Al-Thiabat Mohammad G, Agrawal Mohit, Kumar Sahu Kantrol, Alhawarri Maram B, Banisalman Katreen, Al Jabal Ghazi A, Saleh Elqaderi Haya
Michael Sayegh Faculty of Pharmacy, Aqaba University of Technology, Aqaba, 77110, Jordan.
School of Medical & Allied Sciences, K.R. Mangalam University, Gurugram, Haryana, India.
Chem Biodivers. 2025 Mar;22(3):e202402351. doi: 10.1002/cbdv.202402351. Epub 2024 Nov 19.
This study explores the therapeutic potential of three proaporphine alkaloids-cissamaline, cissamanine, and cissamdine, which were recently isolated from Cissampelos capensis L.f., against Parkinson's disease (PD). Using computational techniques, we investigated their efficacy as inhibitors of a key protein in PD. ADMET analysis demonstrated that these alkaloids conform to the Lipinski, Pfizer, Golden Triangle, and GSK rules, indicating favorable safety, oral bioavailability, and a high probability of passing the human intestinal and blood-brain barriers. They were neither substrates nor inhibitors of any CYP enzymes tested, indicating minimal metabolic interference and an enhanced safety profile. Molecular docking studies revealed binding energies of -9.05 kcal/mol (cissamaline), -9.95 kcal/mol (cissamanine), and -10.65 kcal/mol (cissamdine) against MAO-B, a critical PD target, surpassing the control (zonisamide, -6.96 kcal/mol). The molecular interaction analyses were also promising, with interactions comparable to the control. Molecular dynamics (MD) simulations confirmed stable protein-ligand interactions, with root-mean-square deviation (RMSD) values ranging from 1.03 Å to 3.92 Å, root-mean-square fluctuation (RMSF) values remaining below 1.14 Å, and radius of gyration (RGyr) values between 20.20 Å and 20.50 Å, indicating compact structures. Hydrogen bonding analysis revealed maximum hydrogen bond counts of 6 (cissamanine), 5 (cissamaline), and 4 (cissamdine), demonstrating robust interactions with MAO-B. Density Functional Theory (DFT) calculations revealed the highest electrophilicity (ω =0.151), highest electron affinity (EA =0.075), and smallest HOMO-LUMO gap (ΔE =0.130) for cissamanine, indicating enhanced reactivity. These results advocate for further in vitro and in vivo studies to evaluate the compounds' potential as PD therapeutics.
本研究探索了三种原阿朴菲生物碱——锡生藤宁、锡生藤胺和锡生藤定的治疗潜力，这些生物碱最近从南非锡生藤中分离得到，用于对抗帕金森病（PD）。我们使用计算技术研究了它们作为PD关键蛋白抑制剂的功效。ADMET分析表明，这些生物碱符合Lipinski规则、辉瑞规则、金三角规则和GSK规则，表明其安全性良好、口服生物利用度高，且极有可能通过人体肠道和血脑屏障。它们既不是所测试的任何CYP酶的底物，也不是其抑制剂，表明代谢干扰最小且安全性更高。分子对接研究显示，锡生藤宁、锡生藤胺和锡生藤定与PD关键靶点单胺氧化酶B（MAO-B）的结合能分别为-9.05 kcal/mol、-9.95 kcal/mol和-10.65 kcal/mol，超过了对照药物唑尼沙胺（-6.96 kcal/mol）。分子相互作用分析也很有前景，其相互作用与对照相当。分子动力学（MD）模拟证实了蛋白质-配体相互作用的稳定性，均方根偏差（RMSD）值在1.03 Å至3.92 Å之间，均方根波动（RMSF）值保持在1.14 Å以下，回转半径（RGyr）值在20.20 Å至20.50 Å之间，表明结构紧凑。氢键分析显示，锡生藤胺、锡生藤宁和锡生藤定的最大氢键数分别为6个、5个和4个，表明与MAO-B有强大的相互作用。密度泛函理论（DFT）计算表明，锡生藤胺的亲电性最高（ω =0.151）、电子亲和力最高（EA =0.075）且最高占据分子轨道-最低未占据分子轨道能隙最小（ΔE =0.130），表明其反应活性增强。这些结果支持进一步开展体外和体内研究，以评估这些化合物作为PD治疗药物的潜力。
