Computational Screening of Potential Inhibitors of β-N-Acetyl-D-Hesosaminidases Using Combined Core-Fragment Growth and Pharmacophore Restraints
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As a type of β-N-acetyl-D-hexosaminidase enzyme purified from the Ostriniafurnacalis (Asian corn borer), OfHex1 has been previously reported to participate in chitin degradation, indicating that it may be an ideal target for designing new environmentally friendly pesticides. Besides, a natural product, TMG-chitotriomycin, has been found to be an effective inhibitor of OfHex1, and some studies have shown that the interactions between TMG unit and residues in − 1 subsite of OfHex1 are very conservative and important, inspiring us to design new inhibitors of β-N-acetyl-D-hexosaminidase with a new strategy. In the present study, the virtual screening of TMG unit as the core fragment was conducted using the combined computational methods, such as docking, molecular dynamics, pharmacophore model, and pesticide-likeness rule. Nine compounds with the binding free energy lower than TMG-β-(GlcNAc)2 were obtained. According to the decomposition energy and the interactions analysis, compounds 2, 3, 6 and 8, forming the hydrogen bonds with Val327 and Trp490, were considered as the possible lead structures for the further study. Our findings indicated that fragment-based lead discovery strategy might provide valuable insights into designing novel potential OfHex1 inhibitors.
Keywordsβ-N-Acetyl-D-hexosaminidase Fragment Design Pharmacophore Restraint Molecular Dynamic Simulation Virtual Screening
We thank Prof. Guangfu Yang and Dr. Gefei Hao who provide PFVS program.
This work was supported by the National Natural Science Foundation of China [No. 21272265] and the National Key R&D Program of China [No. 2017YFD0200504].
Conflicts of interest
The authors declare that they have no conflict of interest.
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