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.

Computational exploration of allosteric inhibitors targeting CDK4/CDK6 proteins: a promising approach for multi-target drug development.

Cyclin-dependent kinases (CDKs) play a pivotal role in orchestrating the intricate regulation of the cell cycle, a fundamental process governing cell growth and division. In particular, CDK4 and CDK6 are critical for the transition from the G1 phase to the S phase, where Deoxyribonucleic acid (DNA) replication occurs, and their dysregulation is linked to various diseases, notably cancer. While ATP-binding site inhibitors for CDKs are well-documented, this study focuses on uncovering allosteric inhibitors, providing a fresh perspective on CDK inhibition. Computational techniques were employed in this investigation, utilizing Molecular Operating Environment (MOE) for virtual screening of a drug-like compound library. Moreover, the stability of the most promising binding inhibitors was assessed through Molecular Dynamics (MD) simulations and MMPBSA/MMGBSA analyses. The outcome reveals that three inhibitors (C1, C2, and C3) exhibited the strongest binding affinity for CDK4/CDK6, as corroborated by docking and simulation analyses. The computed binding energies ranged from -6.1 to -7.6 kcal/mol, underscoring the potency of these allosteric inhibitors. Notably, this study identifies key residues (PHE31, HIS95, HIS100, VAL101, ASP102, ASP104, and THR107) that play pivotal roles in mediating inhibitor binding within the allosteric sites. Among the findings, the C1-CDK4 complex and C2-CDK6 complex emerge as particularly promising inhibitors, exhibiting high binding energies, favorable interaction patterns, and sustained presence within the active site. This study contributes significantly to the pursuit of multi-target drugs against CDK4/CDK6 proteins, with potential implications for the development of innovative therapies across various disorders, including cancer and other cell cycle-related conditions.Communicated by Ramaswamy H. Sarma.

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.