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.

The discovery of drugs capable of inhibiting SARS-CoV-2 is a priority for human beings due to the severity of the global health pandemic caused by COVID-19. To this end, natural products can provide therapeutic alternatives that could be employed as an effective safe treatment for COVID-19. Twelve compounds were isolated from the aerial parts of C. officinalis L. and investigated for their inhibitory activities against SARS-CoV-2 Mpro compared to its co-crystallized N3 inhibitor using molecular docking studies. Furthermore, a 100 ns MD simulation was performed for the most active two promising compounds, Calendulaglycoside A (SAP5) and Osteosaponin-I (SAP8). At first, molecular docking studies showed interesting binding scores as compared to the N3 inhibitor. Calendulaglycoside A (SAP5) achieved a superior binding than the co-crystallized inhibitor indicating promising affinity and intrinsic activity towards the Mpro of SARS-CoV-2 as well. Moreover, findings illustrated preferential stability for SAP5 within the Mpro pocket over that of N3 beyond the 40 ns MD simulation course. Structural preferentiality for triterpene-Mpro binding highlights the significant role of 17β-glucosyl and carboxylic 3α-galactosyl I moieties through high electrostatic interactions across the MD simulation trajectories. Furthermore, this study clarified a promising SAR responsible for the antiviral activity against the SARS-CoV-2 Mpro and the design of new drug candidates targeting it as well. The above findings could be promising for fast examining the previously isolated triterpenes both pre-clinically and clinically for the treatment of COVID-19.

Cancer is a leading cause of death worldwide and its incidence is unfortunately anticipated to rise in the next years. On the other hand, vascular endothelial growth factor receptor 2 (VEGFR-2) is highly expressed in tumor-associated endothelial cells, where it affects tumor-promoting angiogenesis. Therefore, VEGFR-2 is considered one of the most promising therapeutic targets for cancer treatment. Furthermore, some FDA-approved benzimidazole anthelmintics have already shown potential anticancer activities. Therefore, repurposing them against VEGFR-2 can provide a rapid and effective alternative that can be implicated safely for cancer treatment. Hence, 13 benzimidazole anthelmintic drugs were subjected to molecular docking against the VEGFR-2 receptor. Among the tested compounds, fenbendazole (FBZ, 1), mebendazole (MBZ, 2), and albendazole (ABZ, 3) were proposed as potential VEGFR-2 antagonists. Furthermore, molecular dynamics simulations were carried out at 200 ns, giving more information on their thermodynamic and dynamic properties. Besides, the anticancer activity of the aforementioned drugs was tested in vitro against three different cancer cell lines, including liver cancer (HUH7), lung cancer (A549), and breast cancer (MCF7) cell lines. The results depicted potential cytotoxic activity especially against both HUH7 and A549 cell lines. Furthermore, to improve the aqueous solubility of MBZ, it was formulated in the form of mixed micelles (MMs) which showed an enhanced drug release with better promising cytotoxicity results compared to the crude MBZ. Finally, an in vitro quantification for VEGFR-2 concentration in treated HUH7 cells has been conducted based on the enzyme-linked immunosorbent assay. The results disclosed that FBZ, MBZ, and ABZ significantly (p < 0.001) reduced the concentration of VEGFR-2, while the lowest inhibition was achieved in MBZ-loaded MMs, which was even much better than the reference drug sorafenib. Collectively, the investigated benzimidazole anthelmintics could be encountered as lead compounds for further structural modifications and thus better anticancer activity, and that was accomplished through studying their structure–activity relationships.

Since its first report in December 2019, the novel coronavirus virus, SARS-CoV-2, has caused an unprecedented global health crisis and economic loss imposing a tremendous burden on the worldwide finance, healthcare system, and even daily life. Even with the introduction of different preventive vaccines, there is still a dire need for effective antiviral therapeutics. Nature has been considered as the historical trove of drug discovery and development, particularly in cases of worldwide crises. Herein, a comprehensive in silico investigation of a highly focused chemical library of 34 pederin-structurally related marine compounds, belonging to four polyketides families, was initiated against the SARS-CoV-2 main protease, Mpro, being the key replicating element of the virus and main target in many drugs development programs. Two of the most potent SARS-CoV-2 Mpro co-crystallized inhibitors, O6K and N3, were added to the tested database as reference standards. Through molecular docking simulation, promising compounds including Pederin (1), Dihydro-onnamide A (11), Onnamide C (14), Pseudo-onnamide A (17), and Theopederin G (29) have been identified from different families based on their superior ligand–protein energies and relevant binding profiles with the key Mpro pocket residues. Thermodynamic behaviors of the identified compounds were investigated through 200 ns all-atom molecular dynamics simulation illustrating their significant stability and pocket accommodation. Furthermore, structural activity preferentiality was identified for the pederin-based marine compounds highlighting the importance of the terminal guanidine and cyclic hemiacetal linker, and the length of the sidechain. Our findings highlight the challenges of targeting SARS-CoV-2 Mpro as well as recommending further in vitro and in vivo studies regarding the examined marine products either alone or in combination paving the way for promising lead molecules.

The development of bacterial resistance to traditional antibiotics constitutes an emerging public health issue. Promising approaches have been innovated to conquer bacterial resistance, and targeting bacterial virulence is one of these approaches. Bacterial virulence mitigation offers several merits, as antivirulence agents do not affect the growth of bacteria and hence do not induce bacteria to develop resistance. In this direction, numerous drugs have been repurposed as antivirulence agents prior to their clinical use alone or in combination with traditional antibiotics. Quorum sensing (QS) plays a key role in controlling bacterial virulence. In the current study, dipeptidase inhibitor-4 (DPI-4) antidiabetic gliptins were screened for their antivirulence and anti-quorum sensing (anti-QS) activities against Gram-negative Pseudomonas aeruginosa and Gram-positive Staphylococcus aureus. Upon assessing their antibiofilm activities, the ten tested gliptins significantly diminished biofilm formation. In particular, sitagliptin exhibited the most efficient antibiofilm activity, so it was chosen as a representative of all gliptins to further investigate its antivirulence activity. Sitagliptin significantly protected mice from P. aeruginosa and S. aureus pathogenesis. Furthermore, sitagliptin downregulated QS-encoding genes in P. aeruginosa and S. aureus. To test the anti-QS activities of gliptins, a detailed molecular docking study was conducted to evaluate the gliptins’ binding affinities to P. aeruginosa and S. aureus QS receptors, which helped explain the anti-QS activities of gliptins, particularly sitagliptin and omarigliptin. In conclusion, this study evaluates the possible antivirulence and anti-QS activities of gliptins that could be promising novel candidates for the treatment of aggressive Gram-negative or -positive bacterial infections either alone or as adjuvants to other antibiotics.

Hydroxyethylamine and hydroxyethylene moieties of β-blockers exert potential SARS-CoV-2 inhibitory effects: rational-based design andin silico,in vitro, and SAR Studies.