Guangzhou Medical University , Guangzhou 510260 , China.
authors.forename: Danqing
authors.initials: D
authors.lastname: Fang
authors.affiliation: a Department of Physical Chemistry , College of Pharmacy, Guangdong Pharmaceutical University , Guangzhou 510006 , China.
authors.forename: Shepei
authors.initials: S
authors.lastname: Tan
authors.affiliation: a Department of Physical Chemistry , College of Pharmacy, Guangdong Pharmaceutical University , Guangzhou 510006 , China.
authors.forename: Weicong
authors.initials: W
authors.lastname: Lin
authors.affiliation: a Department of Physical Chemistry , College of Pharmacy, Guangdong Pharmaceutical University , Guangzhou 510006 , China.
authors.forename: Wenjuan
authors.initials: W
authors.lastname: Wu
authors.affiliation: c School of Chemistry and Chemical Engineering , Sun Yat-Sen University , Guangzhou 510275 , China.
authors.forename: Kangcheng
authors.initials: K
authors.lastname: Zheng
mesh_terms: D000596:Amino Acids / Q000737:chemistry / Q000378:metabolism; D006860:Hydrogen Bonding; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009525:Niacin / Q000031:analogs & derivatives* / Q000737:chemistry; D011485:Protein Binding; D058921:Purinergic P2Y Receptor Antagonists / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D058925:Receptors, Purinergic P2Y12 / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D058921:Purinergic P2Y Receptor Antagonists; D058925:Receptors, Purinergic P2Y12; D009525:Niacin; C044559:6-aminonicotinic acid
keywords: 3D-QSAR; MD simulations; P2Y12 antagonists; anti-platelet; docking