SARS-CoV-2 is causative agent of COVID-19, which is responsible for severe social and economic disruption globally. Lack of vaccine or antiviral drug with clinical efficacy suggested that drug repurposing approach may provide a quick therapeutic solution to COVID-19. Nonstructural protein-15 (NSP15) encodes for an uridylate-specific endoribonuclease (EndoU) enzyme, essential for virus life cycle and an attractive target for drug development. We have performed in silico based virtual screening of FDA approved compounds targeting EndoU in search of COVID-19 drugs from commercially available approved molecules. Two drugs Glisoxepide and Idarubicin used for treatment for diabetes and leukemia, respectively, were selected as stronger binder of EndoU. Both the drugs bound to the active site of the viral endonuclease by forming attractive intermolecular interactions with catalytically essential amino acid residues, His235, His250, and Lys290. Molecular dynamics simulation studies showed stable conformation dynamics upon drugs binding to endoU. The binding free energies for Glisoxepide and Idarubicin were calculated to be-141 ± 11 and-136 ± 16 kJ/mol, respectively. The IC 50 were predicted to be 9.2 mM and 30 mM for Glisoxepide and Idarubicin, respectively. Comparative structural analysis showed the stronger binding of EndoU to Glisoxepide and Idarubicin than to uridine monophosphate (UMP). Surface area calculations showed buried are of 361.8Å 2 by Glisoxepide which is almost double of the area occupied by UMP suggesting stronger binding of the drug than the ribonucleotide. However, further studies on these drugs for evaluation of their clinical efficacy and dose formulations may be required, which may provide a quick therapeutic option to treat COVID-19.

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Multiple-Drug Resistance (MDR) is a mechanism that renders the ineffectiveness of one or more than one antimicrobial agents shown by disease causing microorganisms. MDR has become one of the major public health challenges as initially, the MDR species were restricted only to hospitals, but now they are found everywhere. Due to the slow advancements in the discovery of new or different antibiotics against the MDR organisms, the medical society is facing great challenges in the treatment of infections caused by resistant microorganisms. This chapter outlines the challenges involved in drug discovery, and treatment to fight and prevent MDR infections.