Repurposing 1,2,4-oxadiazoles as SARS-CoV-2 PLpro inhibitors and investigation of their possible viral entry blockade potential

Although vaccines are obviously mitigating the COVID-19 pandemic diffusion, efficient complementary antiviral agents are urgently needed to combat the SARS-CoV-2. The viral papain-like protease (PLpro) is a promising therapeutic target being one of only two essential proteases crucial for viral replication. Nevertheless, it dysregulates the host immune sensing response. Here we report repositioning of the privileged 1,2,4-oxadiazole scaffold as promising SARS-CoV-2 PLpro inhibitor with potential viral entry inhibition profile. The design strategy relied on mimicking the general structural features of the lead benzamide PLpro inhibitor GRL0617 with isosteric replacement of its pharmacophoric amide backbone1,2,4-oxadiazole core. Inspired by the multitarget antiviral agents, the substitution pattern was rationalized to tune the scaffold's potency against other additional viral targets, especially the spike receptor binding domain (RBD) that is responsible for the viral invasion. The Adopted facial synthetic protocol allowed easy access to various rationally substituted derivatives. Among evaluated series, the 2-[5-(pyridin-4-yl)-1,2,4-oxadiazol-3-yl]aniline (5) displayed the most balanced dual inhibitory potential against SARS-CoV-2 PLpro (IC50=7.197 μM) and spike protein RBD (IC50 = 8.673 μM), with acceptable ligand efficiency metrics, practical LogP (3.8) and safety profile on Wi-38 (CC50 = 51.78 μM) and LT-A549 (CC50 = 45.77 μM) lung cells. Docking simulations declared the possible structural determinants of activities and enriched the SAR data for further optimization studies. Graphical Image 1

Repurposing 1,2,4-oxadiazoles as SARS-CoV-2 PLpro inhibitors and investigation of their possible viral entry blockade potential.

Although vaccines are obviously mitigating the COVID-19 pandemic diffusion, efficient complementary antiviral agents are urgently needed to combat SARS-CoV-2. The viral papain-like protease (PLpro) is a promising therapeutic target being one of only two essential proteases crucial for viral replication. Nevertheless, it dysregulates the host immune sensing response. Here we report repositioning of the privileged 1,2,4-oxadiazole scaffold as promising SARS-CoV-2 PLpro inhibitor with potential viral entry inhibition profile. The design strategy relied on mimicking the general structural features of the lead benzamide PLpro inhibitor GRL0617 with isosteric replacement of its pharmacophoric amide backbone by 1,2,4-oxadiazole core. Inspired by the multitarget antiviral agents, the substitution pattern was rationalized to tune the scaffold's potency against other additional viral targets, especially the spike receptor binding domain (RBD) that is responsible for the viral invasion. The Adopted facial synthetic protocol allowed easy access to various rationally substituted derivatives. Among the evaluated series, the 2-[5-(pyridin-4-yl)-1,2,4-oxadiazol-3-yl]aniline (5) displayed the most balanced dual inhibitory potential against SARS-CoV-2 PLpro (IC50=7.197 µM) and spike protein RBD (IC50 = 8.673 µM), with acceptable ligand efficiency metrics, practical LogP (3.8) and safety profile on Wi-38 (CC50 = 51.78 µM) and LT-A549 (CC50 = 45.77 µM) lung cells. Docking simulations declared the possible structural determinants of activities and enriched the SAR data for further optimization studies.

In silico discovery of non-psychoactive scaffolds in Cannabis halting SARS-CoV-2 host entry and replication machinery.

Aim: Coronavirus disease still poses a global health threat which advocates continuous research efforts to develop effective therapeutics. Materials & methods: We screened out an array of 29 cannabis phytoligands for their viral spike-ACE2 complex and main protease (Mpro) inhibitory actions by in silico modeling to explore their possible dual viral entry and replication machinery inhibition. Physicochemical and pharmacokinetic parameters (ADMET) formulating drug-likeness were computed. Results: Among the studied phytoligands, cannabigerolic acid (2), cannabigerol (8), and its acid methyl ether (3) possessed the highest binding affinities to SARS-CoV-hACE2 complex essential for viral entry. Canniprene (24), cannabigerolic methyl ether (3) and cannabichromene (9) were the most promising Mpro inhibitors. Conclusion: These non-psychoactive cannabinoids could represent plausible therapeutics with added-prophylactic value as they halt both viral entry and replication machinery.

In silico study of potential anti-SARS cell entry phytoligands from Phlomis aurea: a promising avenue for prophylaxis.

Aim: The severity of COVID-19 has raised a great public health concern evoking an urgency for developing multitargeted therapeutics. Phlomis species was ethno-pharmacologically practiced for respiratory ailments. Materials & methods: An array of 15 phytoligands previously isolated from Phlomis aurea were subjected to molecular docking to explore their potential SARS-CoV-Spike-angiotensin-converting enzyme 2 complex inhibition, that is essential for virus entry to host cell. Results: Acteoside (11) showed the most potent in silico inhibition with an additional merit, over hesperidin (16), of not binding to angiotensin-converting enzyme 2 with well proven in vivo pulmonary protective role in acute lung injury, followed by chrysoeriol-7-O-ß-glucopyranoside (12) and luteolin-7-O-ß-glucopyranoside (14). Conclusion: Phytoligands (11, 12 and 14) were posed as promising candidates with potential prophylactic action against COVID-19. These phytoligands were prioritized for further biological experimentation because of their acceptable predicted ADME and drug-likeness parameters. Moreover, they could aid in developing multitargeted strategy for better management of COVID-19 using phytomedicines.

In silico identification of SARS-CoV-2 spike (S) protein-ACE2 complex inhibitors from eight Tecoma species and cultivars analyzed by LC-MS.

Coronavirus (CoV) is a positive RNA genome virus causing a global panic nowadays. Tecoma is a medicinally-valuable genus in the Bignoniaceae family, with some of its species exhibiting anti-HIV activity. This encouraged us to conduct an in silico exploration of some phytocompounds in Tecoma species cultivated in Egypt, namely Tecoma capensis and its four varieties i.e. yellow, harmony, pink and red, T. grandiflora Loisel., T. radicans L., and one hybrid i.e. Tecoma × smithii W. Watson. LC/MS-based metabolite profiling of the studied Tecoma plants resulted in the dereplication of 12 compounds (1-12) belonging to different phytochemical classes viz. alkaloids, iridoids, flavonoids and fatty acid esters. The in silico inhibitory action of these compounds against SARS-CoV-2 spike protein C-terminal domain in complex with human ACE2 was assessed via molecular docking. Succinic acid decyl-3-oxobut-2-yl ester (10), a fatty acid ester, possessed the best binding affinity (-6.77 kcal mol-1), as compared to hesperidin (13) (-7.10 kcal mol-1).