Communication in Physical Sciences 2020, 5(3): 391-402 Available at https://journalcps.com/index.php/volumes Communication in Physical Sciences 2020, 5(3): 391-402 Virtual screening for potential inhibitors of Lassa fever nucleoprotein *Amaku James Friday, Kalu Kalu Igwe and Buhari Magaji Abstract The devastating impact of viral haemorrhagic fevers has deeply been felt in South America and Africa. This fever is caused by the arenaviruses Lassa and has posed a matchless fight. Meanwhile, no effective drug or vaccine has been reported. Here we used virtual screening and molecular docking approach to identify a series of novel inhibitors (ZINC64450313 (-10.7 kcal/mol), ZINC00658482 (-10.5 kcal/mol), ZINC40789449 (-10.5 kcal/mol), ZINC14551223 (10.0 kcal/mol) and ZINC73892903 (10.0 kcal/mol)) that can exhibit significant binding affinity to Lassa fever nucleoprotein (PDB ID: 3mx5) than ribavirin (-6.7 kcal/mol). Swiss ADME web tools were used to assess the pharmacokinetics and drug-likeness characteristics of the lead molecule (ZINC64450313). This assay showed that ZINC64450313 obeyed Lipinski, Egan, Verber and Muegge rules. However, pharmacokinetics predictions indicated that CYP1A2, CYP2C9, CYP2D6 and CYP2C19 isoenzyme were not inhibited by ZINC64450313. Toxicity assay of ZINC64450313 was acquired with an average similarity index of 33.25% and prediction accuracy of 23% on the ProTox-II webserver. The lead molecule has an LD50 value of 10 mg/kg and belongs to toxicity class 2. The frontier molecular orbital’s analysis revealed that ZINC64450313 is more reactive than ribavirin due to the possesion of better quantum chemical indices such as its the global hardness. Hence, an in vitro and in vivo assay of these molecules may proffer a pathway to finding effective inhibitors with the potential to truncate functional proteins responsible for the viral life cycle of arenaviruses Lassa. Key Words: Lassa virus, Virtual screening, Ribavirin, Molecular docking *Amaku James Friday Department of Chemistry, Michael Okpara University of Agriculture, Umudike, Abia State, Nigeria Email: amakufj2006@gmail.com Orcid id: 0000-0003-4894-0512 Kalu Kalu Igwe Departmemt of Veterinary Physiology, Pharmacology and Biochemistry Michael Okpara University of Agriculture, Umudike, Abia State, Nigeria Email: kkigwe191@gmail.com Orcid id: 0000-0002-8118-5689 Buhari Magaji Department of Chemistry, Faculty of Science, Gombe State University, Gombe State Email: magaji.buharii@gmail.com Orcid id: 0000-0002-2413-3890 1.0 Introduction Lassa virus (LASV) is the causative agent of Lassa hemorrhagic fever, a member of the Arenaviridae family of viruses (Houlihan and Behrens, 2017; Zhang et al., 2019). It is responsible for 200,000 human infections and around 5000 deaths in West Africa per annum. Available literature reveal that more than 20 cases of Lassa fever have been reported in Japan, Europe, and North America ( Shimojima et al., 2012). At present, there is no FDA-approved LASV-specific drugs or vaccines. However, ribavirin is the sole antiviral drug used for LASV management, it is commonly used for treatment at the early phase (McCormick et al., 1986). Also, the combined therapy of ribavirin with favipiravir demonstrated significant synergistic physiological implication in the in LASV-infected mice (Carrillo-Bustamante et al., 2017). The primary host for Lassa virus is Mastomys natalensis, a species of rodent that is commonly found in domestic residence (Monath et al., 1974). However, the transmission of this disease to human is via Virus-contaminated urine from Mastomys natalensis while human-to-human transmission is through contact with the body fluids of infected patients (Keenlyside et al., 1983). LASV is an enveloped RNA virus and is known to express four viral proteins namely, viral polymerase (L), matrix protein (Z), nucleoprotein (NP), and the glycoprotein complex (GPC) (Hastie et al., 2017). The viral binding to and entry into cells is a function of the glycoprotein