Significance: Tadalafil and vardenafil are among the most widely used drugs for erectile dysfunction, which affects nearly 19% of men over 20 y of age. Older men also suffer from age-related bone loss resulting in crippling fractures. We show that in mice, both agents act on bone cells, resulting in the formation of new bone and reduced removal of old bone. Because of this net gain in bone mass, we posit that tadalafil and vardenafil could be used for cotreating erectile dysfunction and osteoporosis in men of advancing age, as well as for treating osteoporosis in postmenopausal women. We recommend future clinical studies to establish the capability of these drugs to increase bone density and reduce fracture risk in humans.

Microtubules are highly dynamic polymers of α,β-tubulin dimers which play an essential role in numerous cellular processes such as cell proliferation and intracellular transport, making them an attractive target for cancer and neurodegeneration research. To date, a large number of known tubulin binders were derived from natural products, while only one was developed by rational structure-based drug design. Several of these tubulin binders show promising in vitro profiles while presenting unacceptable off-target effects when tested in patients. Therefore, there is a continuing demand for the discovery of safer and more efficient tubulin-targeting agents. Since tubulin structural data is readily available, the employment of computer-aided design techniques can be a key element to focus on the relevant chemical space and guide the design process. Due to the high diversity and quantity of structural data available, we compiled here a guide to the accessible tubulin-ligand structures. Furthermore, we review different ligand and structure-based methods recently used for the successful selection and design of new tubulin-targeting agents.

SARS-CoV-2 M^pro is a chymotrypsin-like cysteine protease playing a relevant role during the replication and infectivity of SARS-CoV-2, the coronavirus responsible for COVID-19. The binding site of M^pro is characterized by the presence of a catalytic Cys145 which carries out the hydrolytic activity of the enzyme. As a consequence, several M^pro inhibitors have been proposed to date in order to fight the COVID-19 pandemic. In our work, we designed, synthesized and biologically evaluated MPD112, a novel inhibitor of SARS-CoV-2 M^pro bearing a trifluoromethyl diazirine moiety. MPD112 displayed in vitro inhibition activity against SARS-CoV-2 M^pro at a low micromolar level (IC₅₀ = 4.1 μM) in a FRET-based assay. Moreover, an inhibition assay against PL^pro revealed lack of inhibition, assuring the selectivity of the compound for the M^pro. Furthermore, the target compound MPD112 was docked within the binding site of the enzyme to predict the established intermolecular interactions in silico. MPD112 was subsequently tested on the HCT-8 cell line to evaluate its effect on human cells’ viability, displaying good tolerability, demonstrating the promising biological compatibility and activity of a trifluoromethyl diazirine moiety in the design and development of SARS-CoV-2 M^pro binders.