A novel identification approach for discovery of 5-HydroxyTriptamine 2A antagonists: combination of 2D/3D similarity screening, molecular docking and molecular dynamics

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.

Keywords:

• drug discovery
• G-protein coupled receptor
• 2D/3D screening
• 2D similarity
• 3D similarity
• ligand-based virtual screening
• 5HT_2A

Abbreviations:

• 5HT, 5-HydroxyTryptamine
• CNS, central nervous system
• PNS, peripheral nervous system
• SCA, stochastic clustering algorithm
• SDF, structure data file
• Tc, tanimoto coefficient
• μM, micromolar
• nm, nanomolar
• Ki, equilibrium dissociation constant for the ligand
• SPC, single point charge
• NHB, number of hydrogen bonds
• SSE, secondary structure elements
• Rg, radius of gyration
• SASA, solvent accessible surface area
• PDB, protein data bank
• MD, molecular dynamic
• β2-AR, β2 adrenergic receptor
• RMSD, root mean square deviation
• GPCRs, G protein-coupled receptors
• TPSA, topological polar surface area
• BLAST, basic local alignment search tool
• JC virus, John Cunningham virus
• POPC, 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine
• DOPE, discrete optimized protein energy
• OCD, obsessive compulsive disorder
• ADHD, attention deficit hyperactivity disorders
• LBVS, ligand-based virtual screening
• 2D, two-dimensional space
• 3D, three-dimensional space
• MW, molecular weight
• HBA, hydrogen bond acceptors
• HBD, hydrogen bond donors
• TPSA, topological polar surface area
• P5/P95, percentile calculation
• SPD, simple point charge
• Cl⁻ ions, chloride ions
• SD, steepest descent
• ns, nanosecond
• fs, femtosecond
• PME, Particle Mesh Ewald
• RMSF, root mean square fluctuations
• PLIP, protein–ligand interaction profiler
• HB, hydrogen bond
• TM, Transmembrane
• kcal/mol, kilocalorie per mole sn-1
• kJ/mol, kilo Joule per mol
• Sn-1/sn-2, Stereospecific number
• MSD, mean square displacement
• PAINS, Pan assay interference compounds
• Å, Ångström