title: Dynamic Docking of Conformationally Constrained Macrocycles: Methods and Applications.
abstract: Many natural products consist of large and flexible macrocycles that engage their targets via multiple contact points. This combination of contained flexibility and large contact area often allows natural products to bind at target surfaces rather than deep pockets, making them attractive scaffolds for inhibiting protein-protein interactions and other challenging therapeutic targets. The increasing ability to manipulate such compounds either biosynthetically or via semisynthetic modification means that these compounds can now be considered as starting points for medchem campaigns rather than solely as ends. Modern medchem benefits substantially from rational improvements made on the basis of molecular docking. As such, docking methods have been enhanced in recent years to deal with the complicated binding modalities and flexible scaffolds of macrocyclic natural products and natural product-like structures. Here, we comprehensively review methods for treating and docking these large macrocyclic scaffolds and discuss some of the resulting advances in medicinal chemistry.
authors.affiliation: Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, and ‡Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
authors.forename: Scott E
authors.initials: SE
authors.lastname: Allen
authors.affiliation: Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, and ‡Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
authors.forename: Nikolay V
authors.initials: NV
authors.lastname: Dokholyan
authors.affiliation: Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, and ‡Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill , Chapel Hill, North Carolina 27599, United States.
authors.forename: Albert A
authors.initials: AA
authors.lastname: Bowers
mesh_terms: D001665:Binding Sites; D016023:Integrins / Q000737:chemistry; D047028:Macrocyclic Compounds / Q000737:chemistry*; D008968:Molecular Conformation; D062105:Molecular Docking Simulation
chemical_list: D016023:Integrins; D047028:Macrocyclic Compounds