The spread of coronavirus infectious disease (COVID-19) is associated with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which has risked public health more than any other infectious disease. Researchers around the globe use multiple approaches to identify an effective approved drug (drug repurposing) that treats viral infections. Most of the drug repurposing approaches target spike protein or main protease. Here we use transmembrane serine protease 2 (TMPRSS2) as a target that can prevent the virus entry into the cell by interacting with the surface receptors. By hypothesizing that the TMPRSS2 binders may help prevent the virus entry into the cell, we performed a systematic drug screening over the current approved drug database. Furthermore, we screened the Enamine REAL fragments dataset against the TMPRSS2 and presented nine potential drug-like compounds that give us clues about which kinds of groups the pocket prefers to bind, aiding future structure-based drug design for COVID-19. Also, we employ molecular dynamics simulations, binding free energy calculations, and well-tempered metadynamics to validate the obtained candidate drug and fragment list. Our results suggested three potential FDA-approved drugs against human TMPRSS2 as a target. These findings may pave the way for more drugs to be exposed to TMPRSS2, and testing the efficacy of these drugs with biochemical experiments will help improve COVID-19 treatment. Supplementary information The online version contains supplementary material available at 10.1007/s11224-022-01960-w.

The ultrafast and precise single-onset action potential (AP) of the bushy cells (BCs) in the anteroventral cochlear nucleus (AVCN) plays an essential role in the precise processing of temporal auditory information for localizing sound sources and communication cues. The specialized properties of high conductance of low-voltage-activated potassium channel (K+LVA) contribute to generate ultrafast and precise single-onset APs in BCs. However, the developmental changes of K+LVA distribution and their contributions to shape neuronal excitability of BCs remain unclear. Therefore, we investigated the developmental changes in neuronal excitability of BCs and K+LVA distribution at different developmental periods. Using electrophysiological recording, we first characterized the firing pattern of BCs in response to a sequence of current injections at different developmental periods. The expression of K+LVA subunit Kv1.1 in AVCN was examined with western blot. The results indicated that BCs showed single-onset AP firing patterns and paused multiple APs firing patterns at the postnatal time of day 7 (P7) and were then refined into single-onset firing pattern at P14 and P21. With development, the active membrane properties, including latency and half-width of AP, and passive membrane properties, including capacitance, input resistance, and time constant, were significantly decreased. Furthermore, the refinement of firing patterns in BCs was correlated with the upregulation of the Kv1.1 channel in AVCN. In summary, the present study indicated that BCs optimize precise and single-onset firing with development, possibly driven by the changes in membrane properties and upregulation of Kv1.1 in AVCN.