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Among neurodegenerative disorders, Alzheimer's disease (AD) is one of the most common disorders showing slow progressive cognitive decline. Targeting acetylcholinesterase (AChE) is one of the major strategies for AD therapeutics, as cholinergic pathways in the cerebral cortex and basal forebrain are compromised. Herein, we report the design of some copper and other metal based donepezil derivatives, employing density functional theory (DFT). All designed compounds are optimized at the B3LYP/SDD level of theory. Dipole moments, electronic energie, enthalpies, Gibbs free energies, and HOMO-LUMO gaps of these modified compounds are also investigated in the subsequent analysis. The molecules were then subjected to molecular docking analysis with AChE to study the molecular interactions broadly. Ensemble based docking and molecular dynamics (MD) simulations of the best candidates were also performed. Docking and MD simulation reveal that modified drugs are more potent than unmodified donepezil, where Trp86, Tyr337, Phe330 residues play some important roles in drug-receptor interactions. According to ensemble based docking, D9 shows greater binding affinity compared to the parent in most conformations obtained from protein data bank and MD simulation. In addition, it is observed that the π- π stacking with the residues of Trp86, Tyr337, Tyr341, Tyr124 and Trp286 may be required for strong ligand binding. Moreover, ADME/T analysis suggests that modified derivatives are less toxic and have improved pharmacokinetic properties than those of the parent drug. These results further confirm the ability of metal-directed drugs to bind simultaneously to the active sites of AChE and support them as potential candidates for the future treatment of Alzheimer's disease.

Hydroxycinnamic acid derivatives are important class of polyphenolic compounds originated from the Mavolanate-Shikimate biosynthesis pathways in plants. Several simple phenolic compounds such as cinnamic acid, p -coumaric acid, ferulic acid, caffeic acid, chlorgenic acid, and rosmarinic acid belong to this class. These phenolic compounds possess potent antioxidant and anti-inflammatory properties. These compounds were also showed potential therapeutic benefit in experimental diabetes and hyperlipidemia. Recent evidences also suggest that they may serve as valuable molecule for the treatment of obesity related health complications. In adipose tissues, hydroxycinnamic acid derivatives inhibit macrophage infiltration and nuclear factor κB (NF-κB) activation in obese animals. Hydroxycinnamic acid derivatives also reduce the expression of the potent proinflammatory adipokines tumor necrosis factor-α (TNFα), monocyte chemoattractant protein-1 (MCP-1), and plasminogen activator inhibitor type-1 (PAI-1), and they increase the secretion of an anti-inflammatory agent adiponectin from adipocytes. Furthermore, hydroxycinnamic acid derivatives also prevent adipocyte differentiation and lower lipid profile in experimental animals. Through these diverse mechanisms hydroxycinnamic acid derivatives reduce obesity and curtail associated adverse health complications.

Objective Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in both men and women. Toll-like receptor 5 (TLR5), an autoimmune signaling receptor that plays a role in cancer, can be exploited for the suppression of human colon cancer. Salmonella flagellin protein, a novel agonist of TLR5 activating downstream signaling, could be a basis for designing anticancer peptides. Methods The three-dimensional crystal structure of TLR5 (PDB ID: 3J0A, Resolution = 26.0 Å) was optimized using the AMBER force field in the YASARA suit. In silico enzymatic digestion tool, PeptideCutter, was used to identify peptides from Salmonella flagellin, an agonist against human TLR5. The 3D structure of the peptides was generated using PEP-FOLD3. These peptides were screened against human TLR5 using shape complementarity principles based on the binding affinity and interactions with the active residue of TLR5 monomer, and the selected peptides were further validated by molecular dynamic (MD) simulation. Results In this study, we generated 42 peptides from Salmonella flagellin protein by in silico protein digestion. Then, based on a new hidden Markov model sub-optimal conformation sampling approach as well as the size of the fragments, we select 38 effective peptides from these 42 cleavages. These peptides were screened against the monomeric Xray structure of human TLR5 using shape complementarity principles. Based on the binding affinity and interactions with the active residue of TLR5 monomer (residues 294 and 366 of TLR5), nine top-scored peptides were selected for the initial molecular dynamic (MD) simulation. Among these peptides, Clv10, Clv17, and Clv28 showed high stability and less flexibility during MD simulation. A 1 μs MD simulation was performed on TLR5-Clv10, TLR-Clv17, and TLR5-Clv28 complexes to further analyze the stability, conformational changes, and binding mode (Clv10, Clv17, and Clv28). During this MD study, the peptides showed high salt bridges and ionic interactions with residue ASP294 and residue ASP366 throughout the simulation and remained in the concave of the human TLR5 monomer. The RMSD and Rg values showed that the peptide-protein complexes become stable after 200 ns of contraction and extraction. Conclusion These findings can facilitate the rational design of selected peptides as an agonist of TLR5, which have antitumor activity, suppress colorectal cancer tumors, and can be used as promising candidates and novel agonists of TLR5. Graphical Abstract

The aim of the current study was to evaluate microbial contamination in terms of microbial load (total aerobic count and total coliform count) and specific pathogenic bacteria (Salmonella spp., Escherichia coli, particularly Escherichia coli 0157) in thirteen antidiabetic herbal preparations (ADHPs) from Dhaka City. All the thirteen ADHPs had been found contaminated with fungi and different pathogenic bacteria. From the data, it is found that only two of these preparations (ADHP-1 and ADHP-12) complied with the safety limit (as stated in different Pharmacopoeias and WHO guidelines) evaluated by all different microbial counts. None of these herbal preparations could assure the safety as all of them were contaminated by fungi. The overall safety regarding heavy metal content (Zn, Cu, Mn, Cr, Cd, and Pb) was assured as none of them exceeded the safety limit of the daily intake. Microbial contaminants in these herbal preparations pose a potential risk for human health and care should be taken in every step involved in the preparation of these herbal preparations to assure safety.

In recent years, multidrug-resistance has become a primary concern in the treatment and management of tuberculosis, an infectious disease caused by Mycobacterium tuberculosis. In this context, searching new anti-tuberculosis agents particularly targeting the β-lactamase (BlaC) is reported to be promising as this enzyme is one of the key player in the development of multidrug resistance. This study reports the design of some Nickel (Ni) based tetradentate N2O2 Schiff bases, employing density functional theory. All analogs are optimized at B3LYP/SDD level of theory. Dipole moment, electronic energy, enthalpy, Gibbs free energy, HOMO–LUMO gap, and softness of these modified drugs are also investigated. Molecular interactions between designed ligands and BlaC have been analyzed by molecular docking approach, followed by molecular dynamics (MD) simulation. All designed compounds show low HOMO–LUMO gap, while addition of halogen increases the dipole moment of the compounds. Docking and MD simulation investigations reveal that the designed compounds are more potent than standard inhibitor, where Ile117, Pro290, Arg236 and Thr253 residues of BlaC are found to play important role in the ligand binding. Through MD simulation study, the best binding compound is also observed to form stable complex by increasing the protein rigidness. The ADME/T analysis suggests that modified drugs are less toxic and shows an improved pharmacokinetic properties than that of the standard drug. These results further confirm the ability of Ni-directed Schiff bases to bind simultaneously to the active site of BlaC and support them as potential candidates for the future treatment of tuberculosis disease.