Potential MAO‐B Inhibitors from Cissampelos capensis L.f.: ADMET, Molecular Docking, Dynamics, and DFT Insights

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.