Green synthesis, in silico modeling, and biological evaluation of N-substituted (Z)-5-arylidene imidazolidine/thiazolidine-2,4-dione/4-thione derivatives catalyzed by Bu SO3H core-shell nanostructures.

In this effort, the immobilization of guanidine-sulfonate on the surface of Fe3O4 MNPs (magnetic nanoparticles) as a novel acid nanocatalyst has been successfully reported for the synthesis of N-substituted (Z)-5-arylidene thiazolidine-2,4-dione and related cyclic derivatives, including rhodanine (RHD) and hydantoin (HYD) via a one-pot multiple-component reaction under green conditions. The products were characterized by SEM, TEM, TGA, EDS, BET techniques, VSM, and FTIR. The novel compounds synthesized using this methodology, designated as series La (1-9), Lb (1-8), and Lc (1-8), were subjected to anticancer screening against A549 and MCF7cell lines via MTT assays. Notably, several compounds (L1a, L2a, L3a, L1b, L2b, L3b, and L4b) exhibited potent antiproliferative activities, with observed IC50 values as low as 1.23 µM and 1.02 µM against MCF-7 cells, thereby outperforming the established anticancer drugs doxorubicin and cisplatin. Molecular docking and dynamics simulations revealed that ligands L1a, L2a, and L3a strongly interact with the protein target 3CD8, with L1a displaying significant hydrophobic and hydrogen bonding interactions and L2a engaging in unique pi-pi stacking with key residues. For protein 2WGJ, ligand L4b exhibited exceptional binding affinity, characterized by robust hydrogen bonding, hydrophobic interactions, and additional stabilizing mechanisms such as water bridges and pi interactions. Hence, N-substituted (Z)-5-arylidene thiazolidine-2,4-dione and its cyclic derivatives may serve as promising candidates for further exploration in the development of new multi-target cancer chemotherapy agents. These findings introduce promising anticancer agents and establish Fe3O4 MNPs as a versatile and environmentally sustainable catalytic platform in drug discovery.

In silico anti-alzheimer study of phytochemicals from Lamiaceae family through GSK3-ß inhibition.

Glycogen synthase kinase 3-beta (GSK3-ß) is a serine-threonine protease expressed in the brain, and its hyperactivity is considered the underlying cause of Alzheimer's disease. This enzyme requires an ATP molecule in its N-terminal lobe to phosphorylate its substrates, with the most important substrate being the Tau protein. This study focuses on the inhibitory mechanism of four naturally occurring compounds-apigenin, luteolin, rosmarinic acid, and salvianolic acid-from the Laminaceae family against GSK3-ß. The orientation of the ligands within the ATP-binding pocket of GSK3-ß and their binding energy were determined through molecular docking. Additionally, molecular dynamics simulations was conducted to study the conformational changes induced by the ligands in the protein structure. The results showed that apigenin and salvianolic acid achieved deeper parts of the cavity compared to luteolin and rosmarinic acid and formed stable complexes with the enzyme. In the rosmarinic acid complex, the enzyme exhibited the most exposed conformation. On the other hand, luteolin binding caused a small closure of the opening, suggesting a potentially ATP-competitive role. Our results suggest these compounds as lead candidates for the design of GSK3-ß inhibitors.

Correction to: In silico investigation of the therapeutic and prophylactic potential of medicinal substances bearing guanidine moieties against COVID-19.

[This corrects the article DOI: 10.1007/s11696-022-02528-y.].

In silico investigation of the therapeutic and prophylactic potential of medicinal substances bearing guanidine moieties against COVID-19.

