title: Conformational analysis of a polyconjugated protein-binding ligand by joint quantum chemistry and polarizable molecular mechanics. Addressing the issues of anisotropy, conjugation, polarization, and multipole transferability.
abstract: We investigate the conformational properties of a potent inhibitor of neuropilin-1, a protein involved in cancer processes and macular degeneration. This inhibitor consists of four aromatic/conjugated fragments: a benzimidazole, a methylbenzene, a carboxythiourea, and a benzene-linker dioxane, and these fragments are all linked together by conjugated bonds. The calculations use the SIBFA polarizable molecular mechanics procedure. Prior to docking simulations, it is essential to ensure that variations in the ligand conformational energy upon rotations around its six main-chain torsional bonds are correctly represented (as compared to high-level ab initio quantum chemistry, QC). This is done in two successive calibration stages and one validation stage. In the latter, the minima identified following independent stepwise variations of each of the six main-chain torsion angles are used as starting points for energy minimization of all the torsion angles simultaneously. Single-point QC calculations of the minimized structures are then done to compare their relative energies ΔE conf to the SIBFA ones. We compare three different methods of deriving the multipoles and polarizabilities of the central, most critical moiety of the inhibitor: carboxythiourea (CTU). The representation that gives the best agreement with QC is the one that includes the effects of the mutual polarization energy E pol between the amide and thioamide moieties. This again highlights the critical role of this contribution. The implications and perspectives of these findings are discussed.
authors.affiliation: Laboratoire de Chimie et Biochimie Pharmacologiques et Toxicologiques, UMR 8601, UFR Biomédicale, Université ParisDescartes, 45, rue des Saints-Pères, 75006, Paris, France.
authors.forename: Elodie
authors.initials: E
authors.lastname: Goldwaser
authors.forename: Benoit
authors.initials: B
authors.lastname: de Courcy
authors.forename: Luc
authors.initials: L
authors.lastname: Demange
authors.forename: Christiane
authors.initials: C
authors.lastname: Garbay
authors.forename: Françoise
authors.initials: F
authors.lastname: Raynaud
authors.forename: Reda
authors.initials: R
authors.lastname: Hadj-Slimane
authors.forename: Jean-Philip
authors.initials: JP
authors.lastname: Piquemal
authors.forename: Nohad
authors.initials: N
authors.lastname: Gresh
mesh_terms: D016880:Anisotropy; D001665:Binding Sites; D004735:Energy Transfer; D008024:Ligands; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D039942:Neuropilin-1 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D011487:Protein Conformation; D011789:Quantum Theory; D015203:Reproducibility of Results; D013329:Structure-Activity Relationship; D013890:Thiourea / Q000031:analogs & derivatives / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D014867:Water / Q000737:chemistry
chemical_list: D008024:Ligands; D014867:Water; D039942:Neuropilin-1; D013890:Thiourea