Structural Elucidation of Rift Valley Fever Virus L Protein towards the Discovery of Its Potential Inhibitors (original) (raw)
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Scientific Reports
The Rift Valley fever virus (RVFV) is a zoonotic arbovirus and pathogenic to both humans and animals. Currently, no proven effective RVFV drugs or licensed vaccine are available for human or animal use. Hence, there is an urgent need to develop effective treatment options to control this viral infection. RVFV glycoprotein N (GN), glycoprotein C (GC), and nucleocapsid (N) proteins are attractive antiviral drug targets due to their critical roles in RVFV replication. In present study, an integrated docking-based virtual screening of more than 6000 phytochemicals with known antiviral activities against these conserved RVFV proteins was conducted. The top five hit compounds, calyxin C, calyxin D, calyxin J, gericudranins A, and blepharocalyxin C displayed optimal binding against all three target proteins. Moreover, multiple parameters from the molecular dynamics (MD) simulations and MM/GBSA analysis confirmed the stability of protein–ligand complexes and revealed that these compounds ma...
Journal of Pharmacy & Pharmacognosy Research, 2025
Context: Rift Valley fever (RVF) is a disease caused by the RVF virus (RVFV), concentrated mostly in Africa. The virus, usually found in animals, can infect humans through contact with infected animals or mosquito vectors. No established treatment exists, as infections are typically mild and self-resolving. However, in 1% of cases, the disease progresses to a more severe form, prompting further research on effective medication. Recently, favipiravir demonstrated the ability to alleviate RVFV symptoms by hindering replication by inhibiting the RdRp protein. This insight opens the door to drug repurposing efforts, focusing on RNA polymerase inhibitors as potential treatment options for RVF. Aims: To evaluate known RdRp inhibitors for the RVFV’s RdRp protein to halt viral replication. Methods: RNA polymerase inhibitors were selected from databases and reference papers using ADME values and toxicity levels followed by structural bioinformatics analysis of four best candidates and control. Results: Molecular docking showed the four candidates having equal or higher binding affinities than the control, favipiravir, across various binding pockets. Further molecular dynamics simulation shows a stable protein-ligand interaction based on the fluctuation plot. Hydrophobic interaction and hydrogen bonds from the 2D and 3D visualization indicate ribavirin has the strongest hydrogen bond, and molnupiravir has the most amino acids contributing to hydrophobic interactions. Conclusions: ADMETox, molecular docking, molecular dynamics simulations, and bond force analysis indicate the possibility of favipiravir, molnupiravir, galidesivir, ribavirin, and tenofovir as promising candidates as inhibitors for the RVFV’s RdRp protein to halt viral replication.
Biomirror
The Crimean-Congo hemorrhagic fever is a widespread tickborne viral disease, a zoonosis of domestic animals and wild animals, that may affect humans caused by Crimean-Congo hemorrhagic fever virus. The membranes of Bunyaviridae family contain viral RNAdependent RNA polymerase (RdRP) to catalyse the synthesis of the RNA strand in to target cells. By inhibiting protein, RdRP could prevent virus replication in to host cells. In order to inhibit RdRP proteins, the amino acid sequence of RdRP was retrieved from NCBI and their 3D model was built using comparative homology modeling program Modeller9v8. The templates of the query RdRP proteins was downloaded from protein databank. The computed models of RdRP was optimized by using molecular dynamics approach through same program Modeller and eventuall. Homology models of RdRP was further used for the prediction of ligand binding site for docking against antiviral drug Ribavirin, through molecular docking studies using AutoDock3.0.5. This study will be useful in broad screening of inhibitors of the protein and can be further implemented in future drug designing.
Research Square (Research Square), 2023
Rift Valley fever is a zoonotic disease that can spread through livestock and mosquitoes, and its symptoms include retinitis, photophobia, hemorrhagic fever and neurological effects. The World Health Organization has identi ed Rift Valley fever as one of the viral infections that has potential to cause a future epidemic. Hence, efforts are urgently needed toward development of therapeutics and vaccine against this infectious disease. Notably, the causative virus namely, the Rift Valley fever virus (RVFV), utilizes the cap-snatching mechanism for viral transcription, rendering its cap-binding domain (CBD) as an effective antiviral target. To date, there are no published studies towards identi cation of potential small molecule inhibitors for the CBD of RVFV. Here, we employ a virtual screening work ow comprising of molecular docking and molecular dynamics (MD) simulation, to identify 5 potential phytochemical inhibitors of the CBD of RVFV. These 5 phytochemical inhibitors can be sourced from Indian medicinal plants, Ferula assa-foetida, Glycyrrhiza glabra and Leucas cephalotes, used in traditional medicine. In sum, the 5 phytochemical inhibitors of the CBD of RVFV identi ed by this purely computational study are promising drug lead molecules which can be considered for detailed experimental validation against RVFV infection.
