Homology modelling and virtual screening to explore potent inhibitors for MAP2K3 protein
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ORIGINAL RESEARCH
Homology modelling and virtual screening to explore potent inhibitors for MAP2K3 protein Manan Bhargavi 1 & Nazmina Vhora 1 & Goverdhan Lanka 1 & Gururaj Somadi 1 & Sivan Sree Kanth 1 & Alok Jain 2 & Sarita Rajender Potlapally 1 Received: 31 March 2020 / Accepted: 19 October 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
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. Keywords Homology modelling . Energy minimization . Virtual screening . Prime MM-GBSA . MD simulations
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
* Sarita Rajender Potlapally [email protected]; [email protected] 1
Molecular Modeling Laboratory, Department of Chemistry, Nizam College, Osmania University, Basheerbagh, Hyderabad, India
2
Department of Bio-Engineering, Birla Institute of Technology, Mesra, Ranchi, India
Introduction Mitogen-activated protein kinases (MAPKs) are signaltransducing enzymes [1]. MAP2K3 protein belongs to the family of specificity mitogen-activated protein kinases. These are serine threonine protein kinases involved in intracellular cell proliferation [2, 3]. The mammalian MAPK family consists of extracellular signal-regulated kinases (ERKs), C-Jun N-terminal kinases (JNKs) and p38kinases which are in conjunction participating in signalling pathway during cell proliferation. Together, p38 MAPK and JNK family are also called as SAPKs (stress-activated protein kinases) [4]. MAP2K3 protein is involved in p38 MAPK signalling pathway which is very importan
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