:
Alzheimer’s disease (AD) is one of the major reasons for 60-80% of cases of senile dementia occurring as a result of the accumulation of plaques and tangles in the hippocampal and cortical neurons of the brain leading to neurodegeneration and cell death. The other pathological features of AD comprise of abnormal microvasculature, network abnormalities, interneuronal dysfunction, increased β-amyloid production, and reduced clearance, increased inflammatory response, elevated production of reactive oxygen species, impaired brain metabolism, hyperphosphorylation of tau, and disruption of acetylcholine signaling. Among all these pathologies, mitochondrial dysfunction (MD), regardless of being an inciting insult or a consequence of the alterations, is related to all the associated AD pathologies. Observed altered mitochondrial morphology, distribution, and movement increased oxidative stress, dysregulation of enzymes involved in mitochondrial functioning, impaired brain metabolism, and impaired mitochondrial biogenesis in AD subjects suggest the involvement of mitochondrial malfunction in the progression of AD. Various pre-clinical and clinical evidence establishing MD as a key mediator in the progression of neurodegeneration in AD are reviewed and discussed with an aim to foster future MD-based drug development research for the management of AD.
:
Cancer treatment has become a major challenge amidst the resistance and relapse caused by the various treatments available. The PROteolysis TAargeting Chimera (PROTAC) technology involves the degradation of target protein against the inhibition by small drug molecules. The PROTACs with high potency and activity have been frequently reported; however, no PROTAC acting against cancer has reached the clinical trials so far. The concept of PROTACs involves the reduction in the disease causing protein by its degradation through ubiquitin-proteosomal enzyme system. This concept has attracted a lot of attention from both industry and academia due to its potential in drug discovery (in the form of PROTACs) which can conquer the resistance associated with current treatments of cancer. Thus, it is the need of hour to identify and synthesize more PROTACs for a viable treatment of cancer. This article reviews the design, activity and the effects produced in cancer by some recently developed PROTACs.
Alzheimer’s disease (AD) is the prime cause of 65–80% of dementia cases and is caused by plaque and tangle deposition in the brain neurons leading to brain cell degeneration. β-secretase (BACE-1) is a key enzyme responsible for depositing extracellular plaques made of β-amyloid protein. Therefore, efforts are being applied to develop novel BACE-1 enzyme inhibitors to halt plaque build-up. In our study, we analyzed some Elenbecestat analogues (a BACE-1 inhibitor currently in clinical trials) using a structure-based drug design and scaffold morphing approach to achieve a superior therapeutic profile, followed by in silico studies, including molecular docking and pharmacokinetics methodologies. Among all the designed compounds, SB306 and SB12 showed good interactions with the catalytic dyad motifs (Asp228 and Asp32) of the BACE-1 enzyme with drug-likeliness properties and a high degree of thermodynamic stability confirmed by the molecular dynamic and stability of the simulated system indicating the inhibitory nature of the SB306 and SB12 on BACE 1.
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.