A novel system for identification of inhibitors of rift valley Fever virus replication
Viruses, 2010
Rift Valley fever virus (RVFV) is a human and livestock pathogen endemic to sub-Saharan Africa. We have developed a T7-dependent system for the efficient production of RVFV-like particles (RVF-VLPs) based on the virulent ZH-501 strain of RVFV. The RVF-VLPs are capable of performing a single round of infection, allowing for the study of viral replication, assembly, and infectivity. We demonstrate that these RVF-VLPs are antigenically indistinguishable from authentic RVFV and respond similarly to a wide array of known and previously unknown chemical inhibitors. This system should be useful for screening for small molecule inhibitors of RVFV replication.
Modeling the Tertiary Structure of the Rift Valley Fever Virus L Protein
Molecules
A tertiary structure governs, to a great extent, the biological activity of a protein in the living cell and is consequently a central focus of numerous studies aiming to shed light on cellular processes central to human health. Here, we aim to elucidate the structure of the Rift Valley fever virus (RVFV) L protein using a combination of in silico techniques. Due to its large size and multiple domains, elucidation of the tertiary structure of the L protein has so far challenged both dry and wet laboratories. In this work, we leverage complementary perspectives and tools from the computational-molecular-biology and bioinformatics domains for constructing, refining, and evaluating several atomistic structural models of the L protein that are physically realistic. All computed models have very flexible termini of about 200 amino acids each, and a high proportion of helical regions. Properties such as potential energy, radius of gyration, hydrodynamics radius, flexibility coefficient, a...
Medicinal Chemistry, 2007
West Nile virus (WNV) is a mosquito-borne disease that emerged in North America. In 2002 it caused the largest arboviral meningoencephalitis outbreak ever recorded in the US and Canada. The key enzyme responsible for the replication of the virus is the RNA-dependent RNA polymerase (RdRp) enzyme represented by nonstructural protein NS5 in WNV. To understand the structural basis and enzymatic activity of WNV RdRp as well as potential drug susceptibility, we have built a homology model of WNV NS5 RdRp based on a combination of motif search, fold recognition and sequence alignments orchestrated by 3D-jury system. We have located conserved sequence motifs shared by all RdRps and described the potential functional role of these motifs and specific residues in the polymerization and in the recognition of potential inhibitors. Virtual docking of several substrates and inhibitors in our WNV RdRp model shows that a non-nucleoside inhibitor such as 2'-methyl-ribofuranosyl-guanosine triphosphate has a higher binding energy indicated by a low free energy obtained upon binding. These results provide a preliminary basis for the development of anti-WNV agents based on RNA dependant RNA polymerase inhibition.
Rift Valley fever virus (RVFV) is an emerging virus that causes serious illness in humans and livestock. There are no approved vaccines or treatments for humans. The purpose of the study was to identify inhibitory compounds of RVFV infection without any preconceived idea of the mechanism of action. A whole-cell-based high-throughput drug screening assay was developed to screen 28,437 small chemical compounds targeting RVFV infection. To accomplish both speed and robustness, a replication-competent NSs-deleted RVFV expressing a fluorescent reporter gene was developed. Inhibition of fluorescence intensity was quantified by spectrophotometry and related to virus infection in human lung epithelial cells (A549). Cell toxicity was assessed by the Resazurin cell viability assay. After primary screening, 641 compounds were identified that inhibited RVFV infection by ≥80%, with ≥50% cell viability at 50 µM concentration. These compounds were subjected to a second screening regarding dose-response profiles, and 63 compounds with ≥60% inhibition of RVFV infection at 3.12 µM compound concentration and ≥50% cell viability at 25 µM were considered hits. Of these, six compounds with high inhibitory activity were identified. In conclusion, the high-throughput assay could efficiently and safely identify several promising compounds that inhibited RVFV infection.
Discovery of novel dengue virus entry inhibitors via a structure-based approach
Bioorganic & medicinal chemistry letters, 2017
Dengue is a mosquito-borne virus that has become a major public health concern worldwide in recent years. However, the current treatment for dengue disease is only supportive therapy, and no specific antivirals are available to control the infections. Therefore, the need for safe and effective antiviral drugs against this virus is of utmost importance. Entry of the dengue virus (DENV) into a host cell is mediated by its major envelope protein, E. The crystal structure of the E protein reveals a hydrophobic pocket occupied by the detergent n-octyl-β-d-glucoside (β-OG) lying at a hinge region between domains I and II, which is important for the low-pH-triggered conformational rearrangement required for fusion. Thus, the E protein is an attractive target for the development of antiviral agents. In this work, we performed prospective docking-based virtual screening to identify small molecules that likely bind to the β-OG binding site. Twenty-three structurally different compounds were i...