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Computational Screening of Potential Inhibitors of β-N-Acetyl-D-Hesosaminidases Using Combined Core-Fragment Growth and Pharmacophore Restraints

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Abstract

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.

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Acknowledgments

We thank Prof. Guangfu Yang and Dr. Gefei Hao who provide PFVS program.

Funding

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].

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Authors and Affiliations

  1. Department of Applied Chemistry, College of Science, China Agricultural University, Beijing, 100193, China

    Song Hu, Xiao Zhao & Li Zhang

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  1. Song Hu
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  2. Xiao Zhao
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  3. Li Zhang
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Correspondence to Li Zhang.

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ESM 1

The following are available online at www.mdpi.com/link, Table S1: The ΔΔGcal values of compounds 10-20,Fig. S1: The structures of compounds 10-20, Fig. S2: The decomposition energies of the important residues on OfHex1 binding compounds 1 and 3-9. Fig. S3-S10: The interactions of compounds 1, 3, 4, 5, 6, 7, 8, 9 and OfHex1 in + 1 subsite, respectively. (DOCX 1367 kb)

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Hu, S., Zhao, X. & Zhang, L. Computational Screening of Potential Inhibitors of β-N-Acetyl-D-Hesosaminidases Using Combined Core-Fragment Growth and Pharmacophore Restraints. Appl Biochem Biotechnol 189, 1262–1273 (2019). https://doi.org/10.1007/s12010-019-03064-4

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