Flavonostilbenes natural hybrids from Rhamnoneuron balansae as potential antitumors targeting ALDH1A1: molecular docking, ADMET, MM-GBSA calculations and molecular dynamics studies

• Published in: Journal of biomolecular structure & dynamics 2024-04, Vol.42 (6), p.3249-3266
• Main Authors: Elsaman, Tilal, Ahmad, Iqrar, Eltayib, Eyman Mohamed, Suliman Mohamed, Malik, Yusuf, Osman, Saeed, Mohamed, Patel, Harun, Mohamed, Magdi Awadalla
• Format: Article
• Language: English
• Subjects: Cancer; flavonostilbenes; natural hybrids; rhamnoneuron balansae; ALDH1A1; in silico drug discovery; Ligands; Molecular Docking Simulation; Molecular Dynamics Simulation; Quercetin; Resveratrol
• ISSN: 0739-1102; 1538-0254
• DOI: 10.1080/07391102.2023.2218936

Several studies have linked Cancer stem cells (CSCs) to cancer resistance development to chemotherapy and radiotherapy. ALDH1A1 is a key enzyme that regulates the gene expression of CSCs and creates an immunosuppressive tumor microenvironment. It was reported that quercetin and resveratrol were among the inhibitors of ALDH1A1. In early 2022, it was reported that new 11 flavonostilbenes (rhamnoneuronal D-N) were isolated from Rhamnoneuron balansae as potential antiaging natural products. Rhamnoneuronal H (5) could be envisioned as a natural hybrid of quercetin and resveratrol. It was therefore hypothesized that 5 and its analogous isolates rhamnoneuronal D-G (1-4) and rhamnoneuronal I-N (6-11) would have potential ALDH1A1 inhibitory activity. To this end, all isolates were subjected to molecular docking, MM-GBSA, ADMET, and molecular dynamics simulations studies to assess their potential as new leads for cancer treatment targeting ALDH1A1. In silico findings revealed that natural hybrid 5 has a similar binding affinity, judged by MM-GBSA, to the ALDH1A1 active site when compared to the co-crystalized ligand (−64.71 kcal/mole and −64.12 kcal/mole, respectively). Despite having lesser affinity than that of the co-crystalized ligand, the rest of the flavonostilbenes, except 2-4, displayed better binding affinities (−37.55 kcal/mole to −58.6 kcal/mole) in comparison to either resveratrol (−34.44 kcal/mole) or quercetin (−36.48 kcal/mole). Molecular dynamic simulations showed that the natural hybrids 1, 5-11 are of satisfactory stability up to 100 ns. ADMET outcomes indicate that these hybrids displayed acceptable properties and hence could represent an ideal starting point for the development of potent ALDH1A1 inhibitors for cancer treatment. Communicated by Ramaswamy H. Sarma