Insights into the baicalein-induced destabilization of LS-shaped Aß42 protofibrils using computer simulations.

Amyloid-ß (Aß) peptides aggregate spontaneously into various aggregating species comprising oligomers, protofibrils, and mature fibrils in Alzheimer's disease (AD). Disrupting ß-sheet rich neurotoxic smaller soluble Aß42 oligomers formed at early stages is considered a potent strategy to interfere with AD pathology. Previous experiments have demonstrated the inhibition of the early stages of Aß aggregation by baicalein; however, the molecular mechanism behind inhibition remains largely unknown. Thus, in this work, molecular dynamics (MD) simulations have been employed to illuminate the molecular mechanism of baicalein-induced destabilization of preformed Aß42 protofibrils. Baicalein binds to chain A of the Aß42 protofibril through hydrogen bonds, π-π interactions, and hydrophobic contacts with the central hydrophobic core (CHC) residues of the Aß42 protofibril. The binding of baicalein to the CHC region of the Aß42 protofibril resulted in the elongation of the kink angle and disruption of K28-A42 salt bridges, which resulted in the distortion of the protofibril structure. Importantly, the ß-sheet content was notably reduced in Aß42 protofibrils upon incorporation of baicalein with a concomitant increase in the coil content, which is consistent with ThT fluorescence and AFM images depicting disaggregation of pre-existing Aß42 fibrils on the incorporation of baicalein. Remarkably, the interchain binding affinity in Aß42 protofibrils was notably reduced in the presence of baicalein leading to distortion in the overall structure, which agrees with the structural stability analyses and conformational snapshots. This work sheds light on the molecular mechanism of baicalein in disrupting the Aß42 protofibril structure, which will be beneficial to the design of therapeutic candidates against disrupting ß-sheet rich neurotoxic Aß42 oligomers in AD.

Unravelling the destabilization potential of ellagic acid on α-synuclein fibrils using molecular dynamics simulations.

The aberrant deposition of α-synuclein (α-Syn) protein into the intracellular neuronal aggregates termed Lewy bodies and Lewy neurites characterizes the devastating neurodegenerative condition known as Parkinson's disease (PD). The disruption of pre-existing disease-relevant α-Syn fibrils is recognized as a viable therapeutic approach for PD. Ellagic acid (EA), a natural polyphenolic compound, is experimentally proven as a potential candidate that prevents or reverses the α-Syn fibrillization process. However, the detailed inhibitory mechanism of EA against the destabilization of α-Syn fibril remains largely unclear. In this work, the influence of EA on α-Syn fibril and its putative binding mechanism were explored using molecular dynamics (MD) simulations. EA interacted primarily with the non-amyloid-ß component (NAC) of α-Syn fibril, disrupting its ß-sheet content and thereby increasing the coil content. The E46-K80 salt bridge, critical for the stability of Greek-key-like α-Syn fibril, was disrupted in the presence of EA. The binding free energy analysis using the MM-PBSA method demonstrates the favourable binding of EA to α-Syn fibril (ΔGbinding = -34.62 ± 11.33 kcal mol-1). Interestingly, the binding affinity between chains H and J of the α-Syn fibril was significantly reduced on the incorporation of EA, which highlights the disruptive ability of EA towards α-Syn fibril. The MD simulations provide mechanistic insights into the α-Syn fibril disruption by EA, which gives a valuable direction for the development of potential inhibitors of α-Syn fibrillization and its associated cytotoxicity.

Mechanistic insights into the mitigation of Aß aggregation and protofibril destabilization by a D-enantiomeric decapeptide rk10.

