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

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.

Understanding the Pyrimethamine Drug Resistance Mechanism via Combined Molecular Dynamics and Dynamic Residue Network Analysis

“…Markedly, residues within or close to pyrimethamine/substrate-binding sites (grey shaded in Figure 6) recorded low average L values. This observation corroborates findings of our previous study associating regions possessing low average L values with residue communities located within the active site (substrate binding site) [30]. Generally, residues 12-16, 18, 59, 63, 101-105, 123, 161-166, 170-171, 174-175, 180, 181, and 183-185 registered significant low average L values across all systems.…”

“…Overall, regions showing significantly high BC values were located within or close to substrate/ligand-binding sites (shaded grey in Figure 7). These results recapitulate previous findings reporting that active sites of proteins possess high and low average BC and average L values, respectively [23,30,33].…”

“…Residue interaction network (RIN) analysis of a protein backbone is useful in identifying key residues involved in intra-protein communication. This can be used to explore differences in information flow between wild type and mutant as well as ligand-bound and ligand-free systems [29,30]. Two fundamental network properties, average shortest path (L) and betweenness centrality (BC), have proven useful in RIN analysis [31,32].…”

“…Both metrics accentuate residue importance in protein communication. The L and BC measures become even more robust when computed as running averages across an MD trajectory, in what is known as dynamic residue network (DRN) analysis [23,24,30,32]. We present per residue reachability as plots of average L in (Figure 6).…”

New Insights Into the Effect of Residue Mutation on the Rotavirus VP1 Function Using Molecular Dynamic Simulations

“…For highly dynamic proteins, it was reported strong positive correlation between L and RMSF [36,37], and moderate and weak inverse correlation between BC and L or RMSF, respectively [37]. These findings were partially supported in the present study by calculating the pairwise Pearson's correlation coefficient of average L, average BC, and RMSF for each VP1 structure ( Table 2).…”