Lead Identification Through In Silico Studies: Targeting Acetylcholinesterase Enzyme Against Alzheimer's Disease.

AIM: In this work, we aimed to acquire the best potential small molecule for Alzheimer's disease (AD) treatment using different models in Biovia Discovery Studio to identify new potential inhibitors of acetylcholinesterase (AChE) via in silico studies. BACKGROUND: The prevalence of cognitive impairment-related neurodegenerative disorders, such as AD, has been observed to escalate rapidly. However, we still know little about the underlying functions, outcome predictors, or intervention targets causing AD. OBJECTIVE: The objective of the study was to optimize and identify the lead compound to target AChE against Alzheimer's disease. METHOD: Different in silico studies were employed, including the pharmacophore model, virtual screening, molecular docking, de novo evolution model, and molecular dynamics. RESULT: The pharmacophoric features of AChE inhibitors were determined by ligand-based pharmacophore models and 3D QSAR pharmacophore generation. Further validation of the best pharmacophore model was done using the cost analysis method, Fischer's randomization method, and test set. The molecules that harmonized the best pharmacophore model with the estimated activity < 1 nM and ADMET parameters were filtered, and 12 molecules were subjected to molecular docking studies to obtain binding energy. 3vsp_EK8_1 secured the highest binding energy of 65.60 kcal/mol. Further optimization led to a 3v_Evo_4 molecule with a better binding energy of 70.17 kcal/mol. The molecule 3v_evo_4 was subjected to 100 ns molecular simulation compared to donepezil, which showed better stability at the binding site. CONCLUSION: A lead compound, 3v_Evo_4 molecule, was identified to inhibit AChE, and it could be further studied to develop as a drug with better efficacy than the existing available drugs for treating AD.

Cellular Senescence and Senolytic Agents: Recent Updates on Their Role and Applications.

Cellular senescence, an eternal condition of cell cycle arrest due to cellular stressors, is a sign of aging. Senescent cells (SCs) build up in tissues as they age, impairing their ability to repair themselves by causing the cell cycle to seize in progenitor cells and producing proinflammatory and the senescence-associated secretory phenotype (SASP) or matrix-degrading molecules. SASP aids in the emergence of several age-related diseases. Genetic studies have shown that removing SCs can delay aging and prolong life. Senolytics are small molecules designed to treat numerous age-related disorders can selectively kill SCs. A detailed discussion on senolytics and their potential as therapeutics to treat neuro-disorder and slow down aging is described herein. Emerging natural products, such as quercetin, dasatinib, fisetin, piperlongumine, and curcumin, have recently been reported to be effective senolytic agents, and some structurally modified analogue of these have also been explored for better selectivity and efficacy in animal models. These showed significant potential in clinical studies and could be developed as senolytic drugs in the future.

Networkodynamic approach to perceive the key phytoconstituents of E. officinalis (Amla) as natural BACE1 inhibitors: an in-silico study.

Alzheimer's disease (AD) is a deteriorating neural disorder, and currently, available drugs are ineffective in its treatment. Emblica officinalis (Amla) is widely recognised in the Indian medicinal system for ameliorative effects in managing diabetes, hyperlipidaemia and neurological diseases. Thus, we aimed to identify the active phytoconstituents of E. officinalis and their role in inhibiting the potential targets for the possible treatment of AD. The network pharmacology approach, gene ontology, molecular docking and molecular dynamics simulation (MDS) studies were performed. A total of 36 bioactive components in E. officinalis, 95 predicted anti-AD targets, and 3398 AD-related targets were identified from different databases. The network analysis showed that BACE1, ABCB1 and AChE, CA2 are the most potential AD targets. Based on gene ontology and topology analysis results, BACE1 was a significant target related to AD pathways, and quercetin, kaempferol and myricetin showed the highest interaction with target genes. The molecular docking results found that rutin and quercetin displayed better binding affinities -7.5, -5.67 kcal/mol than the BACE1 bound internal ligand. Furthermore, MDS results suggested that quercetin and rutin could be potential inhibitors against BACE-1 protein and may have therapeutic effects in treating AD. Such promising results could be further helpful in new drug discovery against AD.Communicated by Ramaswamy H. Sarma.

Recent Advancements in the Treatment of Alzheimer's Disease: A Multitarget-directed Ligand Approach.

Alzheimer's disease (AD) is a neurodegenerative disease and one of the leading causes of progressive dementia, affecting 50 million people worldwide. Many pathogenic processes, including amyloid ß aggregation, tau hyperphosphorylation, oxidative stress, neuronal death, and deterioration of the function of cholinergic neurons, are associated with its progression. The one-compound-one-target treatment paradigm was unsuccessful in treating AD due to the multifaceted nature of Alzheimer's disease. The recent development of multitarget-directed ligand research has been explored to target the complementary pathways associated with the disease. We aimed to find the key role and progress of MTDLs in treating AD; thus, we searched for the past ten years of literature on "Pub- Med", "ScienceDirect", "ACS" and "Bentham Science" using the keywords neurodegenerative diseases, Alzheimer's disease, and multitarget-directed ligands. The literature was further filtered based on the quality of work and relevance to AD. Thus, this review highlights the current advancement and advantages of multitarget-directed ligands over traditional single-targeted drugs and recent progress in their development to treat AD.

Convenient One-Pot Synthesis of Kynurenic Acid Ethyl Ester and Exploration to Direct Synthesis of Neuroprotective Kynurenic Acid and Amide Derivatives.

Kynurenic acid (KYNA) is an endogenous molecule, which is a non-selective antagonist of ionotropic glutamate receptors and has been found to have neuroprotective activity. A supplement of KYNA may be applicable for the treatment of neurodegenerative disease, but it does not cross the blood-brain barrier due to its polar nature. Therefore, its different esters and amide derivatives were explored as a prodrug, which can cross blood-brain barrier and transform into KYNA in situ. However, many esters and amide derivatives of KYNA are synthesized via coupling reaction or multi-step synthesis using different organic or metallic catalysts. Herein, we developed a novel one-pot, catalyst-free, convenient synthesis of KYNA ethyl esters using aniline and diethyl acetylene dicarboxylate in DMF under heating. We also explored the synthesis of KYNA and KYNA amide derivative in a simple manner with overall good yields via hydrolysis and condensation, respectively.

Coumarin as a Privileged and Medicinally Important Scaffold in the Treatment of Tuberculosis.

Coumarin and its derivatives, which are abundant in nature, have a significant role in medicinal chemistry due to their ability to bind with different targets or receptors. In addition, these possess a wide range of biological activity. Thus coumarin-based scaffold has inspired even further research into coumarin and its substituted derivatives, allowing for the creation of a huge variety of structurally different substituted products. In recent, these were reported to have potent antitubercular activity. Tuberculosis (TB) is a serious deadly infectious bacterial disease caused by grampositive Mycobacterium tuberculosis. This review discusses various developments going on in the field of medicinal chemistry towards designing, synthesizing, and discovering coumarin-based antitubercular agents all across the globe.