According to clinical studies, the development of Alzheimer's disease (AD) is linked to the abnormal aggregation of amyloid-ß (Aß) peptides into toxic soluble oligomers, protofibrils as well as mature fibrils. The most acceptable therapeutic strategy for the treatment of AD is to block the Aß aggregation. Sun and co-workers have reported a decapeptide, D-enantiomeric RTHLVFFARK-NH2 (rk10), which acts as a potent inhibitor of Aß aggregation and efficiently disaggregates pre-assembled Aß fibrils. However, the inhibitory mechanism of rk10 against Aß aggregation and disassembly of fibrils remains obscure. To investigate the inhibitory mechanism of rk10 against Aß aggregation and disassembly of fibrils, molecular dynamics (MD) simulations have been performed in the present study. The molecular docking analysis using AutoDock Vina predicted favourable binding of rk10 with the N-terminal and central hydrophobic core (CHC) residues of Aß42 monomer (-5.3 kcal mol-1), and with the residues of chain A of Aß42 protofibril structure (-6.9 kcal mol-1). The MD simulations depicted higher structural stability of Aß42 monomer in the presence of rk10. Notably, rk10 prevented the sampling of ß-sheet rich structures of Aß42 monomer by reducing the side-chain contacts between N-terminal and C-terminal residues of Aß42 monomer. The per-residue binding free energy analysis highlighted the significant contribution of Phe19 and Glu22 of Aß42 monomer in binding with rk10, which corroborate with the 1H NMR (nuclear magnetic resonance) spectra of Aß42 monomer + rk10 complex that depicted a change in the chemical shifts of amide protons of Phe19 and Glu22. Further, rk10 destabilized the Aß42 protofibril structure by lowering the number of interchain hydrogen bonds. The binding free energy analysis predicted lower binding affinity between Aß42 protofibril chains in the presence of rk10 as compared to Aß42 protofibril alone. The insights into the inhibitory mechanism of rk10 against Aß aggregation and disassembly of fibrils will be beneficial for the design and development of potent anti-amyloid inhibitors.

Targeting Human Islet Amyloid Polypeptide Aggregation and Toxicity in Type 2 Diabetes: An Overview of Peptide-Based Inhibitors.

Type 2 diabetes (T2D) is a chronic metabolic disease characterized by insulin resistance and a progressive loss of pancreatic islet ß-cell mass, which leads to insufficient secretion of insulin and hyperglycemia. Emerging evidence suggests that toxic oligomers and fibrils of human islet amyloid polypeptide (hIAPP) contribute to the death of ß-cells and lead to T2D pathogenesis. These observations have opened new avenues for the development of islet amyloid therapies for the treatment of T2D. The peptide-based inhibitors are of great value as therapeutic agents against hIAPP aggregation in T2D owing to their biocompatibility, feasibility of synthesis and modification, high specificity, low toxicity, proteolytic stability (modified peptides), and weak immunogenicity as well as the large size of involved interfaces during self-aggregation of hIAPP. An understanding of what has been done and achieved will provide key insights into T2D pathology and assist in the discovery of more potent drug candidates for the treatment of T2D. In this article, we review various peptide-based inhibitors of hIAPP aggregation, including those derived from the hIAPP sequence and those not based on the sequence, consisting of both natural as well as unnatural amino acids and their derivatives. The present review will be beneficial in advancing the field of peptide medicine for the treatment of T2D.

An α-helix mimetic oligopyridylamide, ADH-31, modulates Aß42 monomer aggregation and destabilizes protofibril structures: insights from molecular dynamics simulations.

Alzheimer's disease (AD), an epidemic growing worldwide due to no effective medical aid available in the market, is a neurological disorder. AD is known to be directly associated with the toxicity of amyloid-ß (Aß) aggregates. In search of potent inhibitors of Aß aggregation, Hamilton and co-workers reported an α-helix mimetic, ADH-31, which acts as a powerful antagonist of Aß42 aggregation. To identify the key interactions between protein-ligand complexes and to gain insights into the inhibitory mechanism of ADH-31 against Aß42 aggregation, molecular dynamics (MD) simulations were performed in the present study. The MD simulations highlighted that ADH-31 showed distinct binding capabilities with residues spanning from the N-terminal to the central hydrophobic core (CHC) region of Aß42 and restricted the conformational transition of the helix-rich structure of Aß42 into another form of secondary structures (coil/turn/ß-sheet). Hydrophobic contacts, hydrogen bonding and π-π interaction contribute to the strong binding between ADH-31 and Aß42 monomer. The Dictionary of Secondary Structure of Proteins (DSSP) analysis highlighted that the probability of helical content increases from 38.5% to 50.2% and the turn content reduces from 14.7% to 6.2% with almost complete loss of the ß-sheet structure (4.5% to 0%) in the Aß42 monomer + ADH-31 complex. The per-residue binding free energy analysis demonstrated that Arg5, Tyr10, His14, Gln15, Lys16, Val18, Phe19 and Lys28 residues of Aß42 are responsible for the favourable binding free energy in Aß42 monomer + ADH-31 complex, which is consistent with the 2D HSQC NMR of the Aß42 monomer that depicted a change in the chemical shift of residues spanning from Glu11 to Phe20 in the presence of ADH-31. The MD simulations highlighted the prevention of sampling of amyloidogenic ß-strand conformations in Aß42 trimer in the presence of ADH-31 as well as the ability of ADH-31 to destabilize Aß42 trimer and protofibril structures. The lower binding affinity between Aß42 trimer chains in the presence of ADH-31 highlights the destabilization of the Aß42 trimer structure. Overall, MD results highlighted that ADH-31 inhibited Aß42 aggregation by constraining Aß peptides into helical conformation and destabilized Aß42 trimer as well as protofibril structures. The present study provides a theoretical insight into the atomic level details of the inhibitory mechanism of ADH-31 against Aß42 aggregation as well as protofibril destabilization and could be implemented in the structure-based drug design of potent therapeutic agents for AD.

