The method of comparative molecular field analysis (CoMFA) was used to develop quantitative structure-activity relationships for physostigmine, 9-amino-1,2,3,4-tetrahydroacridine (THA), edrophonium (EDR), and other structurally diverse inhibitors of acetylcholinesterase (AChE). The availability of the crystal structures of enzyme/inhibitor complexes (EDR/AChE, THA/AChE, and decamethonium (DCM)/AChE) (Harel, M.; et al. Quaternary ligand binding to aromatic residues in the active-site gorge of acetylcholinesterase. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 9031-9035) provided information regarding not only the active conformation of the inhibitors but also the relative mutual orientation of the inhibitors in the active site of the enzyme. Crystallographic conformations of EDR and THA were used as templates onto which additional inhibitors were superimposed. The application of cross-validated R2 guided region selection method, recently developed in this laboratory (Cho, S.J.; Tropsha, A. Cross-Validated R2 Guided Region Selection for Comparative Molecular Field Analysis (CoMFA): A Simple Method to Achieve Consistent Results. J. Med. Chem. 1995, 38, 1060-1066), to 60 AChE inhibitors led to a highly predictive CoMFA model with the q2 of 0.734.

No abstract

The pandemic associated with Severe Acute Respiratory Syndrome Coronavirus type 2 (SARS-CoV2) and its disease named COVID-19 challenged the scientific community to discover effective therapeutic solutions in a short period. Repurposing existing drugs is one viable approach that emphasizes speed during these urgent times. Famotidine, a class A G protein-coupled receptor antagonist used for the treatment of gastroesophageal reflux was recently identified in an in silico screening. Additionally, a recent retrospective clinical report showed that the treatment with famotidine provided a good outcome in patients infected with SARS-CoV2. A clinical trial testing effectiveness of famotidine in combination with hydroxychloroquine is currently ongoing in the United States (US). In the 1990s, famotidine was described as an antiviral agent against human immunodeficiency virus (HIV). Interestingly, some HIV protease inhibitors are presently being used against SARS-CoV2. However, it is not clear if famotidine could be effective against SARS-CoV2. Thus, by using a computational analysis, we aimed to examine if the antiviral effect of famotidine could be related to the inhibition of proteases involved in the virus replication. Our results showed that famotidine could interact within the catalytic site of the three proteases associated with SARS-CoV2 replication. However, weak binding affinity of famotidine to these proteases suggests that a successful famotidine therapy could likely be achieved only in combination with other antiviral drugs. Finally, analysis of famotidine’s pharmacokinetic parameters indicated that its effect against SARS-CoV2 infection could be reached only upon intravenous administration. This work will contribute to the pharmacological knowledge of famotidine as an antiviral agent against SARS-CoV2.

BackgroundPlant extracts are sources of valuable compounds with biological activity, especially for the anti-proliferative activity against pathogens or tumor cells. Myricetin is a flavonoid found in several plants that has been described as an inhibitor of Human immunodeficiency virus type 1 (HIV-1) through its action against the HIV reverse transcriptase, but myricetin derivatives have not been fully studied. The aim of this study was to evaluate the anti-HIV-1 activity of glycosylated metabolites obtained from Marcetia taxifolia and derived from myricetin: myricetin rhamnoside and myricetin 3-(6-rhamnosylgalactoside).MethodsCompounds were obtained from organic extracts by maceration of aerial parts of M. taxifolia. All biological assays were performed in the MT4 cell line. Antiviral activity was measured as inhibition of p24 and reverse transcriptase with a fluorescent assay.ResultsBoth flavonoids have antiviral activity in vitro, with an EC50 of 120 µM for myricetin 3-rhamnoside (MR) and 45 µM for myricetin 3-(6-rhamnosylgalactoside) (MRG), both significantly lower than the EC50 of myricetin (230 µM). Although both compounds inhibited the reverse transcriptase activity, with an IC50 of 10.6 µM for MR and 13.8 µM for MRG, myricetin was the most potent, with an IC50 of 7.6 µM, and an inhibition greater than 80%. Molecular docking approach showed correlation between the free energy of binding with the assays of enzyme inhibition.ConclusionsThe results suggest that glycosylated moiety might enhance the anti-HIV-1 activity of myricetin, probably by favoring the internalization of the flavonoid into the cell. The inhibition of the HIV-1 reverse transcriptase is likely responsible for the antiviral activity.

