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.

Bacterial resistance to antibiotics is an increasing public health threat as it has the potential to affect people at any stage of life, as well as veterinary. Various approaches have been proposed to counteract the bacterial resistance development. Tackling bacterial virulence is one of the most promising approaches that confer several merits. The bacterial virulence is mainly regulated by a communication system known as quorum sensing (QS) system. Meanwhile, bacteria can sense the adrenergic hormones and eavesdrops on the host cells to establish their infection, adrenergic hormones were shown to enhance the bacterial virulence. In this study, β-adrenoreceptor blockers were proposed not only to stop bacterial espionage on our cells but also as inhibitors to the bacterial QS systems. In this context, a detailed in silico study has been conducted to evaluate the affinities of twenty-two β-blockers to compete on different structural QS receptors. Among the best docked and thermodynamically stable β-blockers; atenolol, esmolol, and metoprolol were subjected to further in vitro and in vivo investigation to evaluate their anti-QS activities against Chromobacterium violaceum, Pseudomonas aeruginosa and Salmonella typhimurium. The three tested β-blockers decreased the production of QS-controlled C. violaceum, and the formation of biofilm by P. aeruginosa and S. typhimurium. Additionally, the tested β-blockers down-regulated the P. aeruginosa QS-encoding genes and S. typhimurium sensor kinase encoding genes. Furthermore, metoprolol protected mice against P. aeruginosa and S. typhimurium. Conclusively, these investigated β-blockers are promising anti-virulence agents antagonizing adrenergic hormones induced virulence, preventing bacterial espionage, and blocking bacterial QS systems.

Background and Aim 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. Experimental procedure Twelve compounds were isolated from the aerial parts of C. officinalis L. and investigated for their inhibitory activities against SARS-CoV-2 M pro 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). Results and Conclusion 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 M pro of SARS-CoV-2 as well. Moreover, findings illustrated preferential stability for SAP5 within the M pro pocket over that of N3 beyond the 40 ns MD simulation course. Structural preferentiality for triterpene-M pro binding highlights the significant role of 17 β -glucosyl and carboxylic 3 α -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 M pro 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.

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.

S1: 2D and 3D interactions of the identified herbal drugs and docked N3 inhibitor into the N3 inhibitor binding site of Covid-19 main protease (3CLpro) (6LU7). No. Herbal drug 2D protein interactions 3D protein interactions 1 Glycyrrhizin S4: Receptor interactions and binding energies of the identified herbal drugs and Umifenovir into Umifenovir binding site of COVID-19 Spike protein (6ZCZ). No. Herbal drug S a Kcal/mol RMSD b Amino acid bond Distance A ֯ Glycyrrhizin -6.9575 2.4596 SER 373/H-donor TRP 436/H-pi 3.03 4.58 Lycorine -4.7293 1.4725 TRP 436/H-pi 4.51 Puerarin -5.5529 2.1709 TRP 436/H-acceptor ASN 343/H-acceptor ASN 437/pi-H 3.07 3.10 3.72 Daidzein -4.8154 1.1488 ASN 440/H-donor 2.92 Daidzin -6.4474 1.9450 SER 371/H-donor 3.06 Salvianolic acid B -7.4614