galidesivir and Pneumonia--Viral

The pandemic outbreak of a new coronavirus (CoV), SARS-CoV-2, has captured the world's attention, demonstrating that CoVs represent a continuous global threat. As this is a highly contagious virus, it is imperative to understand RNA-dependent-RNA-polymerase (RdRp), the key component in virus replication. Although the SARS-CoV-2 genome shares 80% sequence identity with severe acute respiratory syndrome SARS-CoV, their RdRps and nucleotidyl-transferases (NiRAN) share 98.1% and 93.2% identity, respectively. Sequence alignment of six coronaviruses demonstrated higher identity among their RdRps (60.9%-98.1%) and lower identity among their Spike proteins (27%-77%). Thus, a 3D structural model of RdRp, NiRAN, non-structural protein 7 (nsp7), and nsp8 of SARS-CoV-2 was generated by modeling starting from the SARS counterpart structures. Furthermore, we demonstrate the binding poses of three viral RdRp inhibitors (Galidesivir, Favipiravir, and Penciclovir), which were recently reported to have clinical significance for SARS-CoV-2. The network of interactions established by these drug molecules affirms their efficacy to inhibit viral RNA replication and provides an insight into their structure-based rational optimization for SARS-CoV-2 inhibition.

Topics: Adenine; Adenosine; Amides; Antiviral Agents; Betacoronavirus; Binding Sites; Coronavirus Infections; COVID-19; Humans; Molecular Docking Simulation; Nucleotidyltransferases; Pandemics; Pneumonia, Viral; Protein Structure, Tertiary; Pyrazines; Pyrrolidines; RNA-Dependent RNA Polymerase; SARS-CoV-2

We started a study on the molecular docking of six potential pharmacologically active inhibitors compounds that can be used clinically against the COVID-19 virus, in this case, remdesivir, ribavirin, favipiravir, galidesivir, hydroxychloroquine and chloroquine interacting with the main COVID-19 protease in complex with a COVID-19 N3 protease inhibitor. The highest values of affinity energy found in order from highest to lowest were chloroquine (CHL), hydroxychloroquine (HYC), favipiravir (FAV), galidesivir (GAL), remdesivir (REM) and ribavirin (RIB). The possible formation of hydrogen bonds, associations through London forces and permanent electric dipole were analyzed. The values of affinity energy obtained for the hydroxychloroquine ligands was -9.9 kcal/mol and for the chloroquine of -10.8 kcal/mol which indicate that the coupling contributes to an effective improvement of the affinity energies with the protease. Indicating that, the position chosen to make the substitutions may be a pharmacophoric group, and cause changes in the protease.

Topics: Adenine; Adenosine; Adenosine Monophosphate; Alanine; Amides; Antiviral Agents; Betacoronavirus; Binding Sites; Chloroquine; Coronavirus 3C Proteases; Coronavirus Infections; COVID-19; COVID-19 Drug Treatment; Cysteine Endopeptidases; Drug Interactions; Humans; Hydrogen Bonding; Hydroxychloroquine; Ligands; Molecular Docking Simulation; Nanotechnology; Pandemics; Pneumonia, Viral; Protease Inhibitors; Pyrazines; Pyrrolidines; Ribavirin; SARS-CoV-2; Static Electricity; Viral Nonstructural Proteins