Abstract
Since the beginning of the COVID‐19 pandemic, scientists across the globe are racing to find a cure for the highly contagious infectious disease caused by the SARS‐CoV‐2 virus. Despite many promising ongoing progress, there are currently no FDA approved drug to treat infected patients. Recently, the crowdsourcing of drug discovery for inhibiting the main protease (Mpro) of SARS‐CoV‐2 have yielded a plenty of drug fragments resolved inside the active site of Mpro via the crystallography method. Following the principle of fragment‐based drug design (FBDD), we are motivated to design a potent drug candidate (named B19) by merging three fragments JFM, U0P, and HWH. Through extensive all‐atom molecular dynamics simulation and molecular docking, we found that B19 among all designed ones is most stable inside the Mpro's active site and the binding free energy of B19 is comparable to or even a little better than that of a native protein ligand processed by Mpro. Our promising results suggest that B19 and its derivatives can potentially be efficacious drug candidates for COVID‐19.
Highlights
The ongoing coronavirus 2019 (COVID-19) pandemic is caused by an enveloped, positivesense, single stranded RNA virus, that is known as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).[1]
We found that B19 by merging three fragments JFM, U0P and HWH is the most stable one, evidenced through extensive (∼ 10 μs totally) all-atom molecular dynamics simulation
We carried out molecular dynamics (MD) simulations to explore a total of 19 designed ligands based on the fragment-based drug design (FBDD) approach and compare them with a native ligand previously resolved in the crystal structure of main protease (Mpro) of SARS-CoV-1.18 Out of these 19 designed ligands, we found that the binding affinity of a designed drug molecule to Mpro is comparable or even slightly better than that of the native ligand, suggesting that B19 is highly promising for inhibiting Mpro of SARS-CoV-2
Summary
The ongoing coronavirus 2019 (COVID-19) pandemic is caused by an enveloped, positivesense, single stranded RNA virus, that is known as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).[1]. It took just a few months for COVID-19 to spread to almost every corner of the world, resulting in detrimental effect on global healthcare systems with a ripple effect on every aspect of human life To combat this disease, dozens of drugs have been tested in clinical as possible treatments for SARS-CoV-2 infections. Dozens of drugs have been tested in clinical as possible treatments for SARS-CoV-2 infections These drugs fall into two general groups: repurposed antiviral drugs (e.g. remdesivir4) to help stop the virus from reproducing, and immune-based therapies (e.g. dexamethasone5) to calm the “cytokine storm” from overreaction of the immune system which can lead to organ failure and death. At this time there are still no FDA-approved drugs to cure or prevent COVID-19 except treatments to ease the symptoms from a supportive care perspective
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