Development of artificial neural network models to predict the PAMPA effective permeability of new, orally administered drugs active against the coronavirus SARS-CoV-2.

Responding to the pandemic caused by SARS-CoV-2, the scientific community intensified efforts to provide drugs effective against the virus. To strengthen these efforts, the "COVID Moonshot" project has been accepting public suggestions for computationally triaged, synthesized, and tested molecules. The project aimed to identify molecules of low molecular weight with activity against the virus, for oral treatment. The ability of a drug to cross the intestinal cell membranes and enter circulation decisively influences its bioavailability, and hence the need to optimize permeability in the early stages of drug discovery. In our present work, as a contribution to the ongoing scientific efforts, we employed artificial neural network algorithms to develop QSAR tools for modelling the PAMPA effective permeability (passive diffusion) of orally administered drugs. We identified a set of 61 features most relevant in explaining drug cell permeability and used them to develop a stacked regression ensemble model, subsequently used to predict the permeability of molecules included in datasets made available through the COVID Moonshot project. Our model was shown to be robust and may provide a promising framework for predicting the potential permeability of molecules not yet synthesized, thus guiding the process of drug design. Supplementary Information: The online version contains supplementary material available at 10.1007/s13721-023-00410-9.

Focused library of phenyl-fused macrocyclic amidinoureas as antifungal agents.

The rise of antimicrobial-resistant phenotypes and the spread of the global pandemic of COVID-19 are worsening the outcomes of hospitalized patients for invasive fungal infections. Among them, candidiases are seriously worrying, especially since the currently available drug armamentarium is extremely limited. We recently reported a new class of macrocyclic amidinoureas bearing a guanidino tail as promising antifungal agents. Herein, we present the design and synthesis of a focused library of seven derivatives of macrocyclic amidinoureas, bearing a second phenyl ring fused with the core. Biological activity evaluation shows an interesting antifungal profile for some compounds, resulting to be active on a large panel of Candida spp. and C. neoformans. PAMPA experiments for representative compounds of the series revealed a low passive diffusion, suggesting a membrane-based mechanism of action or the involvement of active transport systems. Also, compounds were found not toxic at high concentrations, as assessed through MTT assays.

Mechanism of the enhancing effect of glycyrrhizin on nifedipine penetration through a lipid membrane.

The saponin glycyrrhizin from liquorice root shows the ability to enhance the therapeutic activity of other drugs when used as a drug delivery system. Due to its amphiphilic properties, glycyrrhizin can form self-associates (dimers, micelles) and supramolecular complexes with a wide range of hydrophobic drugs, which leads to an increase in their solubility, stability and bioavailability. That is why the mechanism of the biological activity of glycyrrhizin is of considerable interest and has been the subject of intensive physical and chemical research in the last decade. Two mechanisms have been proposed to explain the effect of glycyrrhizin on drug bioavailability, namely, the increase in drug solubility in water and enhancement of the membrane permeability. Interest in the membrane-modifying ability of glycyrrhizic acid (GA) is also growing at present due to its recently discovered antiviral activity against SARS-CoV-2 Bailly and Vergoten (2020) [1]. In the present study, the passive permeability of the DOPC lipid membrane for the calcium channel blocker nifedipine was elucidated by parallel artificial membrane permeability assay (PAMPA) and full atomistic molecular dynamics (MD) simulation with free energy calculations. PAMPA experiments show a remarkable increase in the amount of nifedipine (NF) permeated with glycyrrhizin compared to free NF. In previous studies, we have shown using MD techniques that glycyrrhizin molecules can integrate into the lipid bilayer. In this study, MD simulation demonstrates a significant decrease in the energy barrier of NF penetration through the lipid bilayer in the presence of glycyrrhizin both in the pure DOPC membrane and in the membrane with cholesterol. This effect can be explained by the formation of hydrogen bonds between NF and GA in the middle of the bilayer.