Pharmacophore based virtual screening, molecular docking and molecular dynamic simulation studies for finding ROS1 kinase inhibitors as potential drug molecules

Abstract

Proto-oncogene receptor tyrosine kinase ROS-1 is one of the clinically important biomarker and plays a crucial role in regulation of a number of cellular functions including cell proliferation, migration and angiogenesis. Recently, inhibition of ROS1 kinase has proven to be a promising target of anticancer drugs for non-small cell lung cancer (NSCLC). The very few compounds have been used as potent drug molecules so far and the selective ROS1 inhibitors are relatively rare. Besides the currently available drugs such as Crizotinib and PF-06463922 are becoming sensitive due to mutations in the ROS1 protein. To curtail the problem of the resistant, present study was designed to identify the potent inhibitors against ROS1. Three different screening approaches such as structure based, Atom-based and pharmacophore based screening were carried out against commercially available databases and the retrieved best hits were further evaluated by Lipinski’s filter. Thereafter the lead molecule was subjected to pocket specific docking with ROS1. The results show that, total of 9 molecules (3 from each screening) has good docking score (with range of −9.288 to −12.49 Kcal/Mol) and binding interactions within the active site of ROS1. In order to analyze the stability of the ligand- protein complexes, molecular dynamics simulation was performed. Thus, these identified potential lead molecules with good binding score and binding affinity with ROS1 may act as the potent ROS1 inhibitor, and that are worth considering for further experimental studies.

Communicated by Ramaswamy H. Sarma

Keywords:

• ROS1
• atom-based screening
• molecular docking
• molecular dynamics
• IFD
• ADMET
• MM/GBSA

Acknowledgements

RV thanks UGC for providing DSK postdoctoral fellowship Ref: UGC Award letter. F.4-2/2006 (BSR)/BL/17-18/0210 (76th List)/15th June 2018. The authors extend their appreciation to the Researchers Supporting Project number (RSP-2020/228), King Saud University, Riyadh, Saudi Arabia.

Disclosure statement

None.