Computational insights into the anti-Alzheimer potential of alkynyl-3-carboxamide derivatives.

Integrated Computational Design and Discovery of Novel Indole-Linked Guanidine Derivatives as BACE-1 Inhibitors for Alzheimer's Disease

Alzheimer’s disease (AD) is a chronic, progressive neurodegenerative disorder predominantly affecting 47 million people worldwide. Dysregulation of BACE-1, the initiating enzyme in the amyloidogenic cascade, plays a pivotal role in AD pathogenesis. Conventional anticholinesterase inhibitors can only provide symptomatic relief without stopping disease progression. In this study, we employed an integrated computational approach to rationally design novel indole-based BACE-1 inhibitors through pharmacophore modeling, 3D-QSAR analysis, ligand-protein docking, pharmacophore-guided virtual screening, MD simulation, and ADME studies. DDHRR_1 was identified as the best pharmacophore model with a survival score of 5.7767. Statistically significant 3D-QSAR models were obtained, wherein the atom-based model demonstrated high predictive reliability (R 2 =0.9386, Q 2 =0.7432), while the field-based model exhibited acceptable predictive ability (R 2 =0.8492, Q 2 =0.6644). Among the dataset compounds, compound B38 (3i) displayed the optimal binding affinity (-6.567 kcal/mol; PDB ID: 4DJU), with key interactions at GLY95, TYR132, and PHE169. R-group enumeration generated 2408 derivatives, among which R1 and R2 exhibited strong binding affinity (-10.339 and -9.611 kcal/mol). A comparative analysis of the referenced ligand, the two best-performing ZINC-derived compounds (ZINC43707325 and ZINC03628223), and the two top-ranked R-group compounds revealed that R2 was the major lead compound. However, as these findings are based solely on in-silico analyses, further synthesis, biological evaluation, and BBB permeability studies are necessary to validate the therapeutic potential of R2 against Alzheimer's disease.

Structure-based Design and Computational Evaluation of Spiropyrrolidine Derivatives as Novel Acetylcholinesterase Inhibitors for Alzheimer’s Disease

Acetylcholinesterase (AChE; E.C. 3.1.1.7) is a key enzyme involved in cholinergic neurotransmission, catalyzing the hydrolysis of acetylcholine (ACh). Reduced ACh levels are associated with Alzheimer's disease (AD), making AChE inhibition an effective therapeutic strategy. Structurally, AChE possesses a deep active site gorge with peripheral and catalytic subsites, including the catalytic triad (Ser203, Glu334 and His447), which plays a crucial role in enzyme activity. In the present study, the synthesized pyrrolopiperazine-derived spiropyrrolidine derivatives were evaluated as potential AChE inhibitors using in silico approaches. Molecular docking, induced fit docking (IFD) and conformational analyses were performed to investigate ligand–protein interactions and binding efficiency. The results were compared with dihydrotanshinone I (DHI), a known peripheral site inhibitor. Furthermore, ADME/Tox predictions were carried out to assess pharmacokinetic and safety profiles. The findings revealed that several synthesized spiropyrrolidine compounds exhibited favorable binding interactions with key active site residues and showed promising drug-like properties. These compounds may serve as potential leads for the development of novel AChE inhibitors and may provide new insights for therapeutic strategies in Alzheimer's disease.

Design, Molecular Docking and Neuroprotective Screening of Novel Pyrimidine-Based Acetylcholinesterase Inhibitors

