| Literature DB >> 29468945 |
Rakesh Kumar1, Dhananjay Jade1, Dinesh Gupta1.
Abstract
5-HydroxyTriptamine 2A antagonists are potential targets for treatment of various cerebrovascular and cardiovascular disorders. In this study, we have developed and performed a unique screening pipeline for filtering ZINC database compounds on the basis of similarities to known antagonists to determine novel small molecule antagonists of 5-HydroxyTriptamine 2A. The screening pipeline is based on 2D similarity, 3D dissimilarity and a combination of 2D/3D similarity. The shortlisted compounds were docked to a 5-HydroxyTriptamine 2A homology-based model, and complexes with low binding energies (287 complexes) were selected for molecular dynamics (MD) simulations in a lipid bilayer. The MD simulations of the shortlisted compounds in complex with 5-HydroxyTriptamine 2A confirmed the stability of the complexes and revealed novel interaction insights. The receptor residues S239, N343, S242, S159, Y370 and D155 predominantly participate in hydrogen bonding. π-π stacking is observed in F339, F340, F234, W151 and W336, whereas hydrophobic interactions are observed amongst V156, F339, F234, V362, V366, F340, V235, I152 and W151. The known and potential antagonists shortlisted by us have similar overlapping molecular interaction patterns. The 287 potential 5-HydroxyTriptamine 2A antagonists may be experimentally verified.Entities:
Keywords: , tanimoto coefficient; 2D similarity; 2D, two-dimensional space; 2D/3D screening; 3D similarity; 3D, three-dimensional space; 5HT; 5HT, 5-HydroxyTryptamine; ADHD, attention deficit hyperactivity disorders; BLAST, basic local alignment search tool; CNS, central nervous system; Cl ions, chloride ions; DOPE, discrete optimized protein energy; G-protein coupled receptor; GPCRs, G protein-coupled receptors; HB, hydrogen bond; HBA, hydrogen bond acceptors; HBD, hydrogen bond donors; JC virus, John Cunningham virus; Ki, equilibrium dissociation constant for the ligand; LBVS, ligand-based virtual screening; MD, molecular dynamic; MSD, mean square displacement; MW, molecular weight; NHB, number of hydrogen bonds; OCD, obsessive compulsive disorder; P5/P95, percentile calculation; PAINS, Pan assay interference compounds; PDB, protein data bank; PLIP, protein–ligand interaction profiler; PME, Particle Mesh Ewald; PNS, peripheral nervous system; POPC, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine; RMSD, root mean square deviation; RMSF, root mean square fluctuations; Rg, radius of gyration; SASA, solvent accessible surface area; SCA, stochastic clustering algorithm; SD, steepest descent; SDF, structure data file; SPC, single point charge; SPD, simple point charge; SSE, secondary structure elements; Sn-1/sn-2, Stereospecific number; TM, Transmembrane; TPSA, topological polar surface area; drug discovery; fs, femtosecond; kJ/mol, kilo Joule per mol; kcal/mol, kilocalorie per mole sn-1; ligand-based virtual screening; nm, nanomolar; ns, nanosecond; Å Ångström; β2-AR, β2 adrenergic receptor; μM, micromolar
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Year: 2018 PMID： 29468945 DOI： 10.1080/07391102.2018.1444509
Source DB: PubMed Journal: J Biomol Struct Dyn ISSN： 0739-1102