Interactions of a multifunctional di-triazole derivative with Alzheimer's Aß42 monomer and Aß42 protofibril: a systematic molecular dynamics study.

Amyloid aggregation modulators offer a promising treatment strategy for Alzheimer's disease (AD). We have recently reported a novel di-triazole based compound 6n as a multi-target-directed ligand (MTDL) against AD. 6n effectively inhibits Aß42 aggregation, metal-induced Aß42 aggregation, reactive oxygen species (ROS) generation, and rescues SH-SY5Y cells from Aß42 induced neurotoxicity. However, the underlying inhibitory mechanism remains uncovered. In this regard, molecular dynamics (MD) simulations were performed to understand the effect of 6n on the structure and stability of monomeric Aß42 and a pentameric protofibril structure of Aß42. Compound 6n binds preferably to the central hydrophobic core (CHC) and C-terminal regions of the Aß42 monomer as well as the protofibril structure. The secondary structure analysis suggests that 6n prevents the aggregation of the Aß42 monomer and disaggregates Aß42 protofibrils by sustaining the helical content in the Aß42 monomer and converting the ß-sheet into random coil conformation in the Aß42 protofibril structure. A significant decrease in the average number of hydrogen bonds, binding affinity, and residue-residue contacts between chains D-E of the Aß42 protofibril in the presence of 6n indicates destabilization of the Aß42 protofibril structure. The MM-PBSA (molecular mechanics Poisson-Boltzmann surface area) analysis highlighted favourable binding free energy (ΔGbinding) for the Aß42 monomer-6n and Aß42 protofibril-6n complex. Overall, MD results highlighted that 6n stabilizes the native α-helix conformation of the Aß42 monomer and induces a sizable destabilization in the Aß42 protofibril structure. This work provides theoretical insights into the inhibitory mechanism of 6n against amyloid aggregation and will be beneficial as a molecular guide for structure-based drug design against AD.

Computational design and evaluation of ß-sheet breaker peptides for destabilizing Alzheimer's amyloid-ß42 protofibrils.

The ß-sheet breaker (BSB) peptides interfere with amyloid fibril assembly and used as therapeutic agents in the treatment of Alzheimer's disease (AD). In this regard, a simple yet effective in silico screening methodology was applied in the present study to evaluate a potential 867 pentapeptide library based on known BSB peptide, LPFFD, for destabilizing Aß42 protofibrils. The molecular docking based virtual screening was used to filter out pentapeptides having binding affinities stronger than LPFFD. In the next step, binding free energies of the top 10 pentapeptides were evaluated using the MM-PBSA method. The residue-wise binding free energy analysis reveals that two pentapeptides, PVFFE, and PPFYE, bind to the surface of Aß42 protofibril and another pentapeptide, PPFFE, bind in the core region of Aß42 protofibril. By employing molecular dynamics simulation as a post filter for the top-hit peptides from MM-PBSA, the pentapeptides, PPFFE, PVFFE, and PPFYE, have been identified as potential BSB peptides for destabilizing Aß42 protofibril structure. The conformational microstate analysis, a significant decrease in the ß-sheet content of Aß42 protofibril, a loss in the total number of hydrogen bonds in Aß42 protofibril, Asp23-Lys28 salt bridge destabilization and analysis of the free energy surfaces highlight Aß42 protofibril structure destabilization in presence of pentapeptides. Among three top-hit pentapeptides, PPFFE displayed the most potent Aß42 protofibril destabilization effect that shifted the energy minima toward lowest value of ß-sheet content as well as lowest number of hydrogen bonds in Aß42 protofibril. The in silico screening workflow presented in the study highlight an alternative tool for designing novel peptides with enhanced BSB ability as potential therapeutic agents for AD.

