In Silico Affinity Profiling of Neuroactive Polyphenols for Post-Traumatic Calpain Inactivation: A Molecular Docking and Atomistic Simulation Sensitivity Analysis

Abstract

Calcium-activated nonlysosomal neutral proteases, calpains, are believed to be early mediators of neuronal damage associated with neuron death and axonal degeneration after traumatic neural injuries. In this study, a library of biologically active small molecular weight calpain inhibitors was used for model validation and inhibition site recognition. Subsequently, two natural neuroactive polyphenols, curcumin and quercetin, were tested for their sensitivity and activity towards calpain's proteolytic sequence and compared with the known calpain inhibitors via detailed molecular mechanics (MM), molecular dynamics (MD), and docking simulations. The MM and MD energy profiles (SJA6017 < AK275 < AK295 < PD151746 < quercetin < leupeptin < PD150606 < curcumin < ALLN < ALLM < MDL-28170 < calpeptin) and the docking analysis (AK275 < AK295 < PD151746 < ALLN < PD150606 < curcumin < leupeptin < quercetin < calpeptin < SJA6017 < MDL-28170 < ALLM) demonstrated that polyphenols conferred comparable calpain inhibition profiling. The modeling paradigm used in this study provides the first detailed account of corroboration of enzyme inhibition efficacy of calpain inhibitors and the respective calpain-calpain inhibitor molecular complexes' energetic landscape and in addition stimulates the polyphenol bioactive paradigm for post-SCI intervention with implications reaching to experimental in vitro, in cyto, and in vivo studies.

In silico analytico‐mathematical interpretation of biopolymeric assemblies: Quantification of energy surfaces and molecular attributes via atomistic simulations

“…The results were presented as an analytico‐mathematical representation of potential energy surfaces with total energy composed of bond stretching, angle, and torsional contributions as bonding and van der Waals interactions, H‐bonding and electrostatic functions as nonbonding energies. The reactional profiles for component molecules and their complexes were elucidated by exploring the spatial disposition of the various component molecular attributes . This review report provides an outlook of various molecular modeling templates generated to date and provides a brief account of rationale and results obtained from these in silico studies.…”

“…The reactional profiles for component molecules and their complexes were elucidated by exploring the spatial disposition of the various component molecular attributes. 2 This review report provides an outlook of various molecular modeling templates generated to date and provides a brief account of rationale and results obtained from these in silico studies. The details of the in silico methods employed in the studies are out of scope of this review and can be extracted from the individual references provided within the subsections.…”

Structure based virtual screening, molecular docking and molecular dynamics simulation of drug like small molecules against cell cycle regulator enzyme FtsZ of Mycobacterium tuberculosis

“…Though van der Waals interactions are weaker than covalent and electrostatic bonding but this bond in large is responsible for free energy change and made the major contribution to the total binding energies (Sood et al 2018;Mohanty et al 2018;Keretsu et al 2019). These interactions are known to stabilize the binding interface structures through intermolecular energy minimization (Kumar et al 2015;Arthur and Uzairu 2019). In this study we observed a large number of van der Waals interactions stabilizing the FtsZ and interacted small molecule docking complex.…”

Calpain inhibition modulates glycogen synthase kinase 3β pathways in ischemic myocardium: A proteomic and mechanistic analysis

“…MDL28170 is a cell permeable selective peptidomimetic inhibitor of calpain 1 and 2 that binds to the protease enzymatic site and inhibits its action. 22,23 IM-12 is a novel cell permeable indolyl maleimide which inhibits GSK-3β by competing for ATP binding. 24 The MDL28170 and IM-12 powder was dissolved in dimethyl sulfoxide (DMSO) and administered to the pigs orally.…”