article · Brain Disorders
Alzheimer's disease causes dementia and cognitive decline, yet existing treatments carry substantial side effects and merely address warning symptoms. To pursue improved options, structure-based drug design was used to develop multifunctional small molecule inhibitors based on a hydrazone scaffold. Hydrazone derivatives can disrupt the self-assembly of amyloid beta, a key factor in fibril and oligomer formation, while also counteracting the harmful effects of free radicals on therapeutic agents that penetrate the central nervous system. Using a human protein target selected under code ID 4EY7, fifteen novel hydrazone derivatives were designed. These compounds exhibited stronger interactions, higher binding scores, and improved drug-like properties alongside better drug kinetic parameters compared to the lead template. The resulting designs offer a foundation for developing prospective pharmacotherapeutic treatments for Alzheimer's disease.
Current medications for Alzheimer's disease only manage symptoms and often produce negative side effects. Designing small molecules that target the underlying drivers of the disease, such as amyloid beta accumulation, provides a crucial step towards developing more effective therapies with fewer drawbacks for individuals experiencing cognitive decline.
This work informs early-stage drug discovery for pharmaceutical developers and medicinal chemists targeting neurodegenerative conditions. The designed compounds serve as computational leads with favourable predicted kinetic and binding properties. However, as the findings are based on molecular modelling and design, the research remains at a pre-clinical, early stage that requires chemical synthesis and biological testing before commercial development.
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Alzheimer's disease (AD) is a neurodegenerative disorder that causes dementia and cognitive impairment in the elderly. The exact mechanism of the disease is still unknown. There are four medications available, all of which have a slew of negative side effects and only serve to improve patients' warning symptoms. Medicinal chemists are looking for treatments for this illness. The development and application of a novel class of multifunctional small molecule inhibitors is discussed. A variety of compounds were synthesized using the hydrazone scaffold. This is due to the ability of hydrazone derivatives to interfere with Amyloid beta (A) self-assembly, which is one of the causative agents in fibrils and oligomers. they can also counteract the impacts of toxic substances free radicals on useful therapeutic agents such as central nervous system penetrant drugs. In this study, structure-based drug design techniques utilized. Based on established literature studies and reasons such as lower resolution value (2.35), no mutation, Homo Sapiens, and X-ray diffraction method, a protein target (code ID 4EY7) was chosen. The protein target was designed to interact with compounds of interest (a lead compound with a higher binding energy), and was used as a template to design fifteen Hydrazone derivatives with greater interactions, higher binding scores, and improved enhanced drug-like properties and drug kinetic parameters The findings of these studies can be used to create promising pharmacotherapeutic compounds for the treatment of AD.
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DOI: 10.1016/j.dscb.2022.100041
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