Multifunctional Mono-Triazole Derivatives Inhibit Aß42 Aggregation and Cu2+-Mediated Aß42 Aggregation and Protect Against Aß42-Induced Cytotoxicity.

Amyloid beta (Aß) peptide aggregation is considered as one of the key hallmarks of Alzheimer's disease (AD). Moreover, Aß peptide aggregation increases considerably in the presence of metal ions and triggers the generation of reactive oxygen species (ROS), which ultimately leads to oxidative stress and neuronal damage. Based on the 'multitarget-directed ligands' (MTDLs) strategy, we designed, synthesized, and evaluated a novel series of triazole-based compounds for AD treatment via experimental and computational methods. Among the designed MTDLs [4(a-x)], the triazole derivative 4v exhibited the most potent inhibition of self-induced Aß42 aggregation (78.02%) with an IC50 value of 4.578 ± 0.109 µM and also disassembled the preformed Aß42 aggregates significantly. In addition, compound 4v showed excellent metal chelating ability and maintained copper in the redox-dormant state to prevent the generation of ROS in copper-ascorbate redox cycling. Further, 4v significantly inhibited Cu2+-induced Aß42 aggregation and disassembled the Cu2+-induced Aß42 protofibrils as compared to the reference compound clioquinol (CQ). Importantly, 4v did not show cytotoxicity and was able to inhibit the toxicity induced by Aß42 aggregates in SH-SY5Y cells. Molecular docking results confirmed the strong binding of 4v with Aß42 monomer and Aß42 protofibril structure. The experimental and molecular docking results highlighted that 4v is a promising multifunctional lead compound for AD.

Molecular insights into the inhibitory mechanism of bi-functional bis-tryptoline triazole against ß-secretase (BACE1) enzyme.

The ß-site amyloid precursor protein-cleaving enzyme 1 (ß-secretase, BACE1) is involved in the formation of amyloid-ß (Aß) peptide that aggregates into soluble oligomers, amyloid fibrils, and plaques responsible for the neurodegeneration in Alzheimer disease (AD). BACE1 is one of the prime therapeutic targets for the design of inhibitors against AD as BACE1 participate in the rate-limiting step in Aß production. Jiaranaikulwanitch et al. reported bis-tryptoline triazole (BTT) compound as a potent inhibitor against BACE1, Aß aggregation as well as possessing metal chelation and antioxidant activity. However, the molecular mechanism of BACE1 inhibition by BTT remains unclear. Thus, molecular docking and molecular dynamics (MD) simulations were performed to elucidate the inhibitory mechanism of BTT against BACE1. MD simulations highlight that BTT interact with catalytic aspartic dyad residues (Asp32 and Asp228) and active pocket residues of BACE1. The hydrogen-bond interactions, hydrophobic contacts, and π-π stacking interactions of BTT with flap residues (Val67-Asp77) of BACE1 confine the movement of the flap and help to achieve closed (non-active) conformation. The PCA analysis highlights lower conformational fluctuations for BACE1-BTT complex, which suggests enhanced conformational stability in comparison to apo-BACE1. The results of the present study provide key insights into the underlying inhibitory mechanism of BTT against BACE1 and will be helpful for the rational design of novel inhibitors with enhanced potency against BACE1.

Multi-target-directed triazole derivatives as promising agents for the treatment of Alzheimer's disease.

