The incidence of 2019 novel corona virus (SARS-CoV-2) has created a medical emergency throughout the world. Various efforts have been made to develop the vaccine or effective treatments against the disease. The discovery of crystal structure of SARS-CoV-2 main protease has made the
in silico
identification of its inhibitors possible. Based on its critical role in viral replication, the viral protease can prove to be a promising “target” for antiviral drug therapy. We have systematically screened an
in-house
library of 15,754 natural and synthetic compounds, established at International Center for Chemical and Biological Sciences, University of Karachi. The
in silico
search for potential viral protease inhibitors resulted in nine top ranked ligands (compounds
1
–
9
) against SARS-CoV-2 main protease (PDB ID: 6LU7) based on docking scores, and predictive binding energies. The
in silico
studies were updated
via
carrying out the docking, and predictive binding energy estimation, with a recently reported crystal structure of main protease (PDB ID: 6Y2F) at a better resolution
i
.
e
., 1.95 Å. Compound
2
(molecular bank code AAA396) was found to have highest negative binding energy of −71.63 kcal/mol for 6LU7. While compound
3
(molecular bank code AAD146) exhibited highest negative binding energy of -81.92 kcal/mol for 6Y2F. The stability of the compounds-
in complex
with viral protease was analyzed by Molecular Dynamics simulation studies, and was found to be stable over the course of 20 ns simulation time. Compound
2,
and
3
were predicted to be the significant inhibitors of SARS-CoV-2 3CL hydrolase (Mpro) among the nine short listed compounds.
Breast cancer is the second leading cause of death among women globally. The existing treatment options for breast cancer are largely associated with severe toxicities, and lower efficacies. Therefore, there is an urgent need for the development of non-toxic effective drugs against breast cancer. For this purpose, drug repositioning strategy was used to evaluate the anti-cancer potential of a library of heterocyclic drugs. The major advantage of drug repurposing is that the pharmacokinetic, pharmacodynamic, and toxicity profiles of drugs are well documented. In the current study, we screened 97 drugs of different chemical classes, and among them aripiprazole, an antipsychotic drug, was found to be sufficiently active against breast cancer cell line MCF-7. Aripiprazole showed a cytotoxicity (IC 50 = 12.1 ± 0.40 μM) to MCF-7 cells, comparable to the standard anticancer drug doxorubicin (IC 50 = 1.25 ± 0.34 μM). Aripiprazole was also found to be active against other cancer cell lines, including MDA-MB-231 (IC 50 = 19.83 ± 0.27 μM), AU565 (IC 50 = 18.02 ± 0.44 μM), and BT-474 (IC 50 = 36.42 ± 0.12 μM). Aripiprazole significantly inhibited the cell cycle progression at subG 0 G 1 phase, and enhanced apoptosis in MCF-7 breast cancer cells. The drug was also able to significantly increase the nuclear condensation, and modulated the expression of certain genes involved in breast cancer, such as caspases 3, and 9, BAK-1, C-MYC, BCL2L1, BCL-10, and BCL-2. Further studies are needed to explore the effect of aripiprazole on intrinsic and extrinsic pathways of apoptosis in cancer cells.
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