The current viral pandemic, coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), creates health, mental, economic, and other serious challenges that are better to say global crisis. Despite the existence of successful vaccines, the possible mutations which can lead to the born of novel and possibly more dangerous variants of the virus as well as the absence of definitive treatment for this potentially fatal multiple-organ infection in critically ill patients make us keep searching. Theoretically targeting human and viral receptors and enzymes via molecular docking and dynamics simulations can be considered a wise, rational, and efficient way to develop therapeutic agents against COVID-19. In this way, The RNA-dependent RNA polymerase (RdRP), main protease, and spike glycoprotein of SARS-CoV-2 as well as the human angiotensin-converting enzyme 2 receptor and transmembrane serine protease 2 are the most discussed and studied targets that play essential roles in the viral life and infection cycle. In the current in silico investigation, the guanidine functionality containing drugs and medicinal substances such as metformin, famotidine, neuraminidase inhibitors, antimalarial medications, anticancer drug imatinib, CGP compounds, and human serine protease inhibitor camostat were studied against the above-mentioned therapeutic targets and most of them (especially imatinib) have revealed an incredible spectrum of free docking scores and MD results. The current in silico investigation that its novel perspective of view is corroborated by the different experimental and clinical evaluations, confirms that the guanidine moiety can be considered as a missing promising pharmacophore in drug design and development approaches against SARS-CoV-2. Considering the chemical potency of this polyamine group in chemical interaction creation, the observed outcomes in this virtual screening were not surprising. On the other hand, the guanidine functional group has unique physico-chemical properties such as basicity that can make the target cells intracellular pH undesirable for the virus entry, uncoating, and cytosolic lifecycle. According to the obtained results in the current study that are interestingly confirmed by the previously reported efficacy of some the guanidine carrying drugs in COVID-19, guanidine as a potential multi-target anti-SARS-CoV-2 functional scaffold deserves further comprehensive investigations. Supplementary Information: The online version contains supplementary material available at 10.1007/s11696-022-02528-y.

Design of novel disturbing peptides against ACE2 SARS-CoV-2 spike-binding region by computational approaches.

The SARS-CoV-2, the virus which is responsible for COVID-19 disease, employs its spike protein to recognize its receptor, angiotensin-converting enzyme 2 (ACE2), and subsequently enters the host cell. In this process, the receptor-binding domain (RBD) of the spike has an interface with the α1-helix of the peptidase domain (PD) of ACE2. This study focuses on the disruption of the protein-protein interaction (PPI) of RBD-ACE2. Among the residues in the template (which was extracted from the ACE2), those with unfavorable energies were selected for substitution by mutagenesis. As a result, a library of 140 peptide candidates was constructed and the binding affinity of each candidate was evaluated by molecular docking and molecular dynamics simulations against the α1-helix of ACE2. Finally, the most potent peptides P23 (GFNNYFPHQSYGFMPTNGVGY), P28 (GFNQYFPHQSYGFPPTNGVGY), and P31 (GFNRYFPHQSYGFCPTNGVGY) were selected and their dynamic behaviors were studied. The results showed peptide inhibitors increased the radius, surface accessible area, and overall mobility of residues of the protein. However, no significant alteration was seen in the key residues in the active site. Meanwhile, they can be proposed as promising agents against COVID-19 by suppressing the viral attachment and curbing the infection at its early stage. The designed peptides showed potency against beta, gamma, delta, and omicron variants of SARS-CoV-2.

Inhibition of SARS-CoV-2 pathogenesis by potent peptides designed by the mutation of ACE2 binding region.

