Identification of potential inhibitors of tropomyosin receptor kinase B targeting CNS-related disorders and cancers

Abstract

Tropomyosin receptor kinase B (TrkB), also known as neurotrophic tyrosine kinase receptor type 2 (NTRK2), is a protein that belongs to the family of receptor tyrosine kinases (RTKs). NTRK2 plays a crucial role in regulating the development and maturation of the central nervous system (CNS) and peripheral nervous system (PNS). Elevated TrkB expression levels observed in different pathological conditions make it a potential target for therapeutic interventions against neurological disorders, including depression, anxiety, Alzheimer’s disease, Parkinson’s disease, and certain types of cancer. Targeting TrkB using small molecule inhibitors is a promising strategy for the treatment of a variety of neurological disorders. In this research, a systematic virtual screening was carried out on phytoconstituents found in the IMPPAT library to identify compounds potentially inhibiting TrkB. The retrieved compounds from the IMPPAT library were first filtered using Lipinski’s rule of five. The compounds were then sorted based on their docking score and ligand efficiency. In addition, PAINS, ADMET, and PASS evaluations were carried out for selecting drug-like compounds. Finally, in interaction analysis, we found two phytoconstituents, Wedelolactone and 3,8-dihydroxy-1-methylanthraquinone-2-carboxylic acid (DMCA), which possessed considerable docking scores and specificity on the TrkB ATP-binding pocket. The selected compounds were further assessed employing molecular dynamics (MD) simulations and essential dynamics. The results revealed that the elucidated compounds bind well with the TrkB binding pocket and lead to fewer conformations fluctuations. This study highlighted using phytoconstituents, Wedelolactone and DMCA as starting leads in developing novel TrkB inhibitors.

Communicated by Ramaswamy H. Sarma

Keywords:

• Tropomyosin receptor kinase B
• virtual screening
• phytochemicals
• drug discovery
• molecular dynamics simulations

Acknowledegments

The researchers would like to acknowledge Deanship of Scientific Research, Taif University for funding this work.

Disclosure statement

There is no conflict of interest to declare.

Data availability statement

The data underlying this article is available within the manuscript.

Authors’ contribution

Mohammed Ageeli Hakami: Conceptualization, methodology, software, formal analysis, data curation, writing – original draft, writing – review & editing. Bader S. Alotaibi: Formal analysis, writing – original draft, writing – review & editing. Ali Hazazi: Writing – original draft, writing – review & editing. Alaa Shafie: Writing – review & editing. Ahad Amer Alsaiari: Methodology, investigation, visualization, validation, writing – original draft, writing – review & editing. Amal Adnan Ashour: Formal analysis, data curation, writing – review & editing. Farah Anjum: Writing – review & editing, supervision, project administration. All authors read and approved the final manuscript.