A novel series of triazole-based compounds have been designed, synthesised and evaluated as multi-target-directed ligands (MTDLs) against Alzheimer disease (AD). The triazole-based compounds have been designed to target four major AD hallmarks that include Aß aggregation, metal-induced Aß aggregation, metal dys-homeostasis and oxidative stress. Among the synthesised compounds, 6n having o-CF3 group on the phenyl ring displayed most potent inhibitory activity (96.89% inhibition, IC50 = 8.065 ±â€¯0.129 µM) against Aß42 aggregation, compared to the reference compound curcumin (95.14% inhibition, IC50 = 6.385 ±â€¯0.009 µM). Compound 6n disassembled preformed Aß42 aggregates as effectively as curcumin. Furthermore, 6n displayed metal chelating ability and significantly inhibited Cu2+-induced Aß42 aggregation and disassembled preformed Cu2+-induced Aß42 aggregates. 6n successfully controlled the generation of the reactive oxygen species (ROS) by preventing the copper redox cycle. In addition, 6n did not display cytotoxicity and was able to inhibit toxicity induced by Aß42 aggregates in SH-SY5Y cells. The preferred binding regions and key interactions of 6n with Aß42 monomer and Aß42 protofibril structure was evaluated with molecular docking. Compound 6n binds preferably to the C-terminal region of Aß42 that play a critical role in Aß42 aggregation. The results of the present study highlight a novel triazole-based compound, 6n, as a promising MTDL against AD.

Molecular insights into the effect L17A/F19A double mutation on the structure and dynamics of Aß40 : A molecular dynamics simulation study.

The aggregation of amyloid-ß (Aß) peptide has been associated with the pathogenesis of Alzheimer disease. The recent studies highlighted that L17A/F19A double mutation increases the structural stability of Aß40 and diminish Aß40 aggregation. However, the underlying effect of L17A/F19A double mutation on the Aß40 structure and dynamics remain elusive. In this regard, the influence of L17A/F19A double mutation on the structure and dynamics of Aß40 was investigated using all-atom molecular dynamics (MD) simulation. MD simulation reveals that mechanism behind modulation of Aß40 aggregation is associated with a decrease in the ß-sheet content and dynamics of the salt bridge D23-K28. The secondary structure analysis highlight more abundant α-helix content in the central hydrophobic core and C-terminal region of Aß40 upon L17A/F19A double mutation that is consistent with circular dichroism (CD) results. The free-energy landscape reveal that coil conformation is the most dominant conformation in Aß40 whereas the helical conformation is the most-populated and energetically favorable conformation in Aß40 (L17A/F19A). MD simulation, in accord with the experiment, highlight that L17A/F19A double mutation diminish Aß40 aggregation as the population of the fibril-prone state substantially decreased. The present study, in conjunction with experiment, highlight that L17 and F19 are the critical residues involved in the conformational change that triggers a neurotoxic cascade of Aß40 . Overall, MD simulation provides key structural and physical insights into the reduced Aß40 aggregation upon L17A/F19A double mutation and an atomic picture of the L17A/F19A-mediated conformational changes in Aß40 .

Assessing the effect of D59P mutation in the DE loop region in amyloid aggregation propensity of ß2-microglobulin: A molecular dynamics simulation study.

Dialysis-related amyloidosis (DRA) is a severe condition characterized by the accumulation of amyloidogenic ß2-microglobulin (ß2m) protein around skeletal joints and bones. The recent studies highlighted a critical role of the DE loop region for ß2m stability and amyloid aggregation propensity. Despite significant efforts, the molecular mechanism of enhanced aggregation due to D59P mutation in the DE loop region remain elusive. In the present study, explicit-solvent molecular dynamics (MD) simulations were performed to examine the key changes in the structural and dynamic properties of wild type (wt) ß2m upon D59P mutation. MD simulations reveal a decrease in the average number of hydrogen bonds in the loop regions on D59P mutation that enhances conformational flexibility, which lead to higher aggregation propensity of D59P as compare to wt ß2m. The principal component analysis (PCA) highlight that D59P covers a larger region of phase space and display a higher trace value than wt ß2m, which suggest an overall enhancement in the conformational flexibility. D59P display two minimum energy basins in the free energy landscape (FEL) that are associated with thermodynamically less stable conformational states as compare to single minimum energy basin in wt ß2m. The present study provides theoretical insights into the molecular mechanism behind the higher aggregation propensity of D59P as compare to wt ß2m.

Harnessing the Therapeutic Potential of Peptides for Synergistic Treatment of Alzheimer's Disease by Targeting Aß Aggregation, Metal-Mediated Aß Aggregation, Cholinesterase, Tau Degradation, and Oxidative Stress.

