Aug 2026· Physical Chemistry, Chemical Physics - PCCP· 0 citations· 33 references
Medicine
TL;DR
In this study, molecular-level insights are provided into the interaction mechanisms of γ-secretase inhibitors, contributing to a better understanding of structure-energy relationships that are essential for the rational design of more selective and effective therapeutic agents for Alzheimers disease.
Abstract
Alzheimers disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of β-amyloid (Aβ) plaques and neurofibrillary tangles, leading to cognitive decline. The enzyme γ-secretase (γS) plays a central role in Aβ production and is therefore an important therapeutic target. In this study, interaction energies were evaluated using the Molecular Fragmentation with Conjugated Caps (MFCC) method combined with Density Functional Theory (DFT) calculations to investigate the interactions between γS and the inhibitors Semagacestat (SEM) and Avagacestat (AVA). The SEM-γS complex exhibited a more favorable total interaction energy, primarily driven by interactions with residues such as Ala431, Lys380, and Leu425. In contrast, the AVA-γS complex showed prominent interactions involving key residues, including Leu381, Leu425, and Leu432, which participate in substrate recognition and stabilization within the enzymes binding pocket. Overall, both ligands highlight the combined importance of hydrophobic and hydrophilic interactions in stabilizing the complexes. This study provides molecular-level insights into the interaction mechanisms of γ-secretase inhibitors, contributing to a better understanding of structure-energy relationships that are essential for the rational design of more selective and effective therapeutic agents for Alzheimers disease.
INTRODUCTION
Amyloid-β accumulation, aberrant tau protein, neuroinflammation, and oxidative stress are some of the main pathogenic characteristics of Alzheimer's disease (AD), a degenerative illness characterized by cognitive deterioration. The majority of current AD therapies provide symptomatic alleviation with significant adverse effects, highlighting the urgent need for novel therapeutic approaches.
OBJECTIVE
This study examines nefopam, a centrally acting analgesic with NMDA antagonist and monoaminergic properties, as a potential treatment for AD using in silico methods like Network Pharmacology, Docking, and Molecular Dynamics Simulation studies.
RESULTS
Using network pharmacology, 90 molecular targets shared by the AD and nefopam pathways were identified. Following the selection of important hub proteins for further analysis, eight proteins with accessible 3D structures were put through molecular docking and MMGBSA computations. Nefopam demonstrated significant binding affinities, especially to 5HTR2A, GRIN1, 5HTR2C, SLC6A4, SLC6A3, and MAOB, whereas OPRM1 displayed weaker interactions, consistent with its lower MM-GBSA value (-37.04 kcal/mol) and docking score (-2.963). Molecular dynamics simulations of particular complexes over 100 ns revealed stable contacts and minimal structural changes for SLC6A3, SLC6A4, and 5HTR2A, suggesting strong and long-lasting binding.
DISCUSSION
The findings suggest that nefopam exhibits significant multi-target interactions with several proteins involved in AD pathogenesis, particularly those associated with neurotransmission, neuroprotection, and neuroinflammatory pathways. Its stable binding behavior and favorable interaction profiles support its potential role in modulating disease progression beyond symptomatic management.
CONCLUSION
Overall, this computational analysis confirms that nefopam can target multiple proteins linked to AD. These results show that more experimental research is necessary to validate nefopam's therapeutic potential and provide positive support for its repositioning in AD treatment.
Mayank Saini, Tanuj Hooda, Mohammad Ovais Dar et al.· Current Computer - Aided Dru...· 0 citations
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that involves the formation of amyloid-β (Aβ) aggregates, and the development of targeted therapeutic strategies is needed. In the current work, we report the rational design of H102-CP05, a 22-residue chimeric peptide that integrates the β-sheet breaker peptide H102 with the CD63-targeting anchor CP05 to enable extracellular vesicle (EV)-mediated delivery of an Aβ-inhibitory payload. Computational analysis confirmed favorable physicochemical properties and a non-allergenic profile. In silico immunogenicity assessment and C-IMMSIM simulation demonstrated a low risk of anti-drug antibody formation under chronic dosing conditions. Homology modelling and HADDOCK docking (score: -147.2 ± 4.6) predicted a computationally favourable CD63 binding configuration, while 100 ns molecular dynamics simulations confirmed structural stability in both aqueous and EV-mimetic lipid bilayer environments. In vitro cytotoxicity against HEK-293 cells revealed no significant toxicity (10-100 µM). Zebrafish embryo studies indicated acceptable developmental safety at lower concentrations, with concentration-dependent bradycardia observed at higher doses warranting further cardiovascular evaluation. Thioflavin T fluorescence assays demonstrated dose-dependent inhibition of Aβ fibrillation, with near-complete suppression at 100 µM. These findings collectively support H102-CP05 as a promising EV-displayed therapeutic candidate for AD.
