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Isoindolines are essential from the point of view of synthesis and their biological properties, so this work is focused on the synthesis of new isoindolines derived from the following L‐α‐amino acids, aspartic acid (1), arginine (2), glutamic acid (3‐5), serine (6), and lysine (7). All compounds were characterized by 1H and 13C NMR, infrared, and high‐resolution mass spectrometry. In addition, the synthesized compounds were screened to investigate their antiproliferative activities against five human cancer cell lines, A549, U373, MDA‐MB‐231, MCF‐7, and HeLa, as well as on primary cell culture healthy, MGC, EC, and Vero cells lines. All tested compounds exhibited activity against cancer cell lines at mM concentrations. Notably, compounds 6 derived from Ser, and 7 derived from Lys exhibited remarkable effects on the A549 and U373. The IC50 values for these compounds were determined to be 0.001 and 0.007 mM, respectively. These findings indicate a significantly higher potency of compounds 6 and 7 than the other tested compounds. Among the tested compounds, only compound 5 displayed significant cytotoxic activity against the Vero cell line. [ABSTRACT FROM AUTHOR]

Aflatoxin B1 (AFB1) exhibits the most potent mutagenic and carcinogenic activity among aflatoxins. For this reason, AFB1 is recognized as a human group 1 carcinogen by the International Agency of Research on Cancer. Consequently, it is essential to determine its properties and behavior in different chemical systems. The chemical properties of AFB1 can be explored using computational chemistry, which has been employed complementarily to experimental investigations. The present review includes in silico studies (semiempirical, Hartree–Fock, DFT, molecular docking, and molecular dynamics) conducted from the first computational study in 1974 to the present (2022). This work was performed, considering the following groups: (a) molecular properties of AFB1 (structural, energy, solvent effects, ground and the excited state, atomic charges, among others); (b) theoretical investigations of AFB1 (degradation, quantification, reactivity, among others); (c) molecular interactions with inorganic compounds (Ag+, Zn2+, and Mg2+); (d) molecular interactions with environmentally compounds (clays); and (e) molecular interactions with biological compounds (DNA, enzymes, cyclodextrins, glucans, among others). Accordingly, in this work, we provide to the stakeholder the knowledge of toxicity of types of AFB1-derivatives, the structure–activity relationships manifested by the bonds between AFB1 and DNA or proteins, and the types of strategies that have been employed to quantify, detect, and eliminate the AFB1 molecule. [ABSTRACT FROM AUTHOR]

The coordination of one and two aflatoxin B1 (AFB1, a potent carcinogen) molecules with chlorophyll a (chl a) was studied at a theoretical level. Calculations were performed using the M06-2X method in conjunction with the 6-311G(d,p) basis set, in both gas and water phases. The molecular electrostatic potential map shows the chemical activity of various sites of the AFB1 and chl a molecules. The energy difference between molecular orbitals of AFB1 and chl a allowed for the establishment of an intermolecular interaction. A charge transfer from AFB1 to the central cation of chl a was shown. The energies of the optimized structures for chl a show two configurations, unfolded and folded, with a difference of 15.41 kcal/mol. Chl a appeared axially coordinated to the plane (α-down or β-up) of the porphyrin moiety, either with the oxygen atom of the ketonic group, or with the oxygen atom of the lactone moiety of AFB1. The complexes of maximum stability were chl a 1-α-E-AFB1 and chl a 2-β-E-AFB1, at −36.4 and −39.2 kcal/mol, respectively. Additionally, with two AFB1 molecules were chl a 1-D-2AFB1 and chl a 2-E-2AFB1, at −60.0 and −64.8 kcal/mol, respectively. Finally, biosorbents containing chlorophyll could improve AFB1 adsorption. [ABSTRACT FROM AUTHOR]

Among the multiple factors that induce Alzheimer’s disease, aggregation of the amyloid β peptide (Aβ) is considered the most important due to the ability of the 42-amino acid Aβ peptides (Aβ1–42) to form oligomers and fibrils, which constitute Aβ pathological aggregates. For this reason, the development of inhibitors of Aβ1–42 pathological aggregation represents a field of research interest. Several Aβ1–42 fibrillization inhibitors possess tertiary amine and aromatic moieties. In the present study, we selected 26 compounds containing tertiary amine and aromatic moieties with or without substituents and performed theoretical studies that allowed us to select four compounds according to their free energy values for Aβ1–42 in α-helix (Aβ-α), random coil (Aβ-RC) and β-sheet (Aβ-β) conformations. Docking studies revealed that compound 5 had a higher affinity for Aβ-α and Aβ-RC than the other compounds. In vitro, this compound was able to abolish Thioflavin T fluorescence and favored an RC conformation of Aβ1–42 in circular dichroism studies, resulting in the formation of amorphous aggregates as shown by atomic force microscopy. The results obtained from quantum studies allowed us to identify a possible pharmacophore that can be used to design Aβ1–42 aggregation inhibitors. In conclusion, compounds with higher affinity for Aβ-α and Aβ-RC prevented the formation of oligomeric species. [ABSTRACT FROM AUTHOR]