Alzheimer's disease (AD) is a progressive multifaceted neurodegenerative disease and remains a formidable global health challenge. The current medication for AD gives symptomatic relief and, thus, urges us to look for alternative disease-modifying therapies based on a multitarget directed approach. Looking at the remarkable progress made in peptide drug development in the last decade and the benefits associated with peptides, they offer valuable chemotypes [multitarget directed ligands (MTDLs)] as AD therapeutics. This review recapitulates the current developments made in harnessing peptides as MTDLs in combating AD by targeting multiple key pathways involved in the disease's progression. The peptides hold immense potential and represent a convincing avenue in the pursuit of novel AD therapeutics. While hurdles remain, ongoing research offers hope that peptides may eventually provide a multifaceted approach to combat AD.

Diversity-oriented approaches to unusual α-amino acids and peptides: step economy, atom economy, redox economy, and beyond.

Here we describe several useful strategies to a variety of unusual α-amino acid derivatives and peptides based on "building block" approach. These building blocks are suitable for modification at an amino acid as well as at a peptide level. Moreover, these methods have embedded several points for diversification and are capable of producing a library of modified amino acids and peptides. We have employed highly atom-economic processes such as the Diels-Alder reaction, [2 + 2 + 2] cycloaddition, Suzuki-Miyaura cross-coupling, and olefin metathesis as key steps to assemble various unnatural amino acid derivatives and peptides. In some instances, we have used rongalite to generate Diels-Alder precursors.

Synthesis, analysis, and multi-faceted applications of solid wastes-derived silica nanoparticles: a comprehensive review (2010-2022).

The synthesis of silica nanoparticles (SiNPs) has emerged as an extensive area of research in the last century. Owing to their instinctive properties like modifiable mesoporous structure, high surface area, adjustable pore size, and pore volume, SiNPs could be utilized in numerous fields like chemical, biochemical, catalysis, adsorption, and pollution control. Conventionally, SiNPs are produced by tetraethylorthosilicate (TEOS), tetramethylorthosilicate (TMOS), and sodium silicate, which are toxic and expensive. Therefore, the development of green, cost-effective approaches for the synthesis of SiNPs is highly desirable. In this course, during the last decade, silica-rich solid wastes (rice husk, corn cob, sugarcane bagasse, palm ash, fly ash, waste glass, waste packaging materials, photonic industrial wastes, etc.) were acknowledged as economical precursors to produce green SiNPs. In this respect, the present review focuses on reviewing several solid waste materials used for the synthesis of SiNPs, their properties, and different characterization techniques used for the analysis of SiNPs. The present review also accounts for the potential applications of such green SiNPs in several fields like catalysis, adsorption, biomedical applications, and energy storage. Moreover, despite the potential applications of SiNPs, still there is a lot to explore about their synthesis and utilization. Hence, in the last section of this review, future scope, challenges, and risk assessment of SiNPs have been discussed.

Unveiling How Hydroxytyrosol Destabilizes α-Syn Oligomers Using Molecular Simulations.

The etiology of Parkinson's disease (PD) is mainly linked to the α-synuclein (α-Syn) fibrillogenesis. Hydroxytyrosol (HT), also known as 3,4-dihydroxyphenylethanol, is a naturally occurring polyphenol, found in extra virgin olive oil, and has been shown to have cardioprotective, anticancer, antiobesity, and antidiabetic properties. HT has neuroprotective benefits in neurodegenerative diseases and lessens the severity of PD by reducing the aggregation of α-Syn and destabilizing the preformed toxic α-Syn oligomers. However, the molecular mechanism by which HT destabilizes α-Syn oligomers and alleviates the accompanying cytotoxicity remains unexplored. The impact of HT on the α-Syn oligomer structure and its potential binding mechanism was examined in this work by employing molecular dynamics (MD) simulations. The secondary structure analysis depicted that HT significantly reduces the ß-sheet and concomitantly increases the coil content of α-Syn trimer. Visualization of representative conformations from the clustering analysis depicted the hydrogen bond interactions of the hydroxyl groups in HT with the N-terminal and nonamyloid-ß component (NAC) region residues of α-Syn trimer, which, in turn, leads to the weakening of interchain interactions in α-Syn trimer and resulted in the disruption of the α-Syn oligomer. The binding free energy calculations depict that HT binds favorably to α-Syn trimer (ΔGbinding = -23.25 ± 7.86 kcal/mol) and a notable reduction in the interchain binding affinity of α-Syn trimer on the incorporation of HT, which, in turn, highlights its potential to disrupt α-Syn oligomers. The current research provided mechanistic insights into the destabilization of α-Syn trimer by HT, which, in turn, will provide new clues for developing therapeutics against PD.