V. Singh, Raja Natesan Sella· Journal of drug targeting (P...· 0 citations
Alzheimer's disease is a multifactorial neurodegenerative disorder characterized by amyloid- β aggregation, oxidative stress, neuroinflammation, tau hyperphosphorylation, and cholinergic dysfunction. The limited efficacy of current therapies has driven the development of multitargetdirected ligands (MTDLs). Chalcones represent a versatile scaffold for modulating multiple ADrelated targets. This review provides a concise analysis of the structure-activity relationship (SAR) of chalcone derivatives, highlighting the effects of hydroxylation, methoxylation, halogenation, and heterocyclic hybridization on biological activity. Electron-withdrawing substituents (e.g., halogens, -CF₃) enhance enzyme inhibition and MAO-B selectivity, whereas electron-donating groups (e.g., hydroxyl and methoxy groups) contribute to antioxidant activity, metal chelation, and hydrogen bonding interactions. Scaffold hybridization and optimized linker design further improve multitarget engagement, including AChE/BuChE inhibition, MAO-B modulation, and anti-amyloid activity. However, despite promising in vitro and in silico findings, translational limitations remain due to insufficient in vivo validation and pharmacokinetic constraints. Overall, chalcone-based MTDLs provide a rational framework for the development of next-generation anti-Alzheimer agents.
Deepika Paliwal, Aman Thakur· Mini-Reviews in Medical Chem...· 0 citations
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.
Alzheimer's disease (AD) remains a major global health challenge due to its complex pathological mechanisms and the limited availability of effective disease-modifying therapies. In this study, a dataset of fifty novel alkynyl-3-carboxamide derivatives (1-50) was systematically evaluated as potential inhibitors of asparagine endopeptidase (legumain), a key enzyme implicated in AD-associated neurodegeneration. An integrated computational approach involving molecular docking, molecular dynamics (MD) simulations, molecular mechanics Poisson-Boltzmann surface area (MM/PBSA) binding free energy analysis, density functional theory (DFT) calculations, and ADMET profiling was employed to investigate ligand-protein interactions, structural stability, electronic properties, and drug-likeness. Molecular docking analysis across ten disease-relevant protein targets identified ligand 4 as the most promising candidate, showing the highest binding affinity toward legumain (PDB ID: 5LUA) with a docking score of -8.1 kcal mol-1. Temperature-dependent MD simulations performed at 300, 305, 310, and 320 K confirmed the stability of the 5LUA-ligand 4 complex, as indicated by consistently low root-mean-square deviation (RMSD) fluctuations and stable binding interactions. MM/PBSA calculations further demonstrated favorable binding thermodynamics for ligand 4, with a total Gibbs free energy of binding (ΔG_bind) of -37.05 kcal mol-1. Furthermore, physicochemical and pharmacokinetic assessments revealed favorable drug-like characteristics, including compliance with Lipinski's and Veber's criteria, suitable lipophilicity (c log P = 2.03), topological polar surface area (TPSA = 131.4 Å2), and an acceptable predicted hERG inhibition profile (pIC50 = 0.9881) with no significant toxicity alerts. Overall, these computational findings, supported by previously reported in vitro evidence, suggest that ligand 4 represents a promising alkynyl-3-carboxamide-based lead scaffold for further development as a potential legumain-targeted therapeutic candidate for AD. Additional experimental validation through advanced biological assays and in vivo studies is required to confirm its efficacy and safety profile.
Afifa I Noor, H. N. Suha, Istiak Hossain et al.· Physical Chemistry, Chemical...· 0 citations
Alzheimer's disease (AD) is a progressive neurodegenerative disorder marked by cognitive decline and memory loss, resulting from various pathological processes such as amyloid-β aggregation, tau hyperphosphorylation, oxidative stress, cholinergic dysfunction, and metal ion imbalance. Current treatments, like acetylcholinesterase inhibitors and NMDA receptor antagonists, only help with the symptoms and don't change how the disease gets worse. The fact that AD has many causes shows how important it is to come up with new ways to treat it. Multi-target directed ligands (MTDLs) have become a promising approach in the last few years. They are meant to work on several important molecular targets that are thought to play a role in the development of Alzheimer's disease. This review summarises progress in the creation and design of MTDLs. It talks about hybrid molecules (like tacrine–chromene derivatives), peptide-based scaffolds, flavonoid conjugates, dual GSK-3β/tau aggregation inhibitors, and new PDE- and AChE-targeting compounds. Compared to regular polypharmacy, MTDLs have more benefits, such as better effectiveness, less toxicity, better compliance, and better pharmacological profiles. Recent advances in medicinal chemistry and structure-based design bolster the argument for MTDLs as next-generation therapeutic candidates, notwithstanding challenges like bioavailability and blood–brain barrier penetration. Ongoing enhancement of these compounds may eventually yield disease-modifying therapies that can impede or avert the advancement of Alzheimer's disease.
Sumesh Kumar, Vansh Sharma, Happy et al.· Current Pharmaceutical Resea...· 0 citations