A Docking Score Function for Estimating Ligand−Protein Interactions:  Application to Acetylcholinesterase Inhibition

Abstract

Acetylcholinesterase (AChE) inhibition is an important research topic because of its wide range of associated health implications. A receptor-specific scoring function was developed herein for predicting binding affinities for human AChE (huAChE) inhibitors. This method entails a statistically trained weighted sum of electrostatic and van der Waals (VDW) interactions between ligands and the receptor residues. Within the 53 ligand training set, a strong correlation was found (R 2 ) 0.89) between computed and experimental inhibition constants. Leave-oneout cross-validation indicated high predictive power (Q 2 ) 0.72), and analysis of a separate 16-compound test set also produced very good correlation with experiment (R 2 ) 0.69). Scoring function analysis has permitted identification and characterization of important ligand-receptor interactions, producing a list of those residues making the most important electrostatic and VDW contributions within the main active site, gorge area, acyl binding pocket, and periferal site. These analyses are consistent with X-ray crystallographic and site-directed mutagenesis studies.

Design, Synthesis, and Biological Evaluation of Coumarin Derivatives Tethered to an Edrophonium‐like Fragment as Highly Potent and Selective Dual Binding Site Acetylcholinesterase Inhibitors

“…[47] Given that the role of water molecules in the AChE binding site is not completely understood, docking simulations were performed without taking water molecules into account. [48] The target proteins were prepared by adding hydrogen atoms, completing and optimizing missing residues, removing water and the co-crystallized molecules. The basic amino groups were protonated, aromatic amino functional groups were left uncharged, and carboxylic groups were considered to be deprotonated.…”

Benchmarking docking and scoring protocol for the identification of potential acetylcholinesterase inhibitors

“…Although, many comparative molecular docking studies have been reported for AChE [40][41][42][43][44], the reported findings were devoid of the comments regarding conserved water molecules in the active site of AChE, which can mediate the interaction between amino acid side chains and inhibitors. Similarly probable conformations of Phe330 during docking procedure were also neglected.…”

Studies Towards the Synthesis of Methionine Aminopeptidase Inhibitors: Diversification Utilizing a ROMP-Derived Coupling Reagent

“…Given an increasingly sizable body of screening data for the MetAP enzyme, our plan is to train a comparative binding energy (COMBINE) type model to specifically represent the idiosyncrasies of the MetAP inhibitor structure-activity relationship. We have previously found this to be highly successful in studies of other complex receptors such as acetylcholinesterase 26 and adenylyl cyclase. 27 The compounds reported herein were evaluated in silico according to standard oral availability and absorptiondistribution-metabolism-excretion (ADME) criteria, using SYBYL 28 and VolSurf 29 programs.…”