Identifying Isoononin and Candidissiol as Rho-associated protein kinase 1 (ROCK1) inhibitors: a combined virtual screening and MD simulation approach

Abstract

Rho-associated protein kinase 1 (ROCK1) is a member of the AGC family which plays crucial roles in inflammatory diseases and cancer progression. Elevated expression of ROCK1 has been reported in multiple cancer types, and thus it has emerged as a potential drug target for cancer therapeutics. In this study, we performed a structure-based virtual screening of the natural compounds taken from the IMPPAT database to find some potential molecules as inhibitors of ROCK1. For the first step, we selected the compounds based on the Lipinski rule of five, and then we filtered them based on their ADMET properties and PAINS value. After this, other parameters like binding affinities, docking score, biological properties and selectivity were calculated to find appropriate hits against ROCK1. Finally, we identified two natural compounds, Isoononin and Candidissiol, with appreciable binding affinity and selectivity towards ROCK1. Furthermore, all-atom molecular dynamics simulations were carried out on ROCK1 with the elucidated compounds, which suggested stability throughout the simulated trajectories of 100 ns. Taken together, Isoononin and Candidissiol could be considered as potential inhibitors of ROCK1 for developing anticancer therapeutics.

Communicated by Ramaswamy H. Sarma

Keywords:

• Rho-associated protein kinase 1
• cancer therapy
• natural compounds
• drug discovery
• virtual screening
• molecular dynamic simulation

Disclosure statement

No potential conflict of interest was reported by the authors.

Informed consent statement

Not applicable.

Institutional review board statement

Not applicable.

Data availability statement

Not applicable

Additional information

Funding

Indian Council of Medical Research (Project No. ISRM/12(22)/2020). MSK acknowledges the generous support from Research Supporting Project (RSP-2021/352) by King Saud University, Riyadh, Kingdom of Saudi Arabia. MIH thanks the Department of Science and Technology, Government of India for the FIST support (FIST program No. SR/FST/LSII/2020/782).