In silico investigations on the binding efficacy and allosteric mechanism of six different natural product compounds towards PTP1B inhibition through docking and molecular dynamics simulations.

Protein tyrosine phosphatase 1B (PTP1B) is a major negative regulator of both the insulin and leptin receptor phosphorylation which impacts insulin sensitivity and hence is a major therapeutic target for the treatment of type 2 diabetes and obesity. Identification of PTP1B active site inhibitors has proven to be difficult with none of them clearing the phase II clinical trials. Since the conventional methods of targeting the active site of PTP1B have failed to bring out effective PTP1B inhibitors as potential drugs, recent studies are focussing on identification of potential allosteric inhibitors of PTP1B with better specificity and activity. A complete understanding of the molecular features dynamically involved for allosteric site inhibition is still uncertain, and hence, this study is aimed at evaluating the allosteric effectiveness of six natural compounds isolated from medicinal plants which showed in vitro antidiabetic activity along with PTP1B inhibition. The allosteric binding and inhibition of these compounds are studied using computational methods such as molecular docking, homology modelling and molecular dynamics simulations for a timescale of 100 ns. The molecular dynamics simulations of native PTP1B, along with the modelled allosteric α-7 helix, for a timescale of 100 ns, revealed the spontaneous transition of the native PTP1B from open WPD loop (active) to closed WPD loop (inactive) conformations during the simulations. Similar dynamics was observed in the presence of the active site substrate pTyr (phosphotyrosine), whereas this transition was inhibited in the presence of the compounds at the allosteric site. Results of molecular dynamics simulations and principal component analysis reveal that the hindrance to WPD loop was mediated through structural interactions between the allosteric α-helical triad with Loop11 and WPD loop. The MM-PBSA (Molecular Mechanics - Poisson Boltzmann with Surface Area solvation) binding energy results along with H-bonding analysis show the possible allosteric inhibition of Aloe emodin glycoside (AEG), 3β-taraxerol (3BT), chlorogenic acid (CGA) and cichoric acid (CHA) to be higher in comparison with (3β)-stigmast-5-en-3-ol (SGS) and methyl lignocerate (MLG). The interaction analysis was further validated by scoring the allosteric complexes before and after MD simulations using Glide. These findings on spontaneous PTP1B fluctuations and the allosteric interactions provide a better insight into the role of PTP1B fluctuations in impacting the binding energy of allosteric inhibitors towards optimal drug designing for PTP1B. Graphical abstract.