Identification of NEK7 Inhibitors: Structure based Virtual Screening, Molecular Docking, Density functional theory calculations and Molecular Dynamics Simulations
Mubashir Aziz, Syeda Abida Ejaz, Hafiz Muzzammel Rehman, Mohammed Sultan Al-Buriahi, Farhan Siddique, H.H. Somaily, Ziyad Awadh Alrowaili · Research Square · 2022
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 findings motivated us to design in-silico approach for investigation and identification 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) profile evaluation was also carried out to ascertain toxicity profile of both drugs. The proposed inhibitor–protein complexes were further subjected to Molecular Dynamics (MD) Simulations studies involving root-mean-square deviation and root-mean-square fluctuation 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.