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Structural insights into mode of actions of novel natural Mycobacterium protein tyrosine phosphatase B inhibitors.

ABSTRACT: BACKGROUND: Tuberculosis has become a major health problem being the second leading cause of death worldwide. Mycobacterium tuberculosis secretes a virulence factor, protein tyrosine phosphatase B (mPTPB) in the cytoplasm of host macrophage which suppresses its natural innate immune response and helps the pathogen survive and proliferate in the phagosome. The present study aims at indentifying potent inhibitors of mPTPB by using computational approaches of ligand based molecular modeling and docking studies. RESULTS: A 3D QSAR model was developed using a set of benzofuran salicylic acid based mPTPB inhibitors with experimentally known IC50 values. The model was generated using the statistical method of principle component regression analysis in combination with step wise forward variable selection algorithm. It was observed that steric and hydrophobic descriptors positively contribute towards the inhibitory activity of the ligands. The developed model had a robust internal as well as external predictive power as indicated by the q(2) value of 0.8920 and predicted r(2) value of 0.8006 respectively. Hence, the generated model was used to screen a large set of naturally occurring chemical compounds and predict their biological activity to identify more potent natural compounds targeting mPTPB. The two top potential hits (with pIC50 value of 1.459 and 1.677 respectively) had a similar interaction pattern as that of the most potent compound (pIC50 = 1.42) of the congeneric series. CONCLUSION: The contour plot provided a better understanding of the relationship between structural features of substituted benzofuran salicylic acid derivatives and their activities which would facilitate design of novel mPTPB inhibitors. The QSAR modeling was used to obtain an equation, correlating the important steric and hydrophobic descriptors with the pIC50 value. Thus, we report two natural compounds of inhibitory nature active against mPTPB enzyme of Mycobacterium tuberculosis. These inhibitors have the potential to evolve as lead molecules in the development of drugs for the treatment of tuberculosis.

SUBMITTER: Dhanjal JK

PROVIDER: S-EPMC4046716 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Structural insights into mode of actions of novel natural Mycobacterium protein tyrosine phosphatase B inhibitors.

Dhanjal Jaspreet Kaur JK Grover Sonam S Sharma Sudhanshu S Singh Ajeet A Grover Abhinav A

BMC genomics 20140124

<h4>Background</h4>Tuberculosis has become a major health problem being the second leading cause of death worldwide. Mycobacterium tuberculosis secretes a virulence factor, protein tyrosine phosphatase B (mPTPB) in the cytoplasm of host macrophage which suppresses its natural innate immune response and helps the pathogen survive and proliferate in the phagosome. The present study aims at indentifying potent inhibitors of mPTPB by using computational approaches of ligand based molecular modeling ...[more]

PMID: 24564493

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Project description:BackgroundDevelopment of a cancerous cell takes place when it ceases to respond to growth-inhibiting signals and multiplies uncontrollably and can detach and move to other parts of the body; the process called as metastasis. A particular set of cysteine proteases are very active during cancer metastasis, Cathepsins being one of them. They are involved in tumor growth and malignancy and have also been reported to be overexpressed in tumor cell lines. In the present study, a combinatorial approach comprising three-dimensional quantitative structure-activity relationship (3D QSAR), ligand-based pharmacophore modelling and search followed by cathepsin L structure-based high throughput screening was carried out using an initial set of 28 congeneric thiosemicarbazone derivatives as cathepsin L inhibitors. A 3D QSAR was derived using the alignment of a common thiosemicarbazone substructure. Essential structural features responsible for biological activity were taken into account for development of a pharmacophore model based on 29 congeneric thiosemicarbazone derivatives. This model was used to carry out an exhaustive search on a large dataset of natural compounds. A further cathepsin L structure-based screen identified two top scoring compounds as potent anti-cancer leads.ResultsThe generated 3D QSAR model showed statistically significant results with an r(2) value of 0.8267, cross-validated correlation coefficient q(2) of 0.7232, and a pred_r(2) (r(2) value for test set) of 0.7460. Apart from these, a high F test value of 30.2078 suggested low probability of the model's failure. The pharmacophoric hypothesis chosen for searching the natural compound libraries was identified as DDHRR, where two Ds denote 2 hydrogen donors, H represents a hydrophobic group and two Rs represent aromatic rings, all of which are essential for the biological activity. We report two potential drug leads ZINC08764437 (NFP) and ZINC03846634 (APQ) obtained after a combined approach of pharmacophore-based search and structure-based virtual screen. These two compounds displayed extra precision docking scores of -7.972908 and -7.575686 respectively suggesting considerable binding affinity for cathepsin L. High activity values of 5.72 and 5.75 predicted using the 3D QSAR model further substantiated the inhibitory potential of these identified leads.ConclusionThe present study attempts to correlate the structural features of thiosemicarbazone group with their biological activity by development of a robust 3D QSAR model. Being statistically valid, this model provides near accurate values of the activities predicted for the congeneric set on which it is based. These predicted activities are good for the test set compounds making it indeed a statistically sound 3D QSAR model. The identified pharmacophore model DDHRR.8 comprised of all the essential features required to interact with the catalytic triad of cathepsin L. A search for natural compounds based on this pharmacophore followed by docking studies further screened out two top scoring candidates: NFP and AFQ. The high binding affinity and presence of essential structural features in these two compounds make them ideal for consideration as natural anti-tumoral agents. Activity prediction using 3D QSAR model further validated their potential as worthy drug candidates against cathepsin L for treatment of cancer.

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Structural insights into mode of actions of novel natural Mycobacterium protein tyrosine phosphatase B inhibitors.

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Structural insights into mode of actions of novel natural Mycobacterium protein tyrosine phosphatase B inhibitors.

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