The epidemic caused by the SARS-CoV-2 coronavirus, which has spread rapidly throughout the world, requires urgent and effective treatments considering that the appearance of viral variants limits the efficacy of vaccines. The main protease of SARS-CoV-2 (M^pro) is a highly conserved cysteine proteinase, fundamental for the replication of the coronavirus and with a specific cleavage mechanism that positions it as an attractive therapeutic target for the proposal of irreversible inhibitors. A structure-based strategy combining 3D pharmacophoric modeling, virtual screening, and covalent docking was employed to identify the interactions required for molecular recognition, as well as the spatial orientation of the electrophilic warhead, of various drugs, to achieve a covalent interaction with Cys145 of M^pro. The virtual screening on the structure-based pharmacophoric map of the SARS-CoV-2 M^pro in complex with an inhibitor N3 (reference compound) provided high efficiency by identifying 53 drugs (FDA and DrugBank databases) with probabilities of covalent binding, including N3 (Michael acceptor) and others with a variety of electrophilic warheads. Adding the energy contributions of affinity for non-covalent and covalent docking, 16 promising drugs were obtained. Our findings suggest that the FDA-approved drugs Vaborbactam, Cimetidine, Ixazomib, Scopolamine, and Bicalutamide, as well as the other investigational peptide-like drugs (DB04234, DB03456, DB07224, DB7252, and CMX-2043) are potential covalent inhibitors of SARS-CoV-2 M^pro.

Background: Obesity represents a risk in the development of metabolic and oxidative stress (OS), as well as in male infertility. There is still no pharmacological treatment for obesity‐induced male infertility, but the use of natural antioxidants has been proposed as a treatment.Objective: The aim of this work is to evaluate the effect of a whole tomato lipid extract on rats that decreased their fertility and spermatogenesis after being induced obese with a high carbohydrate diet.Materials and methods: One hundred fourteen male Wistar rats of 12 weeks of age were used. Two groups were randomly formed non‐obese control group (C, n = 54) and obese group (Ob, n = 54) that received 30% w/v sucrose solution for 3 months. Subsequently, the C and Ob group were divided into two groups: vehicle (C‐Vh and Ob‐Vh) that received corn oil as vehicle and tomato lipid extract (C‐Ex and Ob‐Ex) that received whole tomato lipid extract. The groups that received a hypercaloric diet had a gain in visceral and retroperitoneal adipose tissue, an increase in total cholesterol and triglyceride levels, increased OS in the testis, and lesions in testicular histology, as well as a reduction in testicular size and sperm quality parameters (motility, viability, and concentration).Results: Treatment with whole tomato lipid extract significantly decreased the weight of gonadal adipose tissue and OS, maintained testicular size, showed a significant increase in sperm quality parameters and improved histology of seminiferous tubules.Conclusions: These results demonstrate a greater therapeutic and beneficial effect of the tomato lipid extract on sperm quality parameters in obese rats and therefore on fertility.

Breast cancer (BC) is a malignant tumor that develops in the mammary gland due to uncontrolled cell proliferation. Estrogen receptor (ER) signaling, mediated by 17β-estradiol (E2), plays a crucial role in regulating cell proliferation, differentiation, and survival. Specifically, the binding of E2 to the estrogen receptor alpha (ERα) increases cell proliferation. Conversely, selective estrogen receptor beta (ERβ) agonists inhibit cancer cell proliferation by suppressing the expression of oncogenes, making ERβ an important therapeutic target. Given the urgent need for targeted and effective therapies for BC, we implemented a strategy based on multicomplex pharmacophores modeling of ERβ (MPMERβ) and ERα (MPMERα), performing a virtual cross-screening of databases of clinically approved and experimental drugs to identify those with high affinity and stereoelectronic complementarity with the ERβ agonist pharmacophore hypothesis. The implementation of a chemoinformatic strategy enabled the identification of Sobetirome, Labetalol, and Procaterol as molecular hits on the ERβ pharmacophore map. Procaterol showed the most significant antiproliferative activity in vitro assays, with IC₅₀ values of 21.26 and 36.10 µM in MCF-7 and MDA-MB-231, respectively. It is imperative to note that these findings require experimental validation of the ERβ activation pathways to strengthen the possible therapeutic repurposing of the drugs selected through our in silico approach. Finally, this strategy not only facilitates drug repurposing under in silico simulation but also provides valuable information for the rational design of new drugs against BC.