Previous studies on the coordination chemistry of Co-bleomycin have suggested the secondary amine in beta-aminoalanine, the N5 and N1 nitrogens in the pyrimidine and imidazole rings, respectively, and the amide nitrogen in beta-hydroxyhistidine as equatorial ligands to the cobalt ion. The primary amine in beta-aminoalanine and the carbamoyl group of the mannose have been proposed alternatively as possible axial ligands. The first coordination sphere of Co(II) in Co(II)BLM has been investigated in the present study through the use of NMR and molecular dynamics calculations. The data collected from the NMR experiments are in agreement with the equatorial ligands previously proposed, and also support the participation of the primary amine as an axial ligand. The paramagnetic shifts of the gulose and mannose protons could suggest the latter as a second axial ligand. This possibility was investigated by way of molecular dynamics, with distance restraints derived from the relaxation times measured through NMR. The molecular dynamics results indicate that the most favorable structure is six-coordinate, with the primary amine and either the carbamoyl oxygen or a solvent molecule occupying the axial sites. The analysis of the structures previously derived for HOO-Co(III)-bleomycin and HOO-Co(III)-pepleomycin led us to propose the six-coordinate structure with only endogenous ligands, as the one held in solution by the Co(II) derivative of bleomycin.

Leishmaniasis is a chronic disease caused by protozoa of the distinct Leishmania genus transmitted by sandflies of the genus Phlebotomus (old world) and Lutzomyia (new world). Among the molecular factors that contribute to the virulence and pathogenesis of Leishmania are metalloproteases, e.g., glycoprotein 63 (gp63), also known as leishmanolysin or major surface protease (MSP). This protease is a zinc-dependent metalloprotease that is found on the surface of the parasite, abundant in Leishmania promastigote and amastigote. This study describes the prediction of three-dimensional (3D) structures of leishmanolysin (UniProt ID A0A088RJX7) of Leishmania panamensis employing a homology modeling approach. The 3D structure prediction was performed using the SWISS-MODEL web server. The tools PROCHECK, Molprobyty, and Verify3D were used to check the quality of the model, indicating that they are reliable. Best docking configurations were identified applying AutoDock Vina in PyRx 0.8 to obtain a potential antileishmanial activity. Biflavonoids such as lanaroflavone, podocarpusflavone A, amentoflavone, and podocarpusflavone B showed good scores among these molecules. Lanaroflavone appears to be the most suitable compound from binding affinity calculations.

Differential susceptibility to microtubule agents has been demonstrated between mammalian cells and kinetoplastid organisms such as Leishmania spp. and Trypanosoma spp. The aims of this study were to identify and characterize the architecture of the putative colchicine binding site of Leishmania spp. and investigate the molecular basis of colchicine resistance. We cloned and sequenced the β-tubulin gene of Leishmania (Viannia) guyanensis and established the theoretical 3D model of the protein, using the crystallographic structure of the bovine protein as template. We identified mutations on the Leishmania   β-tubulin gene sequences on regions related to the putative colchicine-binding pocket, which generate amino acid substitutions and changes in the topology of this region, blocking the access of colchicine. The same mutations were found in the β-tubulin sequence of kinetoplastid organisms such as Trypanosoma cruzi, T. brucei, and T. evansi. Using molecular modelling approaches, we demonstrated that conformational changes include an elongation and torsion of an α-helix structure and displacement to the inside of the pocket of one β-sheet that hinders access of colchicine. We propose that kinetoplastid organisms show resistance to colchicine due to amino acids substitutions that generate structural changes in the putative colchicine-binding domain, which prevent colchicine access.

Graphical abstract