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Structure-Based Virtual Screening of High-Affinity ATP-Competitive Inhibitors Against Human Lemur Tyrosine Kinase-3 (LMTK3) Domain: A Novel Therapeutic Target for Breast Cancer

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Abstract

Human lemur tyrosine kinase-3 (LMTK3) is an oncogenic kinase known to regulate ER-α through phosphorylation and is considered to be a novel therapeutic target for breast cancer. In this work, we have studied the ATP-binding mechanism with LMTK3 domain and also carried out virtual screening on LMTK3 to identify lead compounds using Dock blaster server. The top scored compounds obtained from Dock blaster were then narrowed down further to six lead compounds (ZINC37996511, ZINC83363046, ZINC3745998, ZINC50456700, ZINC83351792 and ZINC83364581) based on high-binding affinity and non-bonding interactions with LMTK3 using Autodock 4.2 program. We found in comparison to ATP, the lead compounds bind relatively stronger to LMTK3. The relative binding free energy results from MM-PBSA/GBSA method further indicate the strong binding affinity of lead compounds over ATP to LMTK3 in the dynamic system. Further, potential of mean force (PMF) study for ATP and lead compounds with LMTK3 have been performed to explore the unbinding processes and the free energy barrier. From the PMF results, we observed that the lead compounds have higher dissociation energy barriers than the ATP. Our findings suggest that these lead compounds may compete with ATP, and could act as probable potential inhibitors for LMTK3.

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Acknowledgements

We would like to thank Tezpur University and UGC for the start-up Grant, and DBT funded Bioinformatics Infrastructure facility in the Department of Molecular Biology and Biotechnology at Tezpur University for providing us computational facility to carry out this research work. We would also like to thank Miss Sushmita Pradhan, Research Scholar at Molecular Modelling and Simulation Laboratory, Department of MBBT, Tezpur University for helping us in the preparation of figures.

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  1. Molecular Modelling and Simulation Laboratory, Department of Molecular Biology and Biotechnology, Tezpur University, Tezpur, Assam, 784 028, India

    Himakshi Sarma & Venkata Satish Kumar Mattaparthi

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Correspondence to Venkata Satish Kumar Mattaparthi.

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Sarma, H., Mattaparthi, V.S.K. Structure-Based Virtual Screening of High-Affinity ATP-Competitive Inhibitors Against Human Lemur Tyrosine Kinase-3 (LMTK3) Domain: A Novel Therapeutic Target for Breast Cancer. Interdiscip Sci Comput Life Sci 11, 527–541 (2019). https://doi.org/10.1007/s12539-018-0302-7

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