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In silico structural elucidation of the rabies RNA-dependent RNA polymerase (RdRp) toward the identification of potential rabies virus inhibitors.

ABSTRACT: The rabies virus (RABV) is a non-segmented, negative single-stranded RNA virus which causes acute infection of the central nervous system in humans. Once symptoms appear, the result is nearly always death, and to date, post-exposure prophylaxis (PEP) is the only treatment applicable only immediately after an exposure. Previous studies have identified viral RNA-dependent RNA polymerase (RdRp) as a potential drug target due to its significant role in viral replication and transcription. Herein we generated an energy-minimized homology model of RABIES-RdRp and used it for virtual screening against 2045 NCI Diversity Set III library. The best five ligand-RdRp complexes were picked for further energy minimization via molecular dynamics (MDs) where the complex with ligand Z01690699 shows a minimum score characterized with stable hydrogen bonds and hydrophobic interactions with the catalytic site residues. Our study identified an important ligand for development of remedial approach for treatment of rabies infection.

SUBMITTER: Kiriwan D

PROVIDER: S-EPMC8143072 | biostudies-literature |

REPOSITORIES: biostudies-literature

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In silico structural elucidation of RNA-dependent RNA polymerase towards the identification of potential Crimean-Congo Hemorrhagic Fever Virus inhibitors.

Project description:The Crimean-Congo Hemorrhagic Fever virus (CCHFV) is a segmented negative single-stranded RNA virus (-ssRNA) which causes severe hemorrhagic fever in humans with a mortality rate of ~50%. To date, no vaccine has been approved. Treatment is limited to supportive care with few investigational drugs in practice. Previous studies have identified viral RNA dependent RNA Polymerase (RdRp) as a potential drug target due to its significant role in viral replication and transcription. Since no crystal structure is available yet, we report the structural elucidation of CCHFV-RdRp by in-depth homology modeling. Even with low sequence identity, the generated model suggests a similar overall structure as previously reported RdRps. More specifically, the model suggests the presence of structural/functional conserved RdRp motifs for polymerase function, the configuration of uniform spatial arrangement of core RdRp sub-domains, and predicted positively charged entry/exit tunnels, as seen in sNSV polymerases. Extensive pharmacophore modeling based on per-residue energy contribution with investigational drugs allowed the concise mapping of pharmacophoric features and identified potential hits. The combination of pharmacophoric features with interaction energy analysis revealed functionally important residues in the conserved motifs together with in silico predicted common inhibitory binding modes with highly potent reference compounds.

| S-EPMC6497722 | biostudies-literature

<i>In silico</i> investigation to identify potential small molecule inhibitors of the RNA-dependent RNA polymerase (RdRp) nidovirus RdRp-associated nucleotidyltransferase domain.

Project description:The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA-dependent RNA polymerase (RdRp) is a promising target for antiviral drugs. In this study, a chemical library (n = 300) was screened against the nidovirus RdRp-associated nucleotidyltransferase (NiRAN) domain. Blind docking was performed using a selection of 30 compounds and nine ligands were chosen based on their docking scores, safety profile, and availability. Using cluster analysis on a 10 microsecond molecular dynamics simulation trajectory (from D.E. Shaw Research), the compounds were docked to the different conformations. On the basis of our modelling studies, oleuropein was identified as a potential lead compound.

| S-EPMC8273049 | biostudies-literature

Polyphenols as Potential Inhibitors of SARS-CoV-2 RNA Dependent RNA Polymerase (RdRp).

Project description:An increasing number of studies have demonstrated the antiviral nature of polyphenols, and many polyphenols have been proposed to inhibit SARS-CoV or SARS-CoV-2. Our previous study revealed the inhibitory mechanisms of polyphenols against DNA polymerase α and HIV reverse transcriptase to show that polyphenols can block DNA elongation by competing with the incoming NTPs. Here we applied computational approaches to examine if some polyphenols can also inhibit RNA polymerase (RdRp) in SARS-CoV-2, and we identified some better candidates than remdesivir, the FDA-approved drug against RdRp, in terms of estimated binding affinities. The proposed compounds will be further examined to develop new treatments for COVID-19.

| S-EPMC8706955 | biostudies-literature

SARS-CoV-2 RNA dependent RNA polymerase (RdRp) targeting: an <i>in silico</i> perspective.

