Evaluation of in silico acetylcholinesterase inhibitory activity of phytocompounds from Huperzia squarrosa Forst.
DOI:
https://doi.org/10.59294/HIUJS2025087Keywords:
Huperzia squarrosa, in silico, anti-acetylcholinesteraseAbstract
Background: Huperzia squarrosa (Lycopodiaceae) is a valuable source of bioactive compounds with potential neuroprotective effects for memory enhancement. Objectives: This study aimed to screen bioactive compounds from Huperzia squarrosa for AChE inhibitory activity, evaluating their binding affinities and molecular interactions compared to donepezil. Methods: In silico docking screened 26 compounds from Huperzia squarrosa for interactions with AChE, analyzing binding affinities and interaction types (hydrogen bonds, electrostatic, hydrophobic) compared to donepezil. Results: Lycoposerramine U N-oxide (-10.4 kcal/mol), 8-acetoxyfawcettimine (-10.2 kcal/mol), huperzin U, huperzinine N-oxide, 4-epilycopodine, and 8,15-dihydrohuperzine A (-10.1 kcal/mol) showed robust binding affinity against AChE, though less than donepezil (-11.8 kcal/mol). Lycoposerramine U N-oxide formed hydrogen bonds with TYR124 (2.58 Å) and TRP86 (2.79 Å), a π-cation interaction with TYR341 (3.81 Å), and π-σ with TYR337 (3.88 Å). 8-Acetoxyfawcettimine exhibited hydrogen bonds with GLY121 (2.70 Å) and SER203 (2.43 Å), and six π-alkyl interactions (4.1-4.95 Å). Huperzinine N-oxide showed electrostatic interaction with ASP74 (4.28 Å) and five hydrophobic interactions (3.68-5.49 Å). Huperzia compounds targeted key residues TRP86 and TYR337, similar to donepezil. Conclusion: Lycoposerramine U N-oxide and 8-acetoxyfawcettimine are promising AChE inhibitors, warranting further in vitro and in vivo studies for Alzheimer's therapy development.
References
[1] G. Ezio, “Cholinergic function and Alzheimer's disease,” International journal of geriatric psychiatry, vol. 18(S1), pp. S1-S5, 2003.
DOI: https://doi.org/10.1002/gps.935[2] S. Anukanon, P. Pongpamorn, W. Tiyabhorn, J. Chatwichien, W. Niwetmarin, R.B. Sessions, S. Ruchirawat, N. Thasana, “In Silico-guided rational drug design and semi-synthesis of C(2)-functionalized Huperzine a derivatives as acetylcholinesterase inhibitors,” ACS Omega, vol. 6(30), pp. 19924-19939, 2021.
DOI: https://doi.org/10.1021/acsomega.1c02875[3] Y. Ashani, J.O. Peggins, B.P. Doctor, “Mechanism of inhibition of cholinesterases by huperzine A,” Biochemical and biophysical research communications, vol. 184(2), pp. 719-726, 1992.
DOI: https://doi.org/10.1016/0006-291X(92)90649-6[4] DL. Bai, XC. Tang, XC. He, “Huperzine A, a potential therapeutic agent for treatment of Alzheimer's disease,” Current Medicinal Chemistry, vol. 7(3), pp. 355-374, 2000.
DOI: https://doi.org/10.2174/0929867003375281[5] A.I. Calderón, J. Simithy-Williams, R. Sanchez, A. Espinosa, I. Valdespino, M.P. Gupta, “Lycopodiaceae from Panama: a new source of acetylcholinesterase inhibitors,” Nat Prod Res., vol. 27(4-5), pp. 500-505, 2013.
DOI: https://doi.org/10.1080/14786419.2012.701217[6] B.R. Coleman, R.H. Ratcliffe, S.A. Oguntayo, X. Shi, D.P. Doctor, R.K. Gordon, M.P. Nambiar, “[+]-Huperzine A treatment protects against N-methyl-D-aspartate-induced seizure/status epilepticus in rats,” Chemico-biological interactions, vol. 175(1-3), pp. 387-395, 2008.
DOI: https://doi.org/10.1016/j.cbi.2008.05.023[7] D.R. Alicia, J.J. Gickas, K.C Dunican, “Role of huperzine a in the treatment of Alzheimer's disease,” Annals of Pharmacotherapy, vol. 43(3), pp. 514-518, 2009.
DOI: https://doi.org/10.1345/aph.1L402[8] E. Saskia, P. Eyer, F. Worek, “Reversible inhibition of acetylcholinesterase by carbamates or huperzine A increases residual activity of the enzyme upon soman challenge,” Toxicology, vol. 233(1-3), pp. 180-186, 2007.
DOI: https://doi.org/10.1016/j.tox.2006.09.012[9] H.E. Steinunn, J.W. Jaroszewski, E.S. Olafsdottir, “Acetylcholinesterase inhibitory activity of lycopodane-type alkaloids from the Icelandic Lycopodium annotinum ssp. Alpestre,” Phytochemistry, vol. 71(2-3), pp. 149-157, 2010.
DOI: https://doi.org/10.1016/j.phytochem.2009.10.018[10] B.T. Tung, T.T.T. Hang, N.B. Kim, N.H. Nhung, V.K. Linh, D.K. Thu, “Molecular docking and molecular dynamics approach to identify potential compounds in Huperzia squarrosa for treating Alzheimer's disease,” J Complement Integr Med., vol. 19(4), pp. 955-965, 2022.
DOI: https://doi.org/10.1515/jcim-2021-0462[11] N.N. Chuong, N.T.T. Huong, T.M. Hung, T.C. Luan, “Anti-cholinesterase activity of lycopodium alcaloids from Vietnamese Huperzia squarrosa (Forst.) Trevis,” Molecules, vol. 19(11), pp. 19172-19179, 2014.
DOI: https://doi.org/10.3390/molecules191119172[12] H. Cao, T.T. Chai, X. Wang, M.F.B. Morais-Braga, J.H. Yang, F.C.. Wong, R Wang, H. Yao, J. Cao, L. Cornara, B. Burlando, Y. Wang, J. Xiao, H.D.M. Coutinho, “Phytochemicals from fern species: potential for medicine applications,” Phytochem Rev., vol. 16(3), pp. 379-440, 2017.
DOI: https://doi.org/10.1007/s11101-016-9488-7[13] B.T. Tung, N.T. Hai, D.K. Thu, “Antioxidant and acetylcholinesterase inhibitory activities in vitro of different fraction of Huperzia squarrosa (Forst.) Trevis extract and attenuation of scopolamine-induced cognitive impairment in mice,” J Ethnopharmacol., vol. 198, pp. 24-32, 2017.
DOI: https://doi.org/10.1016/j.jep.2016.12.037[14] E. C. Pham, B.N.T. Le, A.M. Ngo, L.B. Vong, T.N. Truong, “Symmetrical di-substituted phenylamino-s-triazine derivatives as anticancer agents: in vitro and in silico approach,” RSC Adv., vol. 15(13), pp. 9968-9984, 2025. DOI: 10.1039/d4ra08508f.
DOI: https://doi.org/10.1039/D4RA08508F[15] E. Ca Pham, H.H.L. Hong, “Anticancer activity of phytocompounds of black ginger (Kaempferia parviflora Wall. Ex Baker): In silico approach,” Chemical Physics Impact, vol. 11, p. 100903, 2025. DOI: 10.1016/j.chphi.2025.100903.
DOI: https://doi.org/10.1016/j.chphi.2025.100903
