2. Academic Validation
  3. Multi-scale In Silico and Biochemical Evaluation of Natural Bisbenzylisoquinoline Alkaloids as Aldose Reductase Inhibitors

Multi-scale In Silico and Biochemical Evaluation of Natural Bisbenzylisoquinoline Alkaloids as Aldose Reductase Inhibitors

  • Protein J. 2025 Nov 8. doi: 10.1007/s10930-025-10297-2.
Emadeldin M Kamel 1,  Noha A Ahmed 2,  Sarah I Othman 3,  Adil Abalkhail 4,  Faris F Aba Alkhayl 5,  Bassam A Abuamarah 6,  Saleh Maodaa 7,  Al Mokhtar Lamsabhi 8
Affiliations

Affiliations

  • 1 Chemistry Department, Faculty of Science, Beni-Suef University, Beni-Suef, 62514, Egypt.
  • 2 Physiology Division, Zoology Department, Faculty of Science, Beni-Suef University, P.O. Box 62521, Beni-Suef, Egypt. [email protected].
  • 3 Department of Biology, College of Science, Princess Nourah bint Abdulrahman University, P.O. BOX 84428, 11671, Riyadh, Saudi Arabia.
  • 4 Department of Public Health, College of Applied Medical Sciences, Qassim University, Buraydah, Saudi Arabia.
  • 5 Department of Medical Laboratories, College of Applied Medical Sciences, Qassim University, 51452, Buraydah, Saudi Arabia.
  • 6 Department of Geology and Geophysics, King Saud University, 11451, Riyadh, Saudi Arabia.
  • 7 Department of Zoology, College of Science, King Saud University, PO Box -2455, 11451, Riyadh, Saudi Arabia.
  • 8 Departamento de Química and Institute for Advanced Research in Chemical Science (IAdChem), Facultad de Ciencias, Módulo 13, Universidad Autónoma de Madrid, 28049, Madrid, Spain.
PMID: 41206377 DOI: 10.1007/s10930-025-10297-2
Abstract

Aldose Reductase (AR) is the rate-limiting enzyme of the polyol pathway and a validated target for preventing micro- and neurovascular complications of diabetes. Here, we combined multi-scale in-silico analyses with biochemical testing to evaluate five commercially available bisbenzylisoquinoline alkaloids-cepharanthine, dauricine, isotetrandrine, fangchinoline and sinomenine-as potential AR inhibitors. Density-functional optimization, structure-based docking and 500 ns molecular-dynamics simulations revealed that the macrocyclic scaffolds of cepharanthine (ΔGDOCK = - 8.4 kcal mol-1) and dauricine (- 9.7 kcal mol-1) fully occupy the Phe122-Trp219-Trp111 aromatic cage and lock AR into a single, deep free-energy basin, whereas sinomenine explores a broad landscape. MM/PBSA calculations on the 150-200 ns of each trajectory ranked binding free energies as dauricine ≈ isotetrandrine ≈ cepharanthine < sinomenine < fangchinoline, with van-der-Waals forces dominating. ADMET profiling predicted high gastrointestinal absorption across the series but flagged a potential hERG potassium-channel liability for the four macrocycles. Enzyme-kinetic assays corroborated the computational hierarchy: cepharanthine, dauricine and isotetrandrine inhibited recombinant AR with IC50 values of 4.25 ± 0.42, 5.38 ± 0.22 and 6.65 ± 0.40 µM, respectively, compared with 2.36 ± 0.32 µM for quercetin. Lineweaver-Burk and Michaelis-Menten analysis showed mixed inhibition for cepharanthine (Ki = 3.71 µM) and non-competitive inhibition for dauricine (Ki = 4.63 µM) and isotetrandrine (Ki = 6.99 µM). Fangchinoline and sinomenine were an order of magnitude weaker (IC50 = 37-57 µM). Taken together, these data position cepharanthine and dauricine as mechanistically validated, hit-stage starting points for next-generation AR inhibitors, and identify isotetrandrine as an allosteric back-up scaffold. More broadly, the study illustrates a transparent, reproducible computational-experimental workflow for prioritizing structurally complex natural products against redox Enzymes implicated in diabetic pathology.

Keywords

Alkaloids; Atomistic MD; Hyperglycemia; In vitro experiments; Kinetics; Polyol-pathway enzyme (aldose reductase).

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