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Homology modelling and virtual screening to explore potent inhibitors for MAP2K3 protein

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Abstract

MAP2K3 protein is mitogen-activated protein kinase belonging to the family of kinases involved in intracellular cell proliferation. The mammalian MAPK family that consists of ERK, p38 and JNK signalling pathway is showing a critical role in the regulation of cell proliferation. MAP2K3 and MAP2K6 are highly selective for p38 MAPKs which actively participate at check point controls and various stages of cell cycle at G0, G1/S and G2/M transitions by differential regulation of specific cyclin A or D1. In the present work, the 3D model of MAP2K3 protein is generated using comparative homology modelling techniques, minimized and validated. Active site of the protein is determined using various server tools and literature studies, for the prediction of important binding pockets to identify the putative active site. Virtual screening was carried out using chalcone library in Schrodinger suite to identify new lead molecules to knock down MAP2K3 target protein and inhibit cell proliferation. An Atomistic MD simulation of screened compound with MAP2K3 not only strengthens our findings but also identified the key interactions involved in protein-ligand complex in the dynamic environment.

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Abbreviations

NAMD:

Nanoscale molecular dynamics

PDB:

Protein Data Bank

CASTp:

Computed Atlas of surface topography of proteins

ProSA:

Protein structure analysis

OPLS:

Optimized potentials for liquid simulations

MMGBSA:

Molecular mechanics generalized born surface area

RMSD:

Root mean square deviation

SAVES:

Structural analysis and verification server

ADME:

Absorption distribution metabolism and excretion

MD:

Molecular dynamics

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Acknowledgement

The author Manan Bhargavi is thankful to the Principal and Head, Department of Chemistry, University College of Science and Nizam College, Osmania University, for providing the facilities to carry out the research work. AJ acknowledges the Department of Biotechnology, Govt of India, for the Ramalingamswami Re-entry Fellowship-2019 and the Birla Institute of Technology Mesra, Ranchi, India, for providing the facilities to carry out the research work.

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Authors and Affiliations

  1. Molecular Modeling Laboratory, Department of Chemistry, Nizam College, Osmania University, Basheerbagh, Hyderabad, India

    Manan Bhargavi, Nazmina Vhora, Goverdhan Lanka, Gururaj Somadi, Sivan Sree Kanth & Sarita Rajender Potlapally

  2. Department of Bio-Engineering, Birla Institute of Technology, Mesra, Ranchi, India

    Alok Jain

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  1. Manan Bhargavi
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  2. Nazmina Vhora
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Correspondence to Sarita Rajender Potlapally.

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Bhargavi, M., Vhora, N., Lanka, G. et al. Homology modelling and virtual screening to explore potent inhibitors for MAP2K3 protein. Struct Chem 32, 1039–1051 (2021). https://doi.org/10.1007/s11224-020-01667-w

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  • DOI: https://doi.org/10.1007/s11224-020-01667-w

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