Alzheimer's disease (AD) remains a multifactorial neurodegenerative disorder and currently there are only a few symptomatic therapies available to treat the cholinergic system. The pyrimidine scaffold has become a privileged scaffold for the design of multi-target directed ligands (MTDLs) that are effective at targeting the cholinergic deficit and downstream neurotoxic cascades. A series of ten new pyrimidine derivatives, 3a-3j, were synthesized, characterized and evaluated for their biological activity as potential anti-AD agents. Molecular docking of compound 3e to Torpedo californica acetylcholinesterase (AChE, PDB: 4EY7) showed that compound 3e had superior binding affinity (–12.4 kcal/mol), which was achieved by dual binding mode with both catalytic anionic site (Trp84, Tyr121) and peripheral anionic site (Trp279, Tyr70). An in vitro enzymatic assay confirmed that 3e was the most potent AChE inhibitor (IC₅₀ = 38 ± 4 nM), similar in potency to donepezil (22 ± 2 nM) and demonstrated a good selectivity for AChE compared to butyrylcholinesterase (BChE) (5.5-fold). Structure-activity relationship (SAR) studies indicated that an unsubstituted pyrimidine ring for π–π stacking, hydrogen bond donors at position 4/5 and an extended lipophilic tail for PAS recognition are essential for potency. No cytotoxicity up to 50 μM was observed with 3e in differentiated SH-SY5Y neuroblastoma cells, where it also resulted in the highest level of neuroprotection against Aβ₁–₄₂-induced toxicity (81 ± 5% viability recovery, similar to donepezil at 77 ± 4%). These results prove that 3e is a promising multi-target lead that has a high degree of AChE inhibition activity and anti-amyloid neuroprotection activity with PAS, justifying further preclinical development as a disease-modifying drug in AD.

Leveraging molecular dynamics to unravel the inhibition mechanism of potential β-secretase (BACE1) inhibitors.

Alzheimer's disease (AD) remains a formidable global health challenge, driving the urgent need for potent and selective therapeutics targeting β-site amyloid precursor protein cleaving enzyme 1 (BACE1), a key enzyme involved in the generation of amyloid-β (Aβ) peptide and a promising target for disease-modifying interventions. In this work, approximately 16 million small molecules from diverse databases were subjected to ligand-based virtual screening (LBVS), using LY3202626 as a reference compound, to identify new potent inhibitors of BACE1. LY3202626 is a highly potent, central nervous system (CNS) penetrant BACE1 inhibitor (IC50 = 0.615 nM) that has progressed to clinical trials, demonstrating efficacy at low doses against BACE1 activity. The lead candidates identified using ensemble molecular docking displayed stronger binding affinities (-11.2 to -9.6 kcal mol-1) to BACE1 as compared to LY3202626. Notably, molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) analysis revealed high-affinity binding of ChEMBL3667410 (C1), ChEMBL3667414 (C2), and ChEMBL3976114 (C5) with binding affinities of -32.9 ± 0.8, -33.6 ± 1.8, and -36.1 ± 1.7 kcal mol-1, respectively, to BACE1 as compared to LY3202626 (-29.9 ± 1.8 kcal mol-1). Furthermore, MD simulations demonstrated enhanced structural stability and reduced residual fluctuations in BACE1 on the incorporation of C1, C2, and C5, as compared to apo-BACE1 and BACE1-LY3202626. Interestingly, the conformational snapshots, flap distances, and free energy landscape (FEL) analyses highlighted a closed flap, Val67-Glu77 (non-active) conformation in BACE1-C5 in comparison to an open flap (active) conformation in apo-BACE1, and partial restriction in the access to the active site of BACE1 due to the flap movement noticed in the presence of LY3202626, C1, and C2. Notably, conformational microstate analysis revealed key hydrogen bond interactions of C5 with the 10s loop (Gly11, Gly13), flap residues (Trp76), the catalytic residue (Asp228), Gly230, and Thr231 of BACE1, depicting its high-affinity binding to key residues of BACE1 and its potential as an effective inhibitor of BACE1 activity. The comprehensive in silico methodology in this work illuminated the inhibitory mechanism of LY3202626 and top hit compounds against BACE1 activity for the first time, which, in turn, will be highly valuable in further optimization and structural refinement using various functional group modifications to yield more potent next-generation therapeutic candidates against BACE1 in AD.

Computational drug repurposing identifies flavoxate as a novel NLRP3 inflammasome inhibitor for Alzheimer’s disease therapy

Computational discovery and dynamic profiling of dual acetylcholinesterase and monoacylglycerol lipase inhibitors for Alzheimer's disease.