Identification of NEK7 inhibitors: structure based virtual screening, molecular docking, density functional theory calculations and molecular dynamics simulations

Abstract

NEK7 plays a crucial role in many signaling pathways and contributes to a variety of cancers. Therefore, NEK7 has long been considered an attractive drug target in anti-cancer drug discovery. However, only a few efforts have been made in development of NEK7 inhibitors with selectivity. In the present study, we have investigated FDA approved kinase inhibitors as potential NEK7 inhibitors. Although more than 200 FDA approved drugs are available but none is known to inhibit NEK7 protein. These ndings motivated us to design in-silico approach for investigation and identi cation of NEK7 protein. In the current study, Structure-based virtual screening and molecular docking were carried out to identify potential NEK7 inhibitors. Dacomitinib and Neratinib was selected depending upon their potential activities against various cancer cell lines. These drugs were subjected to density functional theory calculations which demonstrated the chemical reactivity of both drugs. Furthermore, molecular docking studies were conducted using Molecular Operating environment 2015.10 and conformations with high docking scores and strong interactions were selected for further analysis. Absorption, distribution, metabolism, elimination and toxicity (ADMET) pro le evaluation was also carried out to ascertain toxicity pro le of both drugs. The proposed inhibitorprotein complexes were further subjected to Molecular Dynamics (MD) Simulations studies involving root-mean-square deviation and root-mean-square uctuation to explore the binding mode stability inside active pockets. Finally, both drugs were obtained as potential inhibitors of NEK7 protein. All these analyses provide a reference for the further development of NEk7 inhibitors.

Design, Synthesis, Kinetic Analysis and Pharmacophore-Directed Discovery of 3-Ethylaniline Hybrid Imino-Thiazolidinone as Potential Inhibitor of Carbonic Anhydrase II: An Emerging Biological Target for Treatment of Cancer

“…After 25 ns, the RMSD pattern of the CA-II-6e complex remained steady. The average RMSD for the CA-II-6e complex was 2.92 angstroms, which is quite acceptable [ 33 ]. Compound 6e may be a possible CA-II inhibitor with substantial anticancer effects, based on the development of the RMSD pattern and the establishment of significant interactions with active amino acid residues, GLN92, and PHE131.…”

“…As a result, the MM-GBSA approach provides an accurate estimation of the free energies by accounting for all electrostatic, hydrophilic, and hydrophobic interactions. The binding free energy was calculated using a script-based technique [ 33 ]. Free energies from the MM-GBSA technique were found to be more negative and superior to docking scores from molecular docking.…”

Computational Exploration of Fluorocyclopentenyl‐purines and‐pyrimidines Derivatives as Potential Inhibitors of Epidermal Growth Factor Receptor (EGFR) for the Treatment of Breast Cancer

“…The system was equilibrated in an NVT ensemble for 500000 steps, followed by another 500000 steps in an NPT ensemble. After that, the simulation was run for 50 ns under periodic boundary conditions and results were visualized by using VMD, as earlier [32] …”

“…After that, the simulation was run for 50 ns under periodic boundary conditions and results were visualized by using VMD, as earlier. [32]…”

In silico study to identify novel NEK7 inhibitors from natural source by a combination strategy

“…Given its proven efficacy as an inhibitor of the NEK9 protein, and the structural similarity between NEK7 and NEK9, dabrafenib was also incorporated into the docking analysis as a reference compound, alongside selected popular molecules [29].…”