Journal of Molecular Modeling

, 25:272 | Cite as

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

  • Baskaran SarathKumar
  • Baddireddi Subhadra LakshmiEmail author
Original Paper


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


Molecular docking Homology modelling Molecular dynamics simulation PTP1B allosteric inhibitors PCA MM-PBSA analysis Glide docking Binding energy analysis Allosteric α-7 helix 



The authors thank Dr. T. Kothai and Dr. P. Gautam for their constant support and encouragement. The authors are grateful to Dr. Subrata Chattopadhyay (C-DAC) and Janaki Chintalapati (C-DAC) for providing access to computational resources of the GARUDA Cluster facility, C-DAC, Government of India, to run the Gromacs v4.0.5-MD Simulations during 2013–2015.

Funding information

The authors thank the Department of Biotechnology, Govt of India for financial assistance for the HPC cluster computer for Drug Design and related commercial Schrodinger software through the DBT-BUILDER (BT/PR12153/INF/22/200/2014)., and the DBT-BTIS-DIC facility at Centre for Biotechnology, Anna University, Chennai. The author Mr. SarathKumar B sincerely thanks the Council for Scientific and Industrial Research, Govt. of India, for financial assistance as CSIR-SRF (09/468(0480)/2014-EMR-1).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

894_2019_4172_MOESM1_ESM.docx (28.3 mb)
ESM 1 (DOCX 28.2 mb)


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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Baskaran SarathKumar
    • 1
  • Baddireddi Subhadra Lakshmi
    • 1
    Email author
  1. 1.Department of BiotechnologyAnna UniversityChennaiIndia

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