Project description:New treatment against SARS-CoV-2 now is a must. Nowadays, the world encounters a huge health crisis by the COVID-19 viral infection. Nucleotide inhibitors gave a lot of promising results in terms of its efficacy against different viral infections. In this work, molecular modeling, docking, and dynamics simulations are used to build a model for the viral protein RNA-dependent RNA polymerase (RdRp) and test its binding affinity to some clinically approved drugs and drug candidates. Molecular dynamics is used to equilibrate the system upon binding calculations to ensure the successful reproduction of previous results, to include the dynamics of the RdRp, and to understand how it affects the binding. The results show the effectiveness of Sofosbuvir, Ribavirin, Galidesivir, Remdesivir, Favipiravir, Cefuroxime, Tenofovir, and Hydroxychloroquine, in binding to SARS-CoV-2 RdRp. Additionally, Setrobuvir, YAK, and IDX-184, show better results, while four novel IDX-184 derivatives show promising results in attaching to the SARS-CoV-2 RdRp. There is an urgent need to specify drugs that can selectively bind and subsequently inhibit SARS-CoV-2 proteins. The availability of a punch of FDA-approved anti-viral drugs can help us in this mission, aiming to reduce the danger of COVID-19. The compounds 2 and 3 may tightly bind to the SARS-CoV-2 RdRp and so may be successful in the treatment of COVID-19.

| S-EPMC7222627 | biostudies-literature

SARS-CoV-2 RNA Dependent RNA polymerase (RdRp) - A drug repurposing study.

Project description:The outbreak of SARS-CoV-2 in December 2019 in China subsequently lead to a pandemic. Lack of vaccine and specific anti-viral drugs started a global health disaster. For a sustained control and protection, development of potential anti-viral drugs is one of the targeted approach. Although, designing and developing a panel of new drugs molecules are always encouraged. However, in the current emergency, drug repurposing study is one of the most effective and fast track option. The crystal structure of a SARS-CoV-2 (Severe acute respiratory syndrome coronavirus 2) RNA Dependent RNA Polymerase (RdRp) has recently been deciphered through X-ray crystallography. The single-chain of core RNA Dependent RNA Polymerase relies on virus-encoded cofactors nsp7 and two units of nsp8 for its optimum function. This study explored the FDA approved database of 7922 molecules and screened against the core polymerase along with cofactors. Here we report a panel of FDA approved drugs that show substantial interactions with key amino acid residues of the active site. Interestingly, some of the identified drugs (Ornipressin, Lypressin, Examorelin, Polymyxin B1) bind strongly within the binding pockets of both forms of RdRp. Besides, we found strong candidates for the complex form as well which include Nacortocin, Cistinexine, Cisatracurium (among others). These drugs have the potential to be considered while contriving therapeutic options.

| S-EPMC7377705 | biostudies-literature

RNA dependent RNA polymerase (RdRp) as a drug target for SARS-CoV2.

Project description:RNA-dependent RNA polymerase (RdRp), also called nsp12, is considered a promising but challenging drug target for inhibiting replication and hence, the growth of various RNA-viruses. In this report, a computational study is performed to offer insights on the binding of Remdesivir and Galidesivir with SARS-CoV2 RdRp with natural substrate, ATP, as the control. It was observed that Remdesivir and Galidesivir exhibited similar binding energies for their best docked poses, -6.6 kcal/mole and -6.2 kcal/mole, respectively. ATP also displayed comparative and strong binding free energy of -6.3 kcal/mole in the catalytic site of RdRp. However, their binding locations within the active site are distinct. Further, the interaction of catalytic site residues (Asp760, Asp761, and Asp618) with Remdesivir and Galidesivir is comprehensively examined. Conformational changes of RdRp and bound molecules are demonstrated using 100 ns explicit solvent simulation of the protein-ligand complex. Simulation suggests that Galidesivir binds at the non-catalytic location and its binding strength is relatively weaker than ATP and Remdesivir. Remdesivir also binds at the catalytic site and showed high potency to inhibit the function of RdRp. Binding of co-factor units nsp7 and nsp8 with RdRp (nsp12) complexed with Remdesivir and Galidesivir was also examined. MMPBSA binding energy for all three complexes has been computed across the 100 ns simulation trajectory. Overall, this study suggests, Remdesivir has anti-RdRp activity via binding at a catalytic site. In contrast, Galidesivir may not have direct anti-RdRp activity but it can induce a conformational change in the RNA polymerase.

| S-EPMC7852292 | biostudies-literature

Ratcheting of RNA polymerase toward structural principles of RNA polymerase operations.