The outbreak of COVID-19 has resulted in millions of deaths. Despite all attempts that have been made to combat the pandemic, the re-emergence of new variants complicated SARS-CoV-2 eradication. The ongoing global spread of COVID-19 demands the incessant development of novel agents in vaccination, diagnosis, and therapeutics. Targeting receptor-binding domain (RBD) of spike protein by which the virus identifies host receptor, angiotensin-converting enzyme (ACE2), is a promising strategy for curbing viral infection. This study aims to discover novel peptide inhibitors against SARS-CoV-2 entry using computational approaches. The RBD binding domain of ACE2 was extracted and docked against the RBD. MMPBSA calculations revealed the binding energies of each residue in the template. The residues with unfavorable binding energies were considered as mutation spots by OSPREY. Binding energies of the residues in RBD-ACE2 interface was determined by molecular docking. Peptide inhibitors were designed by the mutation of RBD residues in the virus-receptors complex which had unfavorable energies. Peptide tendency for RBD binding, safety, and allergenicity were the criteria based on which the final hits were screened among the initial library. Molecular dynamics simulations also provided information on the mechanisms of inhibitory action in peptides. The results were finally validated by molecular docking simulations to make sure the peptides are capable of hindering virus-host interaction. Our results introduce three peptides P7 (RAWTFLDKFNHEAEDLRYQSSLASWN), P13 (RASTFLDKFNHEAEDLRYQSSLASWN), and P19 (RADTFLDKFNHEAEDLRYQSSLASWN) as potential effective inhibitors of SARS-CoV-2 entry which could be considered in drug development for COVID-19 treatment.

In silico evaluation of COVID-19 main protease interactions with honeybee natural products for discovery of high potential antiviral compounds.

This research investigates antiviral potential of extracted honeybee products against COVID-19 main protease (Mpro) by computational methods. The crystal structure of COVID-19 Mpro was obtained from the protein data bank. Six synthetic drugs with antiviral properties were used as control samples in order to compare the results with those of natural ligands. The six honeybee components, namely 3,4,5-Tricaffeoylquinic acid, Kaempferol-3-O-glucoside, (E)-2'-Geranyl-3',4',7-Trihydroxyflavanone, 6-Cinnamylchrysin, (+)-Pinoresinol, and (24E)-3-Oxo-27,28-dihydroxycycloart-24-en-26-oic acid, have represented the lowest binding energies of -9.0, -8.5, -8.2, -7.8, -7.7, -7.3 and -6.7 Kcal/mol, respectively. These natural inhibitors were then picked for further investigations on their pharmacokinetic features. Also a 150 ns of Molecular dynamics simulations were carried out in order to evaluate their effects on protein structure and dynamics. The 3, 4, 5-Tricaffeoylquinic acid is hopefully proposed for COVID-19 Mpro inhibition if further in vitro, in vivo, and clinical trial studies will approve its effectiveness against COVID-19.

Inhibition of GSK_3ß by Iridoid Glycosides of Snowberry (Symphoricarpos albus) Effective in the Treatment of Alzheimer's Disease Using Computational Drug Design Methods.

The inhibition of glycogen synthase kinase-3ß (GSK-3ß) activity prevents tau hyperphosphorylation and binds it to the microtubule network. Therefore, a GSK-3ß inhibitor may be a recommended drug for Alzheimer's treatment. In silico methods are currently considered as one of the fastest and most cost-effective available alternatives for drug/design discovery in the field of treatment. In this study, computational drug design was conducted to introduce compounds that play an effective role in inhibiting the GSK-3ß enzyme by molecular docking and molecular dynamics simulation. The iridoid glycosides of the common snowberry (Symphoricarpos albus), including loganin, secologanin, and loganetin, are compounds that have an effect on improving memory and cognitive impairment and the results of which on Alzheimer's have been studied as well. In this study, in the molecular docking phase, loganin was considered a more potent inhibitor of this protein by establishing a hydrogen bond with the ATP-binding site of GSK-3ß protein and the most negative binding energy to secologanin and loganetin. Moreover, by molecular dynamics simulation of these ligands and GSK-3ß protein, all structures were found to be stable during the simulation. In addition, the protein structure represented no change and remained stable by binding ligands to GSK-3ß protein. Furthermore, loganin and loganetin have higher binding free energy than secologanin; thus, these compounds could effectively bind to the active site of GSK-3ß protein. Hence, loganin and loganetin as iridoid glycosides can be effective in Alzheimer's prevention and treatment, and thus, further in vitro and in vivo studies can focus on these iridoid glycosides as an alternative treatment.