Exploring the binding of BACE-1 inhibitors using comparative binding energy analysis (COMBINE)

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.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.It is generally accepted that Alzheimer’s disease (AD) is caused by extracellular amyloid plaque deposition and the intracellular formation of neurofibrillary tangles in the brain [1-4]. β-amyloid peptides (Aβ, forming the amyloid plaques) are formed by the action of the β-secretase (BACE-1) and γ-secretase enzymes on the amyloid precursor protein (APP) [5-8]. BACE-1 is currently widely accepted as a leading target for the therapeutic treatment of AD [9-12]. The inhibition of BACE-1 can prevent the cleavage of APP to Aβ and the formation of amyloid plaques [13].The search for potent BACE-1 inhibitors is being pursued actively in many academic institutes and pharmaceutical companies. Most of these endeavors include computational studies such as pharmacophore modeling [14,15], classical quantitative structure-activity relationships (QSARs) [14-17], docking and virtual screening [18-22] and molecular dynamics (MD) simulations [23-26]. Currently, several hundred BACE-1 inhibitors have been reported, but most of these inhibitors are peptidomimetics [16]. To find novel BACE-1 inhibitors, a few companies are actively screening against BACE-1. A research group from Merck has performed in vitro high-throughput screening (HTS) and found a single molecule