title: Conserved core substructures in the overlay of protein-ligand complexes.
abstract: The method of conserved core substructure matching (CSM) for the overlay of protein-ligand complexes is described. The method relies upon distance geometry to align structurally similar substructures without regard to sequence similarity onto substructures from a reference protein empirically selected to include key determinants of binding site location and geometry. The error in ligand position is reduced in reoriented ensembles generated with CSM when compared to other overlay methods. Since CSM can only succeed when the selected core substructure is geometrically conserved, misalignments only rarely occur. The method may be applied to reliably overlay large numbers of protein-ligand complexes in a way that optimizes ligand position at a specific binding site or subsite or to align structures from large and diverse protein families where the conserved binding site is localized to only a small portion of either protein. Core substructures may be complex and must be chosen with care. We have created a database of empirically selected core substructures to demonstrate the utility of CSM alignment of ligand binding sites in important drug targets. A Web-based interface can be used to apply CSM to align large collections of protein-ligand complexes for use in drug design using these substructures or to evaluate the use of alternative core substructures that may then be shared with the larger user community. Examples show the benefit of CSM in the practice of structure-based drug design.
authors: Department of Medicinal Chemistry, University of Minnesota College of Pharmacy, Minneapolis, Minnesota 55455, USA. finze007@umn.edu
authors: Barry C
authors: BC
authors: Finzel
authors: Ramprasad
authors: R
authors: Akavaram
authors: Aravind
authors: A
authors: Ragipindi
authors: Jeffrey R
authors: JR
authors: Van Voorst
authors: Matthew
authors: M
authors: Cahn
authors: Malcolm E
authors: ME
authors: Davis
authors: Matt E
authors: ME
authors: Pokross
authors: Steven
authors: S
authors: Sheriff
authors: Eric T
authors: ET
authors: Baldwin
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003198:Computer Simulation; D057225:Data Mining; D030562:Databases, Protein; D015195:Drug Design; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D004364:Pharmaceutical Preparations / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D011494:Protein Kinases / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D054852:Small Molecule Libraries; D012984:Software; D019311:Staurosporine / Q000032:analysis* / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
chemical_list: D008024:Ligands; D004364:Pharmaceutical Preparations; D054852:Small Molecule Libraries; D011494:Protein Kinases; D019311:Staurosporine