In silico and saturation transfer difference NMR approaches to unravel the binding mode of an andrographolide derivative to K-Ras oncoprotein

• Published in: Future medicinal chemistry Vol. 12; no. 18; pp. 1611 - 1631
• Main Authors: Quah, Shun Ying, Tan, Michelle Siying, Ho, Kok Lian, Manan, Nizar Abdul, Gorfe, Alemayehu Abebe, Deb, Pran Kishore, Sagineedu, Sreenivasa Rao, Stanslas, Johnson
• Format: Journal Article
• Language: English
• Published: England Newlands Press 01-09-2020
• Subjects: Amino acids; Antitumor activity; Apoptosis; Binding sites; Biological activity; Cancer; Cell cycle; Hydrophobicity; K-Ras protein; Ligands; Molecular dynamics; Mutation; NMR; Nuclear magnetic resonance; Oncoproteins; Operating systems; Proteins; Protons; Random access memory; Signal transduction; Spectrum analysis; Tumors; binding pocket; docking; Desmond; SRJ23; STD-NMR; K-Ras oncoprotein; molecular dynamics; Glide; anticancer; andrographolide
• DOI: 10.4155/fmc-2020-0104
• EISSN: 1756-8927
• ISSN: 1756-8919

Andrographolide and its benzylidene derivatives, SRJ09 and SRJ23, potentially bind oncogenic K-Ras to exert anticancer activity. Their molecular interactions with K-Ras oncoproteins that lead to effective biological activity are of major interest.
docking and molecular dynamics simulation were performed using Glide and Desmond, respectively; while saturation transfer difference NMR was performed using GDP-bound K-RasG12V. SRJ23 was found to bind strongly and selectively to K-RasG12V, by anchoring to a binding pocket (namely p2) principally via hydrogen bond and hydrophobic interactions. The saturation transfer difference NMR analysis revealed the proximity of protons of functional moieties in SRJ23 to K-RasG12V, suggesting positive binding.
SRJ23 binds strongly and interacts stably with K-RasG12V to exhibit its inhibitory activity.