title: Experimental-like affinity constants and enantioselectivity estimates from flexible docking.
abstract: Experimental-like affinity constants and enantioselectivity estimates, not predicted so far computationally, were obtained using a novel flexible modeling/docking combined strategy. The S- and R-warfarin-human serum albumin (HSA, site I) complexes were used as an interaction model. The process for a verified estimation includes the following: (i) ionized open chain forming at physiological pH (a recent focus); (ii) conformational search (molecular mechanics and Monte Carlo methods); (iii) rigid protein-flexible ligand docking (GlideXP) generating low energy paired S- and R-poses; (iv) graphical comparison against the X-ray crystal structure (unsatisfactory verification step); (v) quantum polarized ligand docking (insufficient verification step); (vi) induced fit docking (one pose satisfying the verification criterion; selection step); (vii) converting docking scores to affinity and enantioselectivity estimates (log K(S) = 5.43, log K(R) = 5.34, ES = K(S)/K(R) = 1.23) and numerical comparison against equivalent literature data from bioanalytical techniques (validation step); (viii) intermolecular forces explaining ES (hydrogen bonding and π-π interactions).
authors.affiliation: Department of Chemistry, Mangosuthu University of Technology, P.O. Box 12363, Jacobs, 4026, South Africa.
authors.forename: N J
authors.initials: NJ
authors.lastname: Gumede
authors.forename: P
authors.initials: P
authors.lastname: Singh
authors.forename: M I
authors.initials: MI
authors.lastname: Sabela
authors.forename: K
authors.initials: K
authors.lastname: Bisetty
authors.forename: L
authors.initials: L
authors.lastname: Escuder-Gilabert
authors.forename: M J
authors.initials: MJ
authors.lastname: Medina-Hernández
authors.forename: S
authors.initials: S
authors.lastname: Sagrado
mesh_terms: D000465:Algorithms; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D006860:Hydrogen Bonding; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D062105:Molecular Docking Simulation; D009010:Monte Carlo Method; D011485:Protein Binding; D011789:Quantum Theory; D012107:Research Design; D012709:Serum Albumin / Q000737:chemistry*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D014859:Warfarin / Q000737:chemistry*
chemical_list: D012709:Serum Albumin; D014859:Warfarin