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Molecules 2019, 24(1), 188; https://doi.org/10.3390/molecules24010188

Discorhabdin N, a South African Natural Compound, for Hsp72 and Hsc70 Allosteric Modulation: Combined Study of Molecular Modeling and Dynamic Residue Network Analysis

Research Unit in Bioinformatics (RUBi), Department of Biochemistry and Microbiology, Rhodes University, Grahamstown 6140, South Africa
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Received: 1 December 2018 / Revised: 1 January 2019 / Accepted: 2 January 2019 / Published: 6 January 2019
(This article belongs to the Section Natural Products Chemistry)
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Abstract

The human heat shock proteins (Hsps), predominantly Hsp72 and Hsp90, have been strongly implicated in various critical stages of oncogenesis and progression of human cancers. While drug development has extensively focused on Hsp90 as a potential anticancer target, much less effort has been put against Hsp72. This work investigated the therapeutic potential of Hsp72 and its constitutive isoform, Hsc70, via in silico-based screening against the South African Natural Compounds Database (SANCDB). A comparative modeling approach was used to obtain nearly full-length 3D structures of the closed conformation of Hsp72 and Hsc70 proteins. Molecular docking of SANCDB compounds identified one potential allosteric modulator, Discorhabdin N, binding to the allosteric β substrate binding domain (SBDβ) back pocket, with good binding affinities in both cases. This allosteric region was identified in one of our previous studies. Subsequent all-atom molecular dynamics simulations and free energy calculations exhibited promising protein–ligand association characteristics, indicative of strong binding qualities. Further, we utilised dynamic residue network analysis (DRN) to highlight protein regions actively involved in cross-domain communication. Most residues identified agreed with known allosteric signal regulators from literature, and were further investigated for the purpose of deducing meaningful insights into the allosteric modulation properties of Discorhabdin N. View Full-Text
Keywords: human cancers; South African natural compounds; heat shock proteins; molecular dynamics; allosteric drugs human cancers; South African natural compounds; heat shock proteins; molecular dynamics; allosteric drugs
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Amusengeri, A.; Tastan Bishop, Ö. Discorhabdin N, a South African Natural Compound, for Hsp72 and Hsc70 Allosteric Modulation: Combined Study of Molecular Modeling and Dynamic Residue Network Analysis. Molecules 2019, 24, 188.

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