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

Shun Ying Quah

Department of Medicine, Pharmacotherapeutics Unit, Faculty of Medicine & Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia

,
Michelle Siying Tan

Department of Medicine, Pharmacotherapeutics Unit, Faculty of Medicine & Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia

,
Kok Lian Ho

Department of Pathology, Faculty of Medicine & Health Sciences, Universiti Putra Malaysia, 43400 UPM, Serdang, Selangor, Malaysia

,
Nizar Abdul Manan

Department of Human Anatomy, Faculty of Medicine & Health Sciences, Universiti Putra Malaysia, 43400 UPM, Serdang, Selangor, Malaysia

,
Alemayehu Abebe Gorfe

Department of Integrative Biology & Pharmacology, University of Texas McGovern Medical School in Houston, 6431 Fannin St., MSB 4.108 Houston, TX 77030, USA

,
Pran Kishore Deb

Faculty of Pharmacy, Philadelphia University, 19392 Amman, Jordan

,
Sreenivasa Rao Sagineedu

Department of Pharmaceutical Chemistry, School of Pharmacy, International Medical University, 57000 Kuala Lumpur, Malaysia

&
Johnson Stanslas

*Author for correspondence:

E-mail Address: jstanslas@yahoo.co.uk

Department of Medicine, Pharmacotherapeutics Unit, Faculty of Medicine & Health Sciences, Universiti Putra Malaysia, 43400 Serdang, Selangor, Malaysia

Published Online:https://doi.org/10.4155/fmc-2020-0104

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.

Graphical abstract

Papers of special note have been highlighted as: • of interest; •• of considerable interest

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