DOI: 10.5061/dryad.4f4qrfjqh
title: Enzyme inhibitory activity of marine alkaloid aaptamines for neurodegenerative diseases: An in silico study

description: The enzyme inhibitory activities of a dataset of 28 aaptamines are
 performed to identify potential multifunctional drugs for
 neurodegenerative diseases. First, the drug-like properties and
 pharmacokinetics (ADMET) study excluded 7 molecules, mostly for the
 non-permeability of the blood brain barrier. The binding activities of the
 remaining 21 candidates towards acetylcholinesterase (AChE), monoamine
 oxidase B (MAOB), and catechol-O-methyltransferase (COMT) enzymes are
 initially screened by molecular docking. The top binding complexes
 (A12@MAOB, A24@COMT, and A27@AChE) are simultaneously studied by molecular
 dynamics in water for 500 ns time-scale, and compared with the references
 such as safinamide (SAG), tolcapone (TOL) or donepezil (DON). The results
 show that two aaptamines A12 and A27 are well-positioned within the active
 pocket of the enzymes, exhibiting structural stability, with an RMSD of
 about 0.15-0.2 nm. MM-PBSA calculation indicates that the binding energy
 of the ligands to the corresponding targets is equal (A12vs. SAG) or much
 lower than the references (A24vs. TOL and A27vs. DON). The van der Waals
 interactions contribute more strongly to enzyme binding than the
 electrostatic energy. The study results suggest that A27 (lowest binding
 energy, -170.42 ± 14.24 kJ mol-1) is the most prominent Aaptamine
 candidate for the treatment of neurodegenerative disease.
description: # Enzyme inhibitory activity of marine alkaloid aaptamines for
 neurodegenerative diseases: An in silico study Dataset DOI:
 [10.5061/dryad.4f4qrfjqh](10.5061/dryad.4f4qrfjqh) ## Description of the
 data and file structure The figures and tables presented here, along with
 the data presented in the main paper, provide comprehensive support for
 our research findings. ### List of Figures (supplementary files in Zenodo)
 **Figure S1:** Optimized geometries, HOMO, LUMO, and ESP of the selected
 aaptamines A12, A24, and A27. **Figure S2:** Time dependent RMSD (nm) of
 the complexes of SAG@MAOB, TOL@COMT, and DON@AChE in the time range 500
 ns. **Figure S3:** (Top) Gyration radius (nm) and (Bottom)
 Root-mean-square of fluctuation RMSF (nm) of the complexes A12@MAOB,
 A24@COMT, and A27@AChE in comparison with the corresponding references.
 **Figure S4:** Total energy of A12@MAOB, A24@COMT, and their references,
 SAG@MAOB and TOL@COMT, in relationship with the number of H-bonds of the
 complexes. **Figure S5:** 2D and 3D images of the interactions in the
 complex conformation of: (A) A12, and (B) SAG with MAOB enzymes. **Figure
 S6:** 2D and 3D images of the interactions in the complex conformation of:
 (A) A24, and (B) Tolcapone with COMT enzymes. **Figure S7:** 2D and 3D
 images of the interactions in the complex conformation of Donepezil with
 AChE enzymes. ### List of Tables #### Description of files and variables:
 **Table S1:** Molecular properties of Aaptamines set A (A1-A28). * Cp:
 Compound * N: Number of heavy atom * TPSA (Å^2): Topological Polar Surface
 Area (Å²) * MW (Dalton): Molecular weight (Dalton) * NN,O: Number of
 hydrogen bond acceptor * NNH,OH: Number of hydrogen bond donor * nrotb:
 Number of rotatable bond * V (Å^3): Volume (Å3) * Lipinski violation
 **Table S2:** ADMET properties prediction of set B (A1-A27). * Cp:
 Compound **Absorption** * iLOGP: the logarithm of the octanol-water
 partition coefficient characterizes for lipophilicity of a molecule,
 calculated based on physics method * WLOGP: the logarithm of the
 octanol-water partition coefficient characterize for lipophilicity of a
 molecule, calculated from atomistic method * GI absorption:
 Gastrointestinal absorption * Pgp substrate: Absorption on P-glycoprotein
 **Distribution** * BBB permeant: Blood Brain Barrier permeability *
 Metabolism * CYP1A2 inhibitor, CYP2C19 inhibitor, CYP2C9 inhibitor, CYP2D6
 inhibitor, and CYP3A4 inhibitor: Key Cytochrome P450 enzymes responsible
 for the metabolism of drugs **Excretion** * Total clearance (log
 ml/mim/kg): the body's overall ability to eliminate a drug * Renal
 OCT2 substrate: Renal Organic Cation Transporter 2 substrate plays
 important role in the uptake of positively charged (cationic) drug from
 the blood into renal proximal tubule cells **Toxicity** * AMES toxicity:
 mutagenicity * Max. tolerated dose (human) (log mg/kg/day) * hERG I
 inhibitor: cardiotoxicity risk * hERG II inhibitor: cardiotoxicity risk *
 Oral Rat Acute Toxicity (LD50) (mol/kg) * Oral Rat Chronic Toxicity
 (LOAEL) (log mg/kg_bw/day) **Hepatotoxicity** * Skin Sensitisation *
 T.Pyriformis toxicity (log ug/L) * Minnow toxicity (log mM): environmental
 toxicity **Table S3:** The main interactions, including conventional
 hydrogen bonding, carbon-hydrogen bonding, π-π stacked, and π-σ
 interactions of the most potent aaptamines for ND by molecular docking
 study. Values in parentheses indicate the distance of bonding or
 interaction (Å). ## Code/software All molecular optimized geometries are
 performed by Gaussian 16 package, revision A.03. Molecular docking are
 performed with Autodock4. Molecular dynamics are performed with Gromacs
 2023. Visualization of complex systems are illustrated with ChimeraX.