Abstract
ObjectivesThe aim of this study was to use Ligand-based pharmacophore modelling approach for four established antiviral drugs, namely remdesivir, lopinavir, ritonavir and hydroxychloroquine for COVID-19 inhibitors as training sets. In this study Twenty vanillin derivatives together with monolaurin and tetrodotoxin were used as test sets to evaluate as potential SARS-CoV-2 inhibitors. The Structure-based pharmacophore modelling approach was also performed using 5RE6, 5REX and 5RFZ in order to analyse the binding site and ligand–protein complex interactions.ResultsThe pharmacophore modelling mode of 5RE6 displayed two Hydrogen Bond Acceptors (HBA) and one Hydrophobic (HY) interaction. Besides, the pharmacophore model of 5REX showed two HBA and two HY interactions. Finally, the pharmacophore model of 5RFZ showed three HBA and one HY interaction. Based on ligand-based approach, 20 Schiff-based vanillin derivatives, showed strong MPro inhibition activity. This was due to their good alignment and common features to PDB-5RE6. Similarly, monolaurin and tetrodotoxin displayed some significant activity against SARS-CoV-2. From structure-based approach, vanillin derivatives (1) to (12) displayed some potent MPro inhibition against SARS-CoV-2. Favipiravir, chloroquine and hydroxychloroquine also showed some significant MPro inhibition.
Highlights
In the early twenty-first century, an outbreak of coronaviruses has been causing a number of diseases
Ligand‐based pharmacophore modelling approach The pharmacophore model generated from the training sets are composed of four common features, which are two Hydrogen Bond Acceptors (HBA) and two HBD
In all the vanillin derivatives, the nitrogen in the C=N bond is responsible for one of the HBA feature, whereas the hydroxyl group is responsible for the HBA and HBD features aligned in the pharmacophore model generated
Summary
In the early twenty-first century, an outbreak of coronaviruses has been causing a number of diseases. Coronaviruses are enveloped, positive-sense, single stranded RNA viruses, Law et al BMC Res Notes (2020) 13:527 causal agents of the outbreak of severe acute respiratory syndrome (SARS) in 2002–2003 and Middle East respiratory syndrome in 2012, respectively [4]. Both coronaviruses had accumulated more than 10,000 cases in the past, with 10% death cases from SARS and 37% death cases from MERS [5, 6]. Named as 2019 novel coronavirus (2019-nCoV) by the World Health Organization (WHO), the coronavirus was later named as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) due to the genetic resemblance of about 80% with SARSCoV [7, 8]. The disease was named as coronavirus disease 2019 (COVID-19) by WHO [7]. The situation is further aggravated due to the absence of specific medicinal drugs or vaccines that are licensed or approved by the U.S Food and Drug Administration (FDA) for the treatment of COVID-19 [11]
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