Ricin is a toxin found in the castor seeds and listed as a chemical weapon by the Chemical Weapons Convention (CWC) due to its high toxicity combined with the easiness of obtention and lack of available antidotes. The relatively frequent episodes of usage or attempting to use ricin in terrorist attacks reinforce the urge to develop an antidote for this toxin. In this sense, we selected in this work the current RTA (ricin catalytic subunit) inhibitor with the best experimental performance, as a reference molecule for virtual screening in the PubChem database. The selected molecules were then evaluated through docking studies, followed by drug-likeness investigation, molecular dynamics simulations and Molecular Mechanics Poisson-Boltzmann Surface Area (MM-PBSA) calculations. In every step, the selection of molecules was mainly based on their ability to occupy both the active and secondary sites of RTA, which are located right next to each other, but are not simultaneously occupied by the current RTA inhibitors. Results show that the three PubChem compounds 18309602, 18498053, and 136023163 presented better overall results than the reference molecule itself, showing up as new hits for the RTA inhibition, and encouraging further experimental evaluation.

• Keywords
• chemical/biological warfare agents, ligand-based virtual screening, molecular dynamics, ricin, ricin inhibitors,
• MeSH
• Algorithms MeSH
• Chemical Warfare Agents chemistry   MeSH
• Ligands MeSH
• Molecular Conformation MeSH
• Molecular Structure MeSH
• Drug Discovery MeSH
• Ricin antagonists & inhibitors   chemistry   MeSH
• Molecular Dynamics Simulation MeSH
• Molecular Docking Simulation MeSH
• Binding Sites MeSH
• Hydrogen Bonding MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Chemical Warfare Agents MeSH
• Ligands MeSH
• Ricin MeSH

Inhibiting the formation of amyloid fibrils is a crucial step in the prevention of the human neurological disorder, Alzheimer's disease (AD). Ionic liquid (IL) mediated interactions are an expedient approach that exhibits inhibition effects on amyloid fibrils. In view of the beneficial role of ILs, in this work we have explored complexation of anti-Alzheimer's drugs (i.e., tacrine and PC-37) and an amino acid-functionalized IL [AIL (4-PyC8)]. Maintaining standard physiological conditions, the binding mechanism, thermo-dynamical properties and binding parameters were studied by employing UV-vis, fluorescence, FTIR, 1H NMR, COSY and NOESY spectroscopy. The present investigation uncovers the fact that the interaction of anti-Alzheimer's drugs with 4-PyC8 is mediated through H-bonding and van der Waals forces. The Benesi-Hildebrand relation was used to evaluate the binding affinity and PC-37 showed the highest binding when complexed with 4-PyC8. FTIR spectra showed absorption bands at 3527.98 cm-1 and 3527.09 cm-1 for the PC-37 + 4-PyC8 system which is quite promising compared to tacrine. 1H-NMR experiments recorded deshielding for tacrine at relatively higher concentrations than PC-37. COSY investigations suggest that anti-Alzheimer's drugs after complexation with 4-PyC8 show a 1 : 1 ratio. The cross-peaks of the NOESY spectra involve correlations between anti-Alzheimer's drugs and AIL protons, indicating complexation between them. The observed results indicate that these complexes are expected to have a possible therapeutic role in reducing/inhibiting amyloid fibrils when incorporated into drug formulations.

• Publication type
• Journal Article MeSH

Six quinoline-piperonal hybrids were synthesized and evaluated as potential drugs against Alzheimer's disease (AD). Theoretical analysis of the pharmacokinetic and toxicological properties of the compounds suggest that they present good oral bio-availability and are also capable of penetrating the blood-brain barrier, qualifying as leads for new drugs against AD. Evaluation of their inhibitory capacity against acetyl- and butyrilcholinesterases (AChE and BChE) through Ellmann's test showed that three compounds present promising results with one of them being capable of inhibiting both enzymes. Further docking studies of the six compounds synthesized helped to elucidate the main interactions that may be responsible for the inhibitory activities observed.

• Keywords
• Alzheimer’s disease, acetylcholinesterase, guanil-hydrazones, piperonal, quinolines,
• MeSH
• Alzheimer Disease drug therapy   metabolism   MeSH
• Benzaldehydes * chemistry   MeSH
• Benzodioxoles * chemistry   MeSH
• Quinolines * chemistry   MeSH
• Cholinesterase Inhibitors chemical synthesis   chemistry   pharmacokinetics   pharmacology   MeSH
• Kinetics MeSH
• Humans MeSH
• Magnetic Resonance Spectroscopy MeSH
• Molecular Structure MeSH
• Molecular Dynamics Simulation MeSH
• Molecular Docking Simulation MeSH
• Chemistry Techniques, Synthetic MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Benzaldehydes * MeSH
• Benzodioxoles * MeSH
• Quinolines * MeSH
• Cholinesterase Inhibitors MeSH
• piperonal MeSH Browser
• quinoline MeSH Browser