title: Exploring the binding of BACE-1 inhibitors using comparative binding energy analysis (COMBINE).
abstract: BACKGROUND
  The inhibition of the activity of β-secretase (BACE-1) is a potentially important approach for the treatment of Alzheimer disease. To explore the mechanism of inhibition, we describe the use of 46 X-ray crystallographic BACE-1/inhibitor complexes to derive quantitative structure-activity relationship (QSAR) models. The inhibitors were aligned by superimposing 46 X-ray crystallographic BACE-1/inhibitor complexes, and gCOMBINE software was used to perform COMparative BINding Energy (COMBINE) analysis on these 46 minimized BACE-1/inhibitor complexes. The major advantage of the COMBINE analysis is that it can quantitatively extract key residues involved in binding the ligand and identify the nature of the interactions between the ligand and receptor.
  
  
  RESULTS
  By considering the contributions of the protein residues to the electrostatic and van der Waals intermolecular interaction energies, two predictive and robust COMBINE models were developed: (i) the 3-PC distance-dependent dielectric constant model (built from a single X-ray crystal structure) with a q2 value of 0.74 and an SDEC value of 0.521; and (ii) the 5-PC sigmoidal electrostatic model (built from the actual complexes present in the Brookhaven Protein Data Bank) with a q2 value of 0.79 and an SDEC value of 0.41.
  
  
  CONCLUSIONS
  These QSAR models and the information describing the inhibition provide useful insights into the design of novel inhibitors via the optimization of the interactions between ligands and those key residues of BACE-1.
authors.affiliation: Guangdong Province Key Laboratory of Functional Molecules in Oceanic Microorganism, Zhong Shan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, People’s Republic of China.
authors.forename: Shu
authors.initials: S
authors.lastname: Liu
authors.forename: Rao
authors.initials: R
authors.lastname: Fu
authors.forename: Xiao
authors.initials: X
authors.lastname: Cheng
authors.forename: Sheng-Ping
authors.initials: SP
authors.lastname: Chen
authors.forename: Li-Hua
authors.initials: LH
authors.lastname: Zhou
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D020134:Catalytic Domain; D018360:Crystallography, X-Ray; D030562:Databases, Protein; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D016018:Least-Squares Analysis; D008024:Ligands; D008958:Models, Molecular; D025341:Principal Component Analysis; D011485:Protein Binding; D012984:Software; D055672:Static Electricity; D013816:Thermodynamics
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D053829:Amyloid Precursor Protein Secretases