ABSTRACT
Severe acute respiratory syndrome coronavirus (SARS-CoV-2) is an emerging new viral pathogen that causessevere respiratory disease. SARS-CoV-2 is responsible for the outbreak of COVID-19 pandemic worldwide.As there are no confirmed antiviral drugs or vaccines currently available for the treatment of COVID-19,discovering potent inhibitors or vaccines are urgently required for the benefit of humanity. The glycosylatedSpike protein (S-protein) directly interacts with human angiotensin-converting enzyme 2 (ACE2) receptorthrough the receptor-binding domain (RBD) of S-protein. As the S-protein is exposed to the surface and isessential for entry into the host, the S-protein can be considered as a first-line therapeutic target for antiviraltherapy and vaccine development. In silico screening, docking, and molecular dynamics simulation studieswere performed to identify repurposing drugs using DrugBank and PubChem library against the RBD ofS-protein. The study identified a laxative drug, Bisoxatin (DB09219), which is used for the treatment ofconstipation and preparation of the colon for surgical procedures. It binds nicely at the S-protein–ACE2interface by making substantial p-p interactions with Tyr505 in the ‘Site 1’ hook region of RBD andhydrophilic interactions with Glu406, Ser494, and Thr500. Bisoxatin consistently binds to the proteinthroughout the 100 ns simulation. Taken together, we propose that the discovered molecule, Bisoxatin may bea promising repurposable drug molecule to develop new chemical libraries for inhibiting SARS-CoV-2 entryinto the host.
ABSTRACT
The bromodomains and extra-terminal domain (BET) family proteins recognize acetylated chromatin through their bromodomains (BDs) and help in regulating gene expression. BDs are chromatin ‘readers’: by interacting with acetylated lysines on the histone tails, they recruit chromatin-regulating proteins on the promoter region to regulate gene expression and repression. Extensive efforts have been employed by scientific communities worldwide to identify and develop potential inhibitors of BET family BDs to regulate protein expression by inhibiting acetylated histone (H3/H4) interactions. Several small molecule inhibitors have been reported, which not only have high affinity but also have high specificity to BET BDs. These developments make BET family proteins an important therapeutic targets for major diseases such as cancer, neurological disorders, obesity and inflammation. Here, we review and discuss the structural biology of BET family BDs and their applications in major diseases.