Citation
Shun, Ying Quah and Tan, Michelle Siying and Kok, Lian Ho and Abd Manan, Nizar and Gorfe, Alemayehu A. and Deb, Pran Kishore and Sagineedu, Sreenivasa Rao and Stanslas, Johnson
(2020)
In silico and saturation transfer difference NMR approaches to unravel the binding mode of an andrographolide derivative to K-Ras oncoprotein.
Future Medicinal Chemistry, 12 (18).
1611 - 1631.
ISSN 1756-8919; ESSN: 1756-8927
Abstract
Background: 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. Methods & results: In silico 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. Conclusion: SRJ23 binds strongly and interacts stably with K-RasG12V to exhibit its inhibitory activity.
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