In silico evaluation of bioavailability, pharmacokinetics and toxicological properties of selected dual inhibitors of acetylcholinesterase and monoamino oxidase-B for the treatment of Alzheimer's disease
TL;DR
Computational findings support in vitro and in vivo evaluation of compounds 1, 3, 6, 13, 14, 30, 31, 34, 36-38, and 44-46 as dual AChE/MAO B inhibitors and potential new drug candidates for AD treatment.
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder with a complex pathology. Acetylcholinesterase (AChE) and mono-amine oxidase-B (MAO-B) are key targets regulating neurotransmitter levels, and dual inhibitors (compounds 1-46) were designed as experimental candidates for AD therapy. Drug-likeness parameters were estimated using pkCSM, SwissADME Web tools, and MoloVol software (v1.2.0). SwissADME predicted gastrointestinal absorption and blood-brain barrier penetration, whereas pkCSM evaluated P-glycoprotein recognition and CYP450 inhibition. Toxicological profiles of compounds (1-46) were assessed with DataWarrior software (v06.05.04), which predicted structural alerts as mutagenic, carcinogenic, reproductive, or irritant. Most compounds complied with Lipinski's rule (excluding 12 and 35) indicating favorable absorption and permeability. All compounds showed TPSA<140 Ų, indicating good intestinal absorption, while compounds 1, 3-6, 8, 11-16, 18, 19, 27, 30, 31, 34, 36-38, and 44-46 displayed TPSA<60 Ų, suggesting blood-brain barrier penetration. The majority of compounds were predicted P-glycoprotein substrates. Metabolic profiling predicted inhibition of CYP1A2, 2C19, 2C9, 2D6, and 3A4. Toxicological analysis predicted mutagenicity (compounds 4, 5, 19, 20 and 27), carcinogenicity (compounds 4, 5, 8, 18 and 19), reproductive toxicity (compounds 15, 16 and 19-23), and irritant effects (compounds 7, 11, 17 and 20). Computational findings support further in vitro and in vivo evaluation of compounds 1, 3, 6, 13, 14, 30, 31, 34, 36-38, and 44-46 as dual AChE/MAO B inhibitors and potential new drug candidates for AD treatment.