Identification of Novel Potential β-N-Acetyl-D-Hexosaminidase Inhibitors by Virtual Screening, Molecular Dynamics Simulation and MM-PBSA Calculations

Abstract

Chitinolytic β-N-acetyl-d-hexosaminidases, as a class of chitin hydrolysis enzyme in insects, are a potential species-specific target for developing environmentally-friendly pesticides. Until now, pesticides targeting chitinolytic β-N-acetyl-d-hexosaminidase have not been developed. This study demonstrates a combination of different theoretical methods for investigating the key structural features of this enzyme responsible for pesticide inhibition, thus allowing for the discovery of novel small molecule inhibitors. Firstly, based on the currently reported crystal structure of this protein (OfHex1.pdb), we conducted a pre-screening of a drug-like compound database with 8 × 106 compounds by using the expanded pesticide-likeness criteria, followed by docking-based screening, obtaining 5 top-ranked compounds with favorable docking conformation into OfHex1. Secondly, molecular docking and molecular dynamics simulations are performed for the five complexes and demonstrate that one main hydrophobic pocket formed by residues Trp424, Trp448 and Trp524, which is significant for stabilization of the ligand–receptor complex, and key residues Asp477 and Trp490, are respectively responsible for forming hydrogen-bonding and π–π stacking interactions with the ligands. Finally, the molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) analysis indicates that van der Waals interactions are the main driving force for the inhibitor binding that agrees with the fact that the binding pocket of OfHex1 is mainly composed of hydrophobic residues. These results suggest that screening the ZINC database can maximize the identification of potential OfHex1 inhibitors and the computational protocol will be valuable for screening potential inhibitors of the binding mode, which is useful for the future rational design of novel, potent OfHex1-specific pesticides.

Molecular Dynamics Simulation of Tryptophan Hydroxylase-1: Binding Modes and Free Energy Analysis to Phenylalanine Derivative Inhibitors

“…An appropriate number of chloride counter ions were placed around four TPH1–inhibitor complexes to neutralize the charges of the systems. Finally, the whole system was solvated in a cubic periodic box of TIP3P water molecules, and the distance between the edges of the water box and the closest atom of the solutes was at least 10 Å [26–28]. To avoid edge effects, periodic boundary conditions were applied during the whole molecular dynamics (MD) simulation.…”

Synthesis, Optimization, and Evaluation of Glycosylated Naphthalimide Derivatives as Efficient and Selective Insect β-N-Acetylhexosaminidase OfHex1 Inhibitors

“…Chitin is also a key structural component of the fungal cell wall, nematode eggshell, and arthropod exoskeleton . Moreover, the cuticles of the integument and peritrophic membranes of the midgut have been found to contain chitin . Chitin degradation is catalyzed by two members of the glycoside hydrolase family, GH18 chitinases (EC 3.2.1.14) and GH20 β- N -acetylhexosaminidases (EC 3.2.1.52). , GH18 chitinases catalyze the cleavage of chitin into shorter chito-oligosaccharides, and then GH20 β- N -acetylhexosaminidases hydrolyze these oligosaccharides into GlcNAc from the non-reducing terminal. , Chitin degradation is essential to the growth and maturation of insects. , Interference with insect chitin degradation disrupts molting, pupation, and eclosion processes, eventually leading to insect death. , Chitin is completely absent from higher plants and mammals, and thus, the inhibition of chitin degradation is a promising strategy for the development of green pesticides. − …”

Elucidating the anti-aging mechanism of Si Jun Zi Tang by integrating network pharmacology and experimental validation in vivo

“…It is generally believed that when the binding energy of a ligand and receptor is <−4 kcal/mol, there is potential binding activity between the ligand and receptor [ 35 ]. A binding energy score less than −5 kcal/mol suggests strong binding between the ligand and receptor [ 36 , 37 ]. The results of molecular docking showed that kaempferol and quercetin, two important compounds in SJZT, had good affinity for the top ten core targets.…”