In silico Identification of FDA Approved Drug Candidates Targeting the RNA-binding Region of Andes Hantavirus Nucleocapsid Protein

Abstract

The Andes virus is a rodent-born RNA microorganism that can cause a serious hantavirus pulmonary syndrome (HPS) with a mortality rate approaching 50%. The recent outbreaks of the Andes virus, specifically in south America, represent an emerging public health challenge due to the risk of human-to-human transmission and the lack of approved therapeutics or vaccines. Therefore, the objective of this in silico screening is to recognize FDA drugs candidates that can target the RNA binding site of the Andes virus nucleocapsid protein (NP). Such drug candidates may possess the potential to adversely interfere with the assembly and replication of the viral particles. For this purpose, molecular docking was first applied to screen 1,615 drug molecules against NP crystal. Then, the best five hits were identified and subjected to a molecular dynamics (MD) simulation for a duration of 50 nanoseconds (ns). These results of the MD simulation were analyzed by considering the ligand movement root mean square deviation (RMSD), the radius of gyration (Rg) for solute, the kind of per residue contact with the ligand, and the molecular mechanics Poisson Boltzmann Surface Area (MMPBSA) binding energy. As a result, the computational docking has initially identified five potential hit drugs and these are: Dihydroergotamine, Conivaptan, Dutasteride, Telmisartan, Lifitegrast. Then, the molecular dynamics simulation (MD) has excluded the drug Dutasteride as it seemed to have unfavorable binding energy. On the contrary, the other four drugs are anticipated to have a ligand proximity to NP binding site that didn’t exceed 4.0 Å during 50 ns duration. In fact, the best ligand proximity and binding energy was computed to the drug Lifitegrast during the simulation study. In fact, both Telmisartan and Lifitegrast are believed to be involved in a salt bridge interaction with the Arg 367 and Arg 146 residues respectively in the Andes virus NP binding region. In conclusion, both Lifitegrast and Telmisartan seem to be prioritized computational candidates against RNA binding area of the Andes virus NP target. But, these in silico findings are considered preliminary requiring further experimental validation.