Project description:RNA polymerase (RNAP) performs various tasks during transcription by changing its conformational states, which are gradually becoming clarified. A recent study focusing on the conformational transition of RNAP between the ratcheted and tight forms illuminated the structural principles underlying its functional operations.

| S-EPMC4581356 | biostudies-other

Comparative assessment of RNA-dependent RNA polymerase (RdRp) inhibitors under clinical trials to control SARS-CoV2 using rigorous computational workflow.

Project description:The devastating effect of SARS-CoV2 continues and the scientific community is pursuing to find the strategy to combat the spread of the virus. The approach is adapted to target this virus with medicine in combination with existing vaccines. For this, the medications that can specifically inhibit an enzyme essential for viral replication 'RNA-dependant-RNA polymerase (RdRp)' of SARS-CoV2 are being developed. RdRp is the enzyme commonly found in all RNA viruses but is absent in humans. There are in total 60 different RdRp inhibitors already under clinical trials for combating other RNA viruses, which are sought to even work for SARS-CoV2. These inhibitors are classified as nucleoside/nucleotide analogues and nonnucleoside/nonnucleotide analogues. In this study, all the known RdRp inhibitors were computationally targeted in the native form and their active form making the use of molecular docking, MM-GBSA and molecular dynamics (MD) simulations to find the top two of each nucleoside/nucleotide analogues and nonnucleoside/nonnucleotide analogues. The results showed ribavirin 5'-triphosphate and favipiravir ribonucleoside triphosphate (favipiravir-RTP) to be the top two nucleotide analogues while pimodivir and dihydropyrazolopyridinone analogue 8d were the top two nonnucleosides/non-nucleotide analogues.

| S-EPMC9038185 | biostudies-literature

Identification of a Conserved RNA-dependent RNA Polymerase (RdRp)-RNA Interface Required for Flaviviral Replication.

Project description:Dengue virus, an ?10.7-kb positive-sense RNA virus, is the most common arthropod-communicated pathogen in the world. Despite dengue's clear epidemiological importance, mechanisms for its replication remain elusive. Here, we probed the entire dengue genome for interactions with viral RNA-dependent RNA polymerase (RdRp), and we identified the dominant interaction as a loop-forming ACAG motif in the 3' positive-stranded terminus, complicating the prevailing model of replication. A subset of interactions coincides with known flaviviral recombination sites inside the viral protein-coding region. Specific recognition of the RNA element occurs via an arginine patch in the C-terminal thumb domain of RdRp. We also show that the highly conserved nature of the consensus RNA motif may relate to its tolerance to various mutations in the interacting region of RdRp. Disruption of the interaction resulted in loss of viral replication ability in cells. This unique RdRp-RNA interface is found throughout flaviviruses, implying possibilities for broad disease interventions.

| S-EPMC5016140 | biostudies-literature

Discovering new potential inhibitors to SARS-CoV-2 RNA dependent RNA polymerase (RdRp) using high throughput virtual screening and molecular dynamics simulations.

Project description:RNA dependent RNA polymerase (RdRp), is an essential in the RNA replication within the life cycle of the severely acute respiratory coronavirus-2 (SARS-CoV-2), causing the deadly respiratory induced sickness COVID-19. Remdesivir is a prodrug that has seen some success in inhibiting this enzyme, however there is still the pressing need for effective alternatives. In this study, we present the discovery of four non-nucleoside small molecules that bind favorably to SARS-CoV-2 RdRp over the active form of the popular drug remdesivir (RTP) and adenosine triphosphate (ATP) by utilizing high-throughput virtual screening (HTVS) against the vast ZINC compound database coupled with extensive molecular dynamics (MD) simulations. After post-trajectory analysis, we found that the simulations of complexes containing both ATP and RTP remained stable for the duration of their trajectories. Additionally, it was revealed that the phosphate tail of RTP was stabilized by both the positive amino acid pocket and magnesium ions near the entry channel of RdRp which includes residues K551, R553, R555 and K621. It was also found that residues D623, D760, and N691 further stabilized the ribose portion of RTP with U10 on the template RNA strand forming hydrogen pairs with the adenosine motif. Using these models of RdRp, we employed them to screen the ZINC database of ~ 17 million molecules. Using docking and drug properties scoring, we narrowed down our selection to fourteen candidates. These were subjected to 200 ns simulations each underwent free energy calculations. We identified four hit compounds from the ZINC database that have similar binding poses to RTP while possessing lower overall binding free energies, with ZINC097971592 having a binding free energy two times lower than RTP.

| S-EPMC9676757 | biostudies-literature

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