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Targeting the tumor microenvironment (TME) is an attractive strategy for developing new drugs with anticancer activity against triple-negative breast cancer (TNBC). Interleukins (ILs) are key players in the TME cytokine network promoting cancer progression. Recent studies have highlighted the involvement of IL-20 receptor subunit alpha (IL-20RA) signalling in several cancers, including BC, in which IL-20RA is highly expressed, correlating with poor prognosis and influencing tumoral characteristics such as proliferation, cell death, invasiveness, and TME activity. Therefore, elucidating the role of the IL-20RA signalling pathway could form the basis for developing new therapeutic strategies. This study aimed to identify selective bioactive ligands able to affect IL-20RA activity. Virtual screening of over 310,000 compounds from both the DrugBank and ZINC15 databases identified four potential hit compounds tested for their anticancer activity against TNBC in vitro cell lines. Notably, Ritonavir, a well-known Human Immunodeficiency Virus Type 1 (HIV-1) protease inhibitor, significantly inhibited cell proliferation (about 40% at 50 µM, p < 0.001). IL-20 preincubation counteracted Ritonavir's cytostatic effect while IL-20RA knockdown restored proliferation in Ritonavir-treated TNBC cells. In conclusion, these findings demonstrated that Ritonavir reduced TNBC cell proliferation through IL-20RA activity modulation, suggesting its potential repurposing as a therapeutic agent for TNBC management. [ABSTRACT FROM AUTHOR]

Anti-COVID19 drugs, such as nirmatrelvir, have been developed targeting the SARS-CoV-2 main protease, Mpro, based on the critical requirement of its proteolytic processing of the viral polyproteins into functional proteins essential for viral replication. However, the emergence of SARS-CoV-2 variants with Mpro mutations has raised the possibility of developing resistance against these drugs, likely due to therapeutic targeting of the Mpro catalytic site. An alternative to these drugs is the development of drugs that target an allosteric site distant from the catalytic site in the protein that may reduce the chance of the emergence of resistant mutants. Here, we combine computational analysis with in vitro assay and report the discovery of a potential allosteric site and an allosteric inhibitor of SARS-CoV-2 Mpro. Specifically, we identified an Mpro metastable state with a deformed catalytic site harboring potential allosteric sites, raising the possibility that stabilization of this metastable state through ligand binding can lead to the inhibition of Mpro activity. We then performed a computational screening of a library (∼4.2 million) of drug-like compounds from the ZINC database and identified several candidate molecules with high predicted binding affinity. MD simulations showed stable binding of the three top-ranking compounds to the putative allosteric sites in the protein. Finally, we tested the three compounds in vitro using a BRET-based Mpro biosensor and found that one of the compounds (ZINC4497834) inhibited the Mpro activity. We envisage that the identification of a potential allosteric inhibitor of Mpro will aid in developing improved anti-COVID-19 therapy.

Small molecules targeting biosynthesis of mycolic acids in the tuberculosis causing bacterium carry high potential for anti-tuberculosis drug discovery. Hitherto, benzofuran containing molecules were identified to target the thioesterase domain of polyketide synthase 13 (Pks13), one of the crucial constituents of this pathway. Among these, TAM16 was also reported to be highly potent in vivo. Here we performed a multi-stage virtual screening methodology recruiting both ligand- and structure-based screening tools for identification of novel Pks13 inhibitors. The large ZINC15 database comprising more than 1 billion ligands was reduced to 21,277 ligands with benzofuran rings and similarity to TAM16. This collection was screened by docking and the 20 top scoring ligands were further analyzed by molecular dynamics simulations. Molecular mechanics/generalized Born surface area (MM-GBSA) based binding free energy predictions confirmed five molecules in the ZINC15 database lead to remarkable increases in the binding free energy of TAM16. Essentially, the most potent ligand ZINC840169872, which carries a distinct scaffold with a cyclohexane group fused to the furan ring, produced a twofold change in the ligand efficiency of TAM16. Further, assessments of the structure-based tools on five different Pks13-TAM complex structures suggested a high-level agreement with the experiments, substantiating the validity of our methodology for screening Pks13 inhibitors. Overall, these in silico insights into a low energy benzofuran-based scaffold and an alternative binding mode for the benzofuran ring unravel viable strategies to generate potent anti-tuberculosis drugs, accentuating the applications of virtual screening approaches for exploring large compound libraries that cannot be easily accessed by experimentation. [ABSTRACT FROM AUTHOR]

Chagas disease (CD), or American trypanosomiasis, causes more than 10,000 deaths per year in the Americas. Current medical therapy for CD has low efficacy in the chronic phase of the disease and serious adverse effects; therefore, it is necessary to search for new pharmacological treatments. In this work, the ZINC15 database was filtered using the N-acylhydrazone moiety and a subsequent structure-based virtual screening was performed using the cruzain enzyme of Trypanosoma cruzi to predict new potential cruzain inhibitors. After a rational selection process, four compounds, Z2 (ZINC9873043), Z3 (ZINC9870651), Z5 (ZINC9715287), and Z6 (ZINC9861447), were chosen to evaluate their in vitro trypanocidal activity and enzyme inhibition. Compound Z5 showed the best trypanocidal activity against epimatigote (IC50 = 36.26 ± 9.9 μM) and trypomastigote (IC50 = 166.21 ± 14.5 μM and 185.1 ± 8.5 μM on NINOA and INC-5 strains, respectively) forms of Trypanosoma cruzi. In addition, Z5 showed a better inhibitory effect on Trypanosoma cruzi proteases than S1 (STK552090, 8-chloro-N-(3-morpholinopropyl)-5H-pyrimido[5,4-b]-indol-4-amine), a known cruzain inhibitor. This study encourages the use of computational tools for the rational search for trypanocidal drugs. [ABSTRACT FROM AUTHOR]