The emergence of 2019 novel Coronavirus (COVID-19 or 2019-nCoV) has caused significant global morbidity and mortality with no consensus specific treatment. We tested the hypothesis that FDA-approved antiretrovirals,
antibiotics, and
antimalarials will effectively inhibit
COVID-19 two major
drug targets,
coronavirus nucleocapsid protein (NP) and
hemagglutinin-esterase (HE). To test this hypothesis, we carried out a phylogenic analysis of coronavirus genome to understand the origins of NP and HE, and also modeled the
proteins before molecular docking, druglikeness, toxicity assessment, molecular dynamics simulation (MDS) and
ligand-based pharmacophore modeling of the selected FDA-approved drugs. Our models for NP and HE had over 95% identity with templates 5EPW and 3CL5 respectively in the PDB database, with majority of the
amino acids occupying acceptable regions. The active sites of the
proteins contained conserved residues that were involved in
ligand binding.
Lopinavir and ritonavir possessed greater binding affinities for NP and HE relative to
remdesivir, while
levofloxacin and
hydroxychloroquine were the most notable among the other classes of drugs. The Root Mean Square Deviation (RMSD), Root Mean Square Fluctuation (RMSF), Radius of gyration (Rg), and binding energy values obtained after 100 ns of MDS revealed good stability of these compounds in the binding sites of the
proteins while important pharmacophore features were also identified. The study showed that
COVID-19 likely originated from bat, owing to the over 90% genomic similarity observed, and that
lopinavir,
levofloxacin, and
hydroxychloroquine might serve as potential anti-COVID-19 lead molecules for additional optimization and
drug development for the treatment of COVID-19.Communicated by Ramaswamy H. Sarma.