Acetylcholinesterase Inhibitors: Structure Based Design, Synthesis, Pharmacophore Modeling, and Virtual Screening

Abstract

Acetylcholinesterase (AChE) is a main drug target, and its inhibitors have demonstrated functionality in the symptomatic treatment of Alzheimer's disease (AD). In this study, a series of novel AChE inhibitors were designed and their inhibitory activity was evaluated with 2D quantitative structure-activity relationship (QSAR) studies using a training set of 20 known compounds for which IC₅₀ values had previously been determined. The QSAR model was calculated based on seven unique descriptors. Model validation was determined by predicting IC₅₀ values for a test set of 20 independent compounds with measured IC₅₀ values. A correlation analysis was carried out comparing the statistics of the measured IC₅₀ values with predicted ones. These selectivity-determining descriptors were interpreted graphically in terms of principal component analyses (PCA). A 3D pharmacophore model was also created based on the activity of the training set. In addition, absorption, distribution, metabolism, and excretion (ADME) descriptors were also determined to evaluate their pharmacokinetic properties. Finally, molecular docking of these novel molecules into the AChE binding domain indicated that three molecules (6c, 7c, and 7h) should have significantly higher affinities and solvation energies than the known standard drug donepezil. The docking studies of 2H-thiazolo[3,2-a]pyrimidines (6a-6j) and 5H-thiazolo[3,2-a] pyrimidines (7a-7j) with human AChE have demonstrated that these ligands bind to the dual sites of the enzyme. Simple and ecofriendly syntheses and diastereomeric crystallizations of 2H-thiazolo [3,2-a]pyrimidines and 5H-thiazolo[3,2-a] pyrimidines are described. The solid-state structures for the HBr salts of compounds 6a, 6e, 7a, and 7i have been determined using single-crystal X-ray diffraction techniques, and X-ray powder patterns were measured for the bulk solid remaining after solvent was removed from solutions containing 6a and 7a. These studies provide valuable insight for designing more potent and selective inhibitors for the treatment of AD.

Identification of Human ABAD Inhibitors for Rescuing Aβ-Mediated Mitochondrial Dysfunction

“…In AD, amyloid beta (Aβ) progressively accumulates in synaptic mitochondria resulting in impaired mitochondrial structure and function [7-16]. Interaction of Aβ with mitochondrial proteins such as cyclophilin D, a key component of mitochondrial permeability transition pore, and Aβ-binding alcohol dehydrogenase (ABAD), a mitochondrial enzyme, enhances mitochondrial oxidative stress, mitochondrial toxicity and cognitive decline [3; 7; 9; 17-24]. Thus, strategies that suppresses or attenuates Aβ-induced mitochondrial toxicity in addition to decreasing Aβ levels in the brain may hold potential for preventing and/or halting AD at its early stages by improving mitochondrial function.…”

Novel heteroaryl phosphonicdiamides PTPs inhibitors as anti-hyperglycemic agents

“…The skin permeability values are defined as logKp, cm/hr for all the compounds, where Kp = Km*D/h. Km is distribution coefficient between stratum corneum and vehicle, D is average diffusion coefficient (cm 2 /h) and h is thickness of skin (cm) [41]. …”

Structural and Functional analysis of Staphylococcus aureus NADP-dependent IDH and its comparison with Bacterial and Human NADP-dependent IDH

“…Docking was performed for S. aureus IDH and Human IDH with isocitrate to find out the binding modes and affinity variations. After completion of the process the conformation with least docking score was taken from the total docked conformations in each docking process and the binding conformations of isocitrate was analyzed in the binding sites of S. aureus and human IDHs [11, 19, 20]. …”