Investigating the binding mechanism of novel 6-aminonicotinate-based antagonists with P2Y₁₂ by 3D-QSAR, docking and molecular dynamics simulations

Abstract

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.

The inhibitory mechanism of aurintricarboxylic acid targeting serine/threonine phosphatase Stp1 in Staphylococcus aureus: insights from molecular dynamics simulations

“…Multiple molecular conformations obtained by MD simulations can be used to explain the dynamics of molecular structures [35]. In addition, the combination of docking and MD simulations has been used to investigate the mechanisms of molecules that target proteins, [39,40] prediction of protein-ligand binding [41], and drug design [42,43].…”

Recommended tool compounds and drugs for blocking P2X and P2Y receptors

“…The compound has been applied in a number of experimental studies in vitro and in vivo to block P2Y 12 receptors (e.g., [83][84][85][86]). The acylsulfonamide derivative AZD 1283 ( 40) is another experimental drug that shows good water solubility [72,87,88]. The pK a value of its sulfonamide function is relatively low (4.6), and the compound is therefore deprotonated at pH 7.4.…”

“…The acylsulfonamide derivative AZD 1283 ( 40 ) is another experimental drug that shows good water solubility [ 72 , 87 , 88 ]. The pK a value of its sulfonamide function is relatively low (4.6), and the compound is therefore deprotonated at pH 7.4.…”

Molecular Modeling Applied to the Discovery of New Lead Compounds for P2 Receptors Based on Natural Sources

“…In the field of drug discovery and development, MD has been used extensively for the refinement and optimization of constructed P2 receptor homology models to build templates for molecular docking assays ( Zylberg et al., 2007 ; Trujillo et al., 2015 ; Junker et al., 2016 ; Liu et al., 2018 ). MD simulations have also been used in the evaluation of structure-function relationships between the binding pocket of the P2 receptor of interest and the candidate hits obtained through docking assays ( Zhou et al., 2017 ).…”