Discovery of sulfone-resistant dihydropteroate synthase (DHPS) as a target enzyme for kaempferol, a natural flavanoid

Angamba Meetei Potshangbam; Ravindranath Singh Rathore; Potshangbam Nongdam

doi:10.1016/j.heliyon.2020.e03378

Discovery of sulfone-resistant dihydropteroate synthase (DHPS) as a target enzyme for kaempferol, a natural flavanoid

Heliyon. 2020 Feb 12;6(2):e03378. doi: 10.1016/j.heliyon.2020.e03378. eCollection 2020 Feb.

Authors

Angamba Meetei Potshangbam¹, Ravindranath Singh Rathore², Potshangbam Nongdam¹

Affiliations

¹ Department of Biotechnology, Manipur University, Imphal, India.
² Department of Bioinformatics, School of Earth, Biological and Environmental Sciences, Central University of South Bihar, Gaya, India.

Abstract

Kaempferol is a ubiquitous flavonoid, found in various plants having a wide range of known pharmacological activities, including antioxidant, antiinflammatory, anticancer, antiallergic, antidiabetic, neuroprotective, cardioprotective and antimicrobial activities. Nonetheless various evidence suggest that kaempferol is also able to interact with many unknown therapeutic targets modulating signalling pathways, thus providing an opportunity to explore the potential target space of kaempferol. In this study, we have employed various ligand-based approaches to identify the potential targets of kaempferol, followed by validations using modelling and docking studies. Molecular dynamics, free energy calculations, volume and residue contact map analyses were made to delineate the cause of drug-resistance among mutants. We have discovered dihydropteroate synthase (DHPS) as a novel potential therapeutic target for kaempferol. Further studies employing molecular dynamics simulations and binding free energies indicate that kaempferol has potential to inhibit even the sulfone-resistant DHPS mutants, which makes it a very attractive antibiotic agent. The identification of natural-product based kaempferol opens up the door for the design of antibiotics in a quick and high throughput fashion for identifying antibiotic leads.

Keywords: Antibiotic; Binding free energy; Biochemistry; Bioinformatics; Computational biology; DHPS; Dihydropteroate synthase; Docking; Kaempferol; Molecular dynamics simulations; Pharmaceutical chemistry; Pharmaceutical science; Residue contact map; Shape-based screening.