Identification of new small molecule allosteric SHP2 inhibitor through pharmacophore-based virtual screening, molecular docking, molecular dynamics simulation studies, synthesis and
            <i>in vitro</i>
            evaluation

Mitra, Rangan; Kumar, Sandeep; Ayyannan, Senthil Raja

doi:10.1080/07391102.2023.2291733

Journal of Biomolecular Structure and Dynamics

2023

DOI: 10.1080/07391102.2023.2291733

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Identification of new small molecule allosteric SHP2 inhibitor through pharmacophore-based virtual screening, molecular docking, molecular dynamics simulation studies, synthesis and in vitro evaluation

Rangan Mitra,

Sandeep Kumar,

Senthil Raja Ayyannan

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2024

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Cited by 3 publications

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Design, Synthesis and Evaluation of Thioacetamide‐Tethered Thiadiazole‐1,2,4‐Triazole Hybrids as SHP2 Inhibitors for Cancer Therapy

Mitra,

Kumar,

Chaudhuri

et al. 2024

ChemistrySelect

Self Cite

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Src homology‐2 (SH2) domain‐containing phosphatase‐2 (SHP2), the first protooncogenic phosphatase is a key mediator in the development and progression of various cancers. Several allosteric sites have been identified in SHP2, inhibitors of which are being developed. In the current study, we have designed and synthesized a library of 21 thioacetamide‐tethered thiadiazole‐1,2,4‐triazole hybrids (compounds 16–36) and evaluated their in vitro SHP2 inhibitory potential. Compound 28 (N‐(5‐(benzo[d][1,3]dioxol‐5‐yl)‐1,3,4‐thiadiazol‐2‐yl)‐2‐((5‐(4‐methoxyphenyl)‐4H‐1,2,4‐triazol‐3‐yl)thio)acetamide) emerged as the most potent SHP2 inhibitor (IC50=0.318±0.001 μM) inhibiting the enzyme in a mixed to non‐competitive manner. In silico studies revealed that the lead inhibitor strongly binds to the tunnel allosteric site of SHP2. Further, cytotoxicity studies revealed that compound 28 caused death of SHP2‐driven MCF‐7 (GI50=37.02±0.25 μM) and U87MG cells (GI50=68.69±0.21 μM) in a dose‐dependent manner and inhibited MCF‐7 cell colony formation and migration. Flow cytometric analysis showed that it exerted its antiproliferative effect on U87MG cells by inducing early apoptosis (Q2 phase) and inhibiting cell cycle progression at the G1 and S phase. Compound 28 was shown to increase oxidative stress in the U87 cells by promoting ROS generation and loss of mitochondrial integrity. In summary, the present study produced a potent SHP2 inhibitor (compound 28) with a promising in vitro cytotoxicity profile, thus meriting further investigation.

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Design, Synthesis and Evaluation of Thioacetamide‐Tethered Thiadiazole‐1,2,4‐Triazole Hybrids as SHP2 Inhibitors for Cancer Therapy

Mitra,

Kumar,

Chaudhuri

et al. 2024

ChemistrySelect

Self Cite

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Targeting human progesterone receptor (PR), through pharmacophore-based screening and molecular simulation revealed potent inhibitors against breast cancer

Shahab,

Ziyu,

Waqas

et al. 2024

Sci Rep

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Breast cancer, the prevailing malignant tumor among women, is linked to progesterone and its receptor (PR) in both tumorigenesis and treatment responsiveness. Despite thorough investigation, the precise molecular mechanisms of progesterone in breast cancer remain unclear. The human progesterone receptor (PR) serves as an essential therapeutic target for breast cancer treatment, warranting the rapid design of small molecule therapeutics that can effectively inhibit HPR. By employing cutting-edge computational techniques like molecular screening, simulation, and free energy calculation, the process of identifying potential lead molecules from natural products has been significantly expedited. In this study, we employed pharmacophore-based virtual screening and molecular simulations to identify natural product-based inhibitors of human progesterone receptor (PR) in breast cancer treatment. High-throughput molecular screening of traditional Chinese medicine (TCM) and zinc databases was performed, leading to the identification of potential lead compounds. The analysis of binding modes for the top five compounds from both database provides valuable structural insights into the inhibition of HPR for breast cancer treatment. The top five hits exhibited enhanced stability and compactness compared to the reference compound. In conclusion, our study provides valuable insights for identifying and refining lead compounds as HPR inhibitors.

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In silico validation of allosteric inhibitors targeting Zika virus NS2B–NS3 protease

Wang,

Hsieh,

2024

Phys. Chem. Chem. Phys.

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Identification of new small molecule allosteric SHP2 inhibitor through pharmacophore-based virtual screening, molecular docking, molecular dynamics simulation studies, synthesis and in vitro evaluation

Cited by 3 publications

References 45 publications

Design, Synthesis and Evaluation of Thioacetamide‐Tethered Thiadiazole‐1,2,4‐Triazole Hybrids as SHP2 Inhibitors for Cancer Therapy

Design, Synthesis and Evaluation of Thioacetamide‐Tethered Thiadiazole‐1,2,4‐Triazole Hybrids as SHP2 Inhibitors for Cancer Therapy

Targeting human progesterone receptor (PR), through pharmacophore-based screening and molecular simulation revealed potent inhibitors against breast cancer

In silico validation of allosteric inhibitors targeting Zika virus NS2B–NS3 protease

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