Triazole-Peptide Conjugate as a Modulator of Aß-Aggregation, Metal-Mediated Aß-Aggregation, and Cytotoxicity.

Amyloid-ß (Aß) aggregation plays a key role in the pathogenesis of Alzheimer's disease (AD). Along with this, the presence of redox-active metals like Cu2+ further enhances Aß aggregation, oxidative stress, and cellular toxicity. In this study, we have rationally designed, synthesized, and evaluated a series of triazole-peptide conjugates as potential promiscuous ligands capable of targeting different pathological factors of AD. In particular, peptidomimetic DS2 showed the best inhibitory activity against Aß aggregation with an IC50 value of 2.43 ± 0.05 µM. In addition, DS2 disaggregates preformed Aß42 fibrils, chelates metal ions, inhibits metal-mediated Aß aggregation, significantly controls reactive oxygen species production, and reduces oxidative stress. DS2 exhibited very low cytotoxicity and significantly ameliorated the Aß-induced toxicity in differentiated neuroblastoma cells, SH-SY5Y. In addition, alteration in the fibrillary architecture of Aß42 in the absence and presence of DS2 was validated by transmission electron microscopy (TEM) images. To shed light on the inhibitory mechanism of DS2 against Aß aggregation and disassembly of the protofibril structure, molecular dynamics (MD) simulations have been performed. DS2 binds preferentially with the central hydrophobic core (CHC) residues of Aß42 monomer and chains D-E of Aß42 protofibril. The dictionary of secondary structure of proteins analysis indicated a noteworthy increase in the helix content from 38.5 to 61% and, notably, a complete loss of ß-sheet content of Aß42 monomer when DS2 is added to it. DS2 suppressed Aß42 monomer aggregation by preserving helical conformations and was able to reduce the production of aggregation-prone ß-sheet structures, which are consistent with ThT, circular dichroism, and TEM assay that indicate a reduction in the formation of toxic Aß42 aggregated species on the addition of DS2. Moreover, DS2 destabilized the Aß42 protofibril structure by significantly reducing the binding affinity between chains D-E of protofibril, which highlighted the disruption of interchain interactions and subsequent deformation of the protofibril structure. The results of the present study demonstrate that triazole-peptide conjugates may be valuable chemotypes for the development of promising multifunctional AD therapeutic candidates.

Turkish perlite supported nickel oxide as the heterogeneous acid catalyst for a series of Claisen-Schmidt condensation reactions.

Potentially active and eco-friendly solid acid catalysts have been synthesized by loading different weight percentages (10, 15, and 50) of nickel oxide on thermally activated Turkish perlite through the deposition-precipitation method. Structural features of prepared catalysts were analyzed using BET surface area analysis, X-ray diffraction, scanning electron microscope (SEM), SEM-EDX, transmission electron microscopy (TEM), Fourier-transform infrared (FT-IR), pyridine adsorbed FT-IR, UV-Vis diffuse reflectance spectroscopy (DRS), and thermogravimetric analysis (TGA) techniques. Pyridine adsorbed FT-IR analysis confirmed the presence of the optimum amount of Bronsted acidic sites in a catalyst having 15 wt. % loading of nickel oxide, which was tested for catalyzing a series of Claisen-Schmidt condensation of cyclohexanone and aromatic aldehydes to produce good isolated yield (90%-93%) of 2,6-bis(substituted benzylidene)cyclohexanones, significantly used in anti-tumor and cytotoxic activities. The high catalytic efficiency of the chosen catalyst remains almost intact up to six reaction cycles. On higher wt. % loading of nickel oxide, crystallite size increases along with agglomeration of larger nickel oxide particles on catalyst surface resulting in pore blockage and poor catalytic activity. Loading of NiO on the surface of thermally activated Turkish perlite was confirmed by SEM-EDX analysis, and TEM observations show that the particle size of the preferred catalyst was less than 50 nm. Based on results drawn from XRD, FT-IR, pyridine adsorbed FT-IR, UV-Vis DRS studies, model structures were proposed for Turkish perlite and all prepared catalysts. During this work, the catalytic potential of the preferred catalyst was compared with other previously reported catalysts, and it showed appreciable results. The formed products were further confirmed by their melting point and 1H-NMR analysis.

