The rapid and global spread of a new human coronavirus, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has produced an immediate urgency to discover promising targets for the treatment of COVID-19. Here, we consider drug repurposing as an attractive approach that can facilitate the drug discovery process by repurposing existing pharmaceuticals to treat illnesses other than their primary indications. We review current information concerning the global health issue of COVID-19 including promising approved drugs, e.g., human angiotensin-converting enzyme inhibitors (hACEIs). Besides, we describe computational approaches to be used in drug repurposing and highlight examples of in-silico studies of drug development efforts against SARS-CoV-2. Alacepril and lisinopril were found to interact with human angiotensin-converting enzyme 2 (hACE2), the host entranceway for SARS-CoV-2 spike protein, through exhibiting the most acceptable rmsd_refine values and the best binding affinity through forming a strong hydrogen bond with Asn90, which is assumed to be essential for the activity, as well as significant extra interactions with other receptor-binding residues. Furthermore, molecular dynamics (MD) simulations followed by calculation of the binding free energy were also carried out for the most promising two ligand-pocket complexes from docking studies (alacepril and lisinopril) to clarify some information on their thermodynamic and dynamic properties and confirm the docking results as well. These results we obtained probably provided an excellent lead candidate for the development of therapeutic drugs against COVID-19. Eventually, animal experiments and accurate clinical trials are needed to confirm the potential preventive and treatment effect of these compounds.

Drug repurposing is the most rapid and economic way nowadays to rapidly provide effective drugs for our pandemic coronavirus disease 2019 . It was a great debate about ARBs whether to be stopped or continued for patients using them especially at the beginning of the COVID-19 pandemic. In this study, we carried out a virtual screening for almost all members of ARBs (nine) against COVID-19 main protease. Molecular docking as one of the important computational techniques was performed in this work. Interestingly, the tested compounds showed variable binding affinities in the order of N3 inhibitor (10, docked) > Fimasartan ( 8 6) > Telmisartan (4). Moreover, Fimasartan (8), Candesartan (2), and Olmesartan (7) were additionally estimated through molecular dynamic simulations monitored via computing the binding free energy using MM-GBSA. The results are promising for rapidly repurposing such drugs (especially, Fimasartan (8) and Candesartan (2)) after further preclinical and clinical studies either alone or in combination with others for the treatment of COVID-19 virus especially known to cause vasodilatation (to prevent blood coagulation) and to reduce inflammation and fibrosis (to prevent pulmonary fibrosis), with well-known safety profiles. In vitro, the virtual findings were consistent with the experimental testing of four representative ARBs. Out of the tested compounds, Olmesartan (7) showed the most promising anti-SARS-CoV-2 activity (IC 50 ¼ 1.808 μM, and CC 50 ¼ 557.6 μM) with high selectivity index (308.4) against SARS-CoV-2 in Vero E6 cells. This work may clarify and approve not only the safety of ARBs used by a large group of patients worldwide but also their possible effectiveness against the COVID-19 virus either as a prophylactic or treatment option. It intended also to give a clear spot on the structure-activity relationship (SAR) required for the future design of new drugs targeting the newly emerged SARS-CoV-2 protease by medicinal chemists.

Triple-negative breast cancers (TNBCs) comprise 10−15% of all breast cancers but with more resistance affinity against chemotherapeutics. Although doxorubicin (DOX) is the recommended first choice, it has observed cardiotoxicity together with apparent drug resistance. The anti-hyperglycemic drug, empagliflozin (EMP), was recently indicated to have in vitro anticancer potential together with its previously reported cardioprotective properties related to calmodulin inhibition. In this study, we carried out molecular docking studies which revealed the potential blocking of the calmodulin receptor by EMP through its binding with similar crucial amino acids compared to its cocrystallized inhibitor (AAA) as a proposed mechanism of action. Moreover, combination of DOX with EMP showed a slightly lower cytotoxic activity against the MDA-MB-231 cell line (IC 50 = 1.700 ± 0.121) compared to DOX alone (IC 50 = 1.230 ± 0.131), but it achieved a more characteristic arrest in the growth of cells by 4.67-fold more than DOX alone (with only 3.27-fold) in comparison to the control as determined by cell cycle analysis, and at the same time reached an increase in the total apoptosis percentage from 27.05-to 29.22-fold, compared to DOX alone as indicated by Annexin V-FITC apoptosis assay. Briefly, the aforementioned in vitro studies in addition to PCR of pro-and antiapoptotic genes (mTOR, p21, JNK, Bcl2, and MDR1) suggest the chemosensitization effect of EMP combination with DOX which can reduce the required therapeutic dose of DOX in TNBC and eventually will decrease its toxic side effects (especially cardiotoxicity), along with decreasing the chemoresistance of TNBC cells to DOX treatment.

Novel series of benzoxazoles 4a‐f‐16 were designed, synthesized, and evaluated for anticancer activity against HepG2, HCT‐116, and MCF‐7 cells. HCT‐116 was the most sensitive cell line to the influence of the new derivatives. In particular, compound 5e was found to be the most potent against HepG2, HCT‐116, and MCF‐7 with IC50 = 4.13 ± 0.2, 6.93 ± 0.3, and 8.67 ± 0.5 µM, respectively. Compounds 5c, 5f, 6b, 5d, and 6c showed the highest anticancer activities against HepG2 cells with IC50 of 5.93 ± 0.2, 6.58 ± 0.4, 8.10 ± 0.7, 8.75 ± 0.7, and 9.95 ± 0.9 µM, respectively; HCT‐116 cells with IC50 of 7.14 ± 0.4, 9.10 ± 0.8, 7.91 ± 0.6, 9.52 ± 0.5, and 12.48 ± 1.1 µM, respectively; and MCF‐7 cells with IC50 of 8.93 ± 0.6, 10.11 ± 0.9, 12.31 ± 1.0, 9.95 ± 0.8, and 15.70 ± 1.4 µM, respectively, compared with sorafenib as a reference drug with IC50 of 9.18 ± 0.6, 5.47 ± 0.3, and 7.26 ± 0.3 µM, respectively. The most active compounds 5c‐f and 6b,c were further evaluated for their vascular endothelial growth factor receptor‐2 (VEGFR‐2) inhibition. Compounds 5e and 5c potently inhibited VEGFR‐2 at lower IC50 values of 0.07 ± 0.01 and 0.08 ± 0.01 µM, respectively, compared with sorafenib (IC50 = 0.1 ± 0.02 µM). Compound 5f potently inhibited VEGFR‐2 at low IC50 value (0.10 ± 0.02 µM) equipotent to sorafenib. Our design was based on the essential pharmacophoric features of the VEGFR‐2 inhibitor sorafenib. Molecular docking was performed for all compounds to assess their binding pattern and affinity toward the VEGFR‐2 active site.

Tanshinone IIA shows the most promising anti-SARS-CoV-2 biological activity: molecular docking, molecular dynamics, in vitro, and SAR studies.