Targeting EGFR, RSK1, RAF1, PARP2 and LIN28B for several cancer type therapies with newly synthesized pyrazole derivatives via a computational study

Abstract

Cancer remains the leading cause of death in the world despite the significant advancements made in anticancer drug discovery. This study is aimed to computationally evaluate the efficacy of 63 in-house synthesized pyrazole derivatives targeted to bind with prominent cancer targets namely EGFR, RSK1, RAF1, PARP2 and LIN28B known to be expressed, respectively, in lung, colon, skin, ovarian and pancreatic cancer cells. Initially, we perform the molecular docking investigations for all pyrazole compounds with a comparison to known standard drugs for each target. Docking studies have revealed that some pyrazole compounds possess better binding affinity scores than standard drug compounds. Thereafter, a long-range of 1 μs molecular dynamic (MD) simulation study for top ranked docked compounds with all respective proteins was carried out to assess the interaction stability in a dynamic environment. The results suggested that the top ranked complexes showed a stable interaction profile for a longer period of time. The outcome of this study suggests that pyrazole compounds, M33, M36, M76 and M77, are promising molecular candidates that can modulate the studied target proteins significantly in comparison to their known inhibitor based on their selective binding interactions profile. Furthermore, ADME-T profile has been explored to check for the drug-likeness and pharmacokinetics profiles and found that all proposed compounds exhibited acceptable values for being a potential drug-like candidate with non-toxic characteristics. Overall, extensive computational investigations indicate that the four proposed pyrazole inhibitors/modulators studied against each respective target protein will be helpful for future cancer therapeutic developments.

Communicated by Ramaswamy H. Sarma

Keywords:

• Cancer
• pyrazole derivatives
• molecular docking
• molecular dynamics simulation
• ADME-T

Disclosure statement

No potential conflict of interest was reported by the authors.

Data and software availability

For molecular docking, we used AutoDock Vina, for molecular dynamics simulation, we used Desmond v.4.2 molecular dynamics system simulation wizard integrated in Schrodinger suite LLC, and finally, to draw structures, we used ChemDraw 15.0.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.