Inhibitory effects of bioactive molecules against nonstructural protein (NSs) of Rift Valley Fever Virus (RVFv): A molecular modeling study

<h2>Abstract</h2> Rift Valley fever (RVF), a vector-borne zoonotic disease caused by the Rift Valley Fever Virus arbovirus (RVFv), has had a significant impact on livestock and poses a risk to human health. This RNA virus belongs to the <i>Bunyaviridae</i> family of the genus <i>Phlebovirus</i>. Limited treatment options are available for this mosquito-borne RVF disease. The non-structural protein (NSs) has emerged as one of the prominent drug targets due to its role in mediating the innate immune antagonism of RVFv. In the present study, we evaluated the inhibition potencies of phytochemicals derived from three species of holy basil (<i>Croton bonplandianus</i>, <i>Ocimum gratissimum,</i> and <i>Ocimum tenuiflorum</i>) as potential inhibitors against NSs of RVFv by employing integrated molecular modeling approaches. A total of 1269 natural compounds were manually curated based on an extensive literature survey. After the removal of duplicate entries, a total number of 339 non-redundant compounds were considered for the virtual screening. Out of 339, four molecules, ursolic acid (−7.9 kcal/mol), apigenin-7-o-glucuronide (−7.3 kcal/mol), cynaroside (−7.2 kcal/mol), and stenocereol (−6.7 kcal/mol), were shortlisted as the top-ranked molecules based on their binding affinity values, molecular interaction patterns, and molecular weight. These shortlisted molecules were found to have higher negative binding energies than the positive control, lactacystin (−5.7 kcal/mol). The dynamic behaviours of these top-ranked complexes were evaluated using state-of-the-art all-atoms molecular dynamics simulations over a time scale of 300 nanoseconds which affirms stable interaction patterns with NSs at the atomic level. Moreover, the principal component analysis (PCA) further supports strong interactions and positive correlations between these top-ranked molecules and NSs protein. Overall, these screened potent phytochemicals can be utilized as therapeutics against RVFv after <i>in</i><i>-</i><i>vitro</i> and <i>in</i><i>-</i><i>vivo</i> experimental validation, which may pave the way for the development of effective inhibitors targeting non-structural proteins of RVFv.