Among the multiple factors that induce Alzheimer’s disease, aggregation of the amyloid β peptide (Aβ) is considered the most important due to the ability of the 42-amino acid Aβ peptides (Aβ1–42) to form oligomers and fibrils, which constitute Aβ pathological aggregates. For this reason, the development of inhibitors of Aβ1–42 pathological aggregation represents a field of research interest. Several Aβ1–42 fibrillization inhibitors possess tertiary amine and aromatic moieties. In the present study, we selected 26 compounds containing tertiary amine and aromatic moieties with or without substituents and performed theoretical studies that allowed us to select four compounds according to their free energy values for Aβ1–42 in α-helix (Aβ-α), random coil (Aβ-RC) and β-sheet (Aβ-β) conformations. Docking studies revealed that compound 5 had a higher affinity for Aβ-α and Aβ-RC than the other compounds. In vitro, this compound was able to abolish Thioflavin T fluorescence and favored an RC conformation of Aβ1–42 in circular dichroism studies, resulting in the formation of amorphous aggregates as shown by atomic force microscopy. The results obtained from quantum studies allowed us to identify a possible pharmacophore that can be used to design Aβ1–42 aggregation inhibitors. In conclusion, compounds with higher affinity for Aβ-α and Aβ-RC prevented the formation of oligomeric species. [ABSTRACT FROM AUTHOR]

The formation of fibrils and oligomers of amyloid beta (Aβ) with 42 amino acid residues (Aβ1-42) is the most important pathophysiological event associated with Alzheimer's disease (AD). The formation of Aβ fibrils and oligomers requires a conformational change from an α-helix to a β-sheet conformation, which is encouraged by the formation of a salt bridge between Asp 23 or Glu 22 and Lys 28. Recently, Cu2+ and various drugs used for AD treatment, such as galanthamine (Reminyl®), have been reported to inhibit the formation of Aβ fibrils. However, the mechanism of this inhibition remains unclear. Therefore, the aim of this work was to explore how Cu2+ and galanthamine prevent the formation of Aβ1-42 fibrils using molecular dynamics (MD) simulations (20 ns) and in vitro studies using fluorescence and circular dichroism (CD) spectroscopies. The MD simulations revealed that Aβ1-42 acquires a characteristic U-shape before the α-helix to β-sheet conformational change. The formation of a salt bridge between Asp 23 and Lys 28 was also observed beginning at 5 ns. However, the MD simulations of Aβ1−42 in the presence of Cu2+ or galanthamine demonstrated that both ligands prevent the formation of the salt bridge by either binding to Glu 22 and Asp 23 (Cu2+) or to Lys 28 (galanthamine), which prevents Aβ1−42 from adopting the U-characteristic conformation that allows the amino acids to transition to a β-sheet conformation. The docking results revealed that the conformation obtained by the MD simulation of a monomer from the 1Z0Q structure can form similar interactions to those obtained from the 2BGE structure in the oligomers. The in vitro studies demonstrated that Aβ remains in an unfolded conformation when Cu2+ and galanthamine are used. Then, ligands that bind Asp 23 or Glu 22 and Lys 28 could therefore be used to prevent β turn formation and, consequently, the formation of Aβ fibrils. [ABSTRACT FROM AUTHOR]

The number of patients diagnosed with Alzheimer's disease (AD) increases each year, and there are currently few treatment strategies to decrease the symptoms of AD; furthermore, these strategies are not sufficient to reduce memory loss in AD patients. In this work , in vitro and in silico studies were performed to evaluate the effects of fucosterol, which was extracted from an algal source and characterized by liquid chromatography-mass spectra (LC-MS), as an inhibitor of Aβ 1-42 aggregation. Experimental studies, including protein gel electrophoresis, atomic force microscopy and fluorescence studies with thioflavin T (ThT), highlighted that fucosterol can decrease oligomer formation more than galantamine, which was used as a positive control. Docking and molecular dynamics simulations coupled with an MMGBSA approach showed that fucosterol is capable of recognizing the hydrophobic regions of monomeric Aβ 1-42 , suggesting that fucosterol could affect amyloid-beta (Aβ 1-42 ) aggregation by preventing the formation of oligomers, preventing the development of AD.Communicated by Ramaswamy H. Sarma.

Myeloperoxidase (MPO) is the most abundant heme protein in neutrophils, and MPO catalyzes hypochlorous acid (HOCl) formation. MPO inhibitors (MPOis) can be used to treat several diseases in which MPO and HOCl levels are elevated. The molecular details of several MPOis have not been extensively studied to elucidate their molecular recognition properties. In addition, it is not known whether MPO has only one binding site or more binding sites for aryl compounds, which would explain its promiscuity properties. Therefore, docking simulations were performed to analyze the MPO binding site recognition using several X-ray structures and snapshots retrieved from molecular dynamics (MD) simulations to simulate the binding of MPO with several known aryl ligands. All of the evaluated ligands were recognized by MPO at the same site, which was identified by the Q-Site Finder as being one of the principal sites and named herein as the "principal binding site" (PBS). The PBS is composed of Q91, H95, F99, R239, E242, F366 and F407. The results indicate that the MPO ligand recognition is mediated by π-π interactions with an aromatic cluster (F99, F366, F407 and a heme group), giving rise to high MPO promiscuity. In addition, MD simulations and X-ray crystallography show limited conformational variations in the MPO. In addition, either MPOis or another substrate (tyrosine) reaches the same site, but different interactions were observed. Therefore, the results indicate minor movement in the side chain of the mentioned amino acids that allow ligands to be recognized in the same MPO site with different interactions that are dependent on their chemical structures. Furthermore, docking study samples of several conformations retrieved from the MD simulations showed that ABAH was one of the ligands that always had the same interaction. This result provides potential evidence for hydrazides being very good MPOis.