In recent times, review topics on Alzheimer's disease (AD) have received massive attention, especially on drug design and development of potent inhibitors targeting specific pathway(s) of this multifaceted disease. Drug design and development through the use of computer has taken an intriguing dimension over the last two decades, and AD drug design is not an exception. Computational approaches have found usage in identifying potentially active molecules targeting specific enzyme or gene in the pathological pathway of a disease such as AD. Herein, we present an overview of research contributions over the last ten years from different authors who had used computational approaches to explore potent dual inhibitors of the cholinesterase enzymes linked with AD patho-genesis. We gave an introductory background of the disease, highlight challenges of in silico approach to drug design, and discuss its pros and cons. The overview also covers previously reported review works which are related to the topic. We proposed that continued research efforts to unravel more effective dual acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors through computational tools could plausibly be a successful approach to AD cure. Computational researchers should leverage on the available cost-effective resources to identify lead compounds and work in collaboration with experimental personnel to push their discovery forward.
1,4,7-Triazacyclononane-1,4,7-triacetic acid (NOTA) is a key bifunctional chelator utilized for the complexation of metal ions in radiopharmaceutical applications; the ability of these chelators depends on the strength of their binding with ions. The focus of the present work is to evaluate the complexation of Cu, Ga, Sc, and In radiometal ions with NOTA using density functional theory (B3LYP functional) and 6-311+G(2d,2p)/DGDZVP basis sets. The significant role of ion-water interactions in the chelation interaction energies in solution reflects the competition between ion-water and NOTA-ion interaction in the chelation process. There is reasonable agreement between experimental and theoretical binding constants, geometries, and H NMR chemical shifts. Chelation interaction energies, Gibbs free energies, and entropies in solution show that the NOTA-Ga and NOTA-Cu are the most and least stable complexes, respectively. The natural atomic charges and second order perturbation analysis reveal charge transfer between NOTA and radiometal ions. The theoretical H NMR chemical shifts of NOTA are in good agreement with experiment; these values are influenced by the presence of the ions, which have a deshielding effect on the protons of NOTA. Global scalar properties such as E/E, ΔE, and chemical hardness/softness confirm that the NOTA-Cu complex, which has a singly occupied molecular orbital, has the lowest ΔE value, the least chemical hardness, and the highest chemical softness. The significant variation of the hardness and ΔE values of the complexes can be attributed to the different positions of the metal ions on the periodic table. This study affirms that, among the radiometal ions, Ga can be used to effectively radiolabel NOTA chelator for radiopharmaceutical usage as it binds most stably with NOTA.
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.