Carnosine to Combat Novel Coronavirus (nCoV): Molecular Docking and Modeling to Cocrystallized Host Angiotensin-Converting Enzyme 2 (ACE2) and Viral Spike Protein

Abstract

Aims: Angiotensin-converting enzyme 2 (ACE2) plays an important role in the entry of coronaviruses into host cells. The current paper described how carnosine, a naturally occurring supplement, can be an effective drug candidate for coronavirus disease (COVID-19) on the basis of molecular docking and modeling to host ACE2 cocrystallized with nCoV spike protein. Methods: First, the starting point was ACE2 inhibitors and their structure–activity relationship (SAR). Next, chemical similarity (or diversity) and PubMed searches made it possible to repurpose and assess approved or experimental drugs for COVID-19. Parallel, at all stages, the authors performed bioactivity scoring to assess potential repurposed inhibitors at ACE2. Finally, investigators performed molecular docking and modeling of the identified drug candidate to host ACE2 with nCoV spike protein. Results: Carnosine emerged as the best-known drug candidate to match ACE2 inhibitor structure. Preliminary docking was more optimal to ACE2 than the known typical angiotensin-converting enzyme 1 (ACE1) inhibitor (enalapril) and quite comparable to known or presumed ACE2 inhibitors. Viral spike protein elements binding to ACE2 were retained in the best carnosine pose in SwissDock at 1.75 Angstroms. Out of the three main areas of attachment expected to the protein–protein structure, carnosine bound with higher affinity to two compared to the known ACE2 active site. LibDock score was 92.40 for site 3, 90.88 for site 1, and inside the active site 85.49. Conclusion: Carnosine has promising inhibitory interactions with host ACE2 and nCoV spike protein and hence could offer a potential mitigating effect against the current COVID-19 pandemic.

Small-molecule metabolome identifies potential therapeutic targets against COVID-19

“…Our data show that even basal levels of the dipeptide are completely exhausted in COVID-19 patients. Saadah et al (15) predicted that COVID-19-induced oxidative stress would result in carnosine depletion. The protective effects of carnosine are widely attributed to its antioxidant, anti-glycation, and anti-inflammatory properties (10).…”

“…Intriguingly, recent papers suggest that carnosine may also protect against SARS-CoV-2 infection through more specific mechanisms. Molecular docking and modelling studies identified carnosine as the most promising drug candidate to prevent the binding of SARS-CoV-2 to the ACE2 receptor (15). Sustentacular cells of the olfactory system co-express the ACE2 receptor as well as TMPRSS2, a protease that facilitates viral entry, making these cells highly susceptible to SARS-CoV-2 (18).…”

Covid-19, Carnosine and Cognition

“…A recent study has produced evidence suggesting that carnosine may act as an inhibitor of angiotensin-converting enzyme 2 (ACE2) which could then inhibit viral cellular entry via this protein. 36 Thus carnosine could suppress not only viral infection but also Covid-19-induced metabolic changes.…”

Nutritional Interventions for COVID-19: A Role for Carnosine?

“…It has been proposed that the anti-oxidant and anti-glycating properties of carnosine may provide protection from this hypercoagulability, particularly in patients with altered glucose metabolism, who are known to have increased COVID-19 morbidity and mortality [ 16 , 17 ]. Others have suggested that carnosine may in fact prevent binding and internalization of SARS-CoV-2, potentially reducing both the incidence and severity of disease [ 20 ]. The SARS-CoV-2 spike protein has high binding affinity for angiotensin-converting enzyme 2 (ACE2), using this as a means of attachment and entry to the host cell [ 21 ].…”

“…The SARS-CoV-2 spike protein has high binding affinity for angiotensin-converting enzyme 2 (ACE2), using this as a means of attachment and entry to the host cell [ 21 ]. In silico modelling of known pharmaceutical and therapeutic compounds revealed that carnosine is also able to bind to ACE2 as an inhibitor, potentially competing with the SARS-CoV-2 spike protein and reducing effective entry to host cells [ 20 ].…”