Targeting the Dimerization of the Main Protease of Coronaviruses: A Potential Broad-Spectrum Therapeutic Strategy.

A new coronavirus (CoV) caused a pandemic named COVID-19, which has become a global health care emergency in the present time. The virus is referred to as SARS-CoV-2 (severe acute respiratory syndrome-coronavirus-2) and has a genome similar (∼82%) to that of the previously known SARS-CoV (SARS coronavirus). An attractive therapeutic target for CoVs is the main protease (Mpro) or 3-chymotrypsin-like cysteine protease (3CLpro), as this enzyme plays a key role in polyprotein processing and is active in a dimeric form. Further, Mpro is highly conserved among various CoVs, and a mutation in Mpro is often lethal to the virus. Thus, drugs targeting the Mpro enzyme significantly reduce the risk of mutation-mediated drug resistance and display broad-spectrum antiviral activity. The combinatorial design of peptide-based inhibitors targeting the dimerization of SARS-CoV Mpro represents a potential therapeutic strategy. In this regard, we have compiled the literature reports highlighting the effect of mutations and N-terminal deletion of residues of SARS-CoV Mpro on its dimerization and, thus, catalytic activity. We believe that the present review will stimulate research in this less explored yet quite significant area. The effect of the COVID-19 epidemic and the possibility of future CoV outbreaks strongly emphasize the urgent need for the design and development of potent antiviral agents against CoV infections.

How Does the Mono-Triazole Derivative Modulate Aß42 Aggregation and Disrupt a Protofibril Structure: Insights from Molecular Dynamics Simulations.

Clinical studies have identified that abnormal self-assembly of amyloid-ß (Aß) peptide into toxic fibrillar aggregates is associated with the pathology of Alzheimer's disease (AD). The most acceptable therapeutic approach to stop the progression of AD is to inhibit the formation of ß-sheet-rich structures. Recently, we designed and evaluated a series of novel mono-triazole derivatives 4(a-x), where compound 4v was identified as the most potent inhibitor of Aß42 aggregation and disaggregates preformed Aß42 fibrils significantly. Moreover, 4v strongly averts the Cu2+-induced Aß42 aggregation and disaggregates the preformed Cu2+-induced Aß42 fibrils, halts the generation of reactive oxygen species, and shows neuroprotective effects in SH-SY5Y cells. However, the underlying molecular mechanism of inhibition of Aß42 aggregation by 4v and disaggregation of preformed Aß42 fibrils remains obscure. In this work, molecular dynamics (MD) simulations have been performed to explore the conformational ensemble of the Aß42 monomer and a pentameric protofibril structure of Aß42 in the presence of 4v. The MD simulations highlighted that 4v binds preferentially at the central hydrophobic core region of the Aß42 monomer and chains D and E of the Aß42 protofibril. The dictionary of secondary structure of proteins analysis indicated that 4v retards the conformational conversion of the helix-rich structure of the Aß42 monomer into the aggregation-prone ß-sheet conformation. The binding free energy calculated by the molecular mechanics Poisson-Boltzmann surface area method revealed an energetically favorable process with ΔG binding = -44.9 ± 3.3 kcal/mol for the Aß42 monomer-4v complex. The free energy landscape analysis highlighted that the Aß42 monomer-4v complex sampled conformations with significantly higher helical contents (35 and 49%) as compared to the Aß42 monomer alone (17%). Compound 4v displayed hydrogen bonding with Gly37 (chain E) and π-π interactions with Phe19 (chain D) of the Aß42 protofibril. Further, the per-residue binding free energy analysis also highlighted that Phe19 (chain D) and Gly37 (chain E) of the Aß42 protofibril showed the maximum contribution in the binding free energy. The decreased binding affinity and residue-residue contacts between chains D and E of the Aß42 protofibril in the presence of 4v indicate destabilization of the Aß42 protofibril structure. Overall, the structural information obtained through MD simulations indicated that 4v stabilizes the native helical conformation of the Aß42 monomer and persuades a destabilization in the protofibril structure of Aß42. The results of the study will be useful in the rational design of potent inhibitors against amyloid aggregation.