A set of 221 phenols, for which toxicity data to the ciliate Tetrahymena pyriformis were available, was subjected to stepwise linear discriminant analysis (LDA) in order to classify their toxic mechanisms of action. The compounds were a priori grouped into the following four mechanisms according to structural rules: polar narcotics, weak acid respiratory uncouplers, pro-electrophiles and soft electrophiles. Hydrophobicity with and without correction for ionisation (log K ow , log D ow u ), acidity constant (pK a ), frontier orbital energies (E LUMO , E HOMO ) and hydrogenbond donor and acceptor counts were used as molecular descriptors. LDA models employing 3 ± 6 variables achieved 86 ± 89% overall correct classification of the four mechanisms, with more varied performance for respiratory uncouplers and pro-electrophiles. For the latter, a separate model was developed that discriminated compounds undergoing metabolic activation from compounds with different mechanisms very accurately. Model validation was performed by evaluating the simulated external prediction through LDA models built from complementary subsets.
The inhibition of the enzyme acetylcholinesterase (AChE) increases the levels of the neurotransmitter acetylcholine and symptomatically improves the affected cognitive function. In the present study, we searched for novel AChE inhibitors by docking-based virtual screening of the standard lead-like set of ZINC database containing more than 6 million small molecules using GOLD software. The top 10 best-scored hits were tested in vitro for AChE affinity, neurotoxicity, GIT and BBB permeability. The main pharmacokinetic parameters like volume of distribution, free fraction in plasma, total clearance, and half-life were predicted by previously derived models. Nine of the compounds bind to the enzyme with affinities from 0.517 to 0.735 µM, eight of them are non-toxic. All hits permeate GIT and BBB and bind extensively to plasma proteins. Most of them are low-clearance compounds. In total, seven of the 10 hits are promising for further lead optimisation. These are structures with ZINC IDs: 00220177, 44455618, 66142300, 71804814, 72065926, 96007907, and 97159977.
Galantamine (GAL) as an acetylcholinesterase inhibitor (AChEI) is among the main drugs approved for the treatment of Alzheimer's disease. It fits perfectly into acetylcholinesterase (AChE) binding gorge, but it is too short to fill it. The amyloid beta (Aβ) peptide binds in the peripheral anionic site (PAS) at the entrance of the binding gorge of AChE and initiates the formation of amyloid plaques. The blockade of PAS prevents from AChE-induced Aβ aggregation. In this study, we describe the design of a series of galantamine-camphane hybrids as AChEIs. Camphane (CAM) is a bulky fragment that disposes well on the wide gorge entrance. The designed hybrids have linkers of different length. They were docked into AChE, and the highest scored compounds were synthesized and tested for AChE inhibitory activity. Some of the novel hybrids showed 191- and 369-fold better inhibition than GAL. The CAM fragment of the best binders fits in the same region, proximal to PAS, where the Ω-loop of Aβ binds to AChE. The hybrids cross blood-brain barrier by passive diffusion and are non-neurotoxic at the inhibitory concentrations.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.