scholarly journals Unveiling of Pyrimidindinones as Potential Anti-Norovirus Agents—A Pharmacoinformatic-Based Approach

Molecules ◽  
2022 ◽  
Vol 27 (2) ◽  
pp. 380
Author(s):  
Oluwakemi Ebenezer ◽  
Nkululeko Damoyi ◽  
Maryam A. Jordaan ◽  
Michael Shapi
Keyword(s):  
Electrostatic Interactions ◽  
Single Point ◽  
Antiviral Agents ◽  
Antiviral Agent ◽  
Salt Bridge ◽  
Induced Fit Docking ◽  
Rna Dependent Rna Polymerase ◽  
Dynamic Simulations ◽  
Point Energy ◽  
Backbone Conformation

The RNA-dependent RNA polymerase (RdRp) receptor is an attractive target for treating human norovirus (HNV). A computer-aided approach like e-pharmacophore, molecular docking, and single point energy calculations were performed on the compounds retrieved from the Development Therapeutics Program (DTP) AIDS Antiviral Screen Database to identify the antiviral agent that could target the HNV RdRp receptor. Induced-fit docking (IFD) results showed that compounds ZINC1617939, ZINC1642549, ZINC6425208, ZINC5887658 and ZINC32068149 bind with the residues in the active site-B of HNV RdRp receptor via hydrogen bonds, salt bridge, and electrostatic interactions. During the molecular dynamic simulations, compounds ZINC6425208, ZINC5887658 and ZINC32068149 displayed an unbalanced backbone conformation with HNV RdRp protein, while ZINC1617939 and ZINC1642549 maintained stability with the protein backbone when interacting with the residues. Hence, the two new concluding compounds discovered by the computational approach can be used as a chemotype to design promising antiviral agents aimed at HNV RdRp.

scholarly journals Novel Antiviral Agent DTriP-22 Targets RNA-Dependent RNA Polymerase of Enterovirus 71

2009 ◽  
Vol 53 (7) ◽  
pp. 2740-2747 ◽  
Author(s):  
Tzu-Chun Chen ◽  
Hwan-You Chang ◽  
Pei-Fen Lin ◽  
Jyh-Haur Chern ◽  
John Tsu-An Hsu ◽  
...  
Keyword(s):  
Potent Inhibitor ◽  
Antiviral Agents ◽  
Enterovirus 71 ◽  
Antiviral Agent ◽  
Viral Rna ◽  
Drug Resistant ◽  
Rna Dependent Rna Polymerase ◽  
Rna Accumulation ◽  
Elongation Activity

ABSTRACT Enterovirus 71 (EV71) has emerged as an important virulent neurotropic enterovirus in young children. DTriP-22 (4{4-[(2-bromo-phenyl)-(3-methyl-thiophen-2-yl)-methyl]-piperazin-1-yl}-1-pheny-1H-pyrazolo[3,4-d]pyrimidine) was found to be a novel and potent inhibitor of EV71. The molecular target of this compound was identified by analyzing DTriP-22-resistant viruses. A substitution of lysine for Arg163 in EV71 3D polymerase rendered the virus drug resistant. DTriP-22 exhibited the ability to inhibit viral replication by reducing viral RNA accumulation. The compound suppressed the accumulated levels of both positive- and negative-stranded viral RNA during virus infection. An in vitro polymerase assay indicated that DTriP-22 inhibited the poly(U) elongation activity, but not the VPg uridylylation activity, of EV71 polymerase. These findings demonstrate that the nonnucleoside analogue DTriP-22 acts as a novel inhibitor of EV71 polymerase. DTriP-22 also exhibited a broad spectrum of antiviral activity against other picornaviruses, which highlights its potential in the development of antiviral agents.

Recent Advances towards Drug Design Targeting the Protease of 2019 novel coronavirus (2019-nCoV)

2020 ◽  
Vol 27 ◽  
Author(s):  
Sehrish Bano ◽  
Abdul Hameed ◽  
Mariya Al-Rashida ◽  
Shafia Iftikhar ◽  
Jamshed Iqbal
Keyword(s):  
Drug Design ◽  
Rna Polymerase ◽  
Drug Targets ◽  
Antiviral Agents ◽  
Structural Features ◽  
Antiviral Drugs ◽  
Rna Dependent Rna Polymerase ◽  
Mortality And Morbidity ◽  
Functional Relationships ◽  
Novel Coronavirus

Background: The 2019 novel coronavirus (2019-nCoV), also known as coronavirus 2 (SARS-CoV-2) acute respiratory syndrome has recently emerged and continued to spread rapidly with high level of mortality and morbidity rates. Currently, no efficacious therapy is available to relieve coronavirus infections. As new drug design and development takes much time, there is a possibility to find an effective treatment from existing antiviral agents. Objective: In this case, there is a need to find out the relationship between possible drug targets and mechanism of action of antiviral drugs. This review discusses about the efforts to develop drug from known or new molecules. Methods: Viruses usually have two structural integrities, proteins and nucleic acids, both of which can be possible drug targets. Herein, we systemically discuss the structural-functional relationships of the spike, 3-chymotrypsin-like protease (3CLpro), papain like protease (PLpro) and RNA-dependent RNA polymerase (RdRp), as these are prominent structural features of corona virus. Certain antiviral drugs such as Remdesivir are RNA dependent RNA polymerase inhibitor. It has the ability to terminate RNA replication by inhibiting ATP. Results: It is reported that ATP is involved in synthesis of coronavirus non-structural proteins from 3CLpro and PLpro. Similarly, mechanisms of action of many other antiviral agents has been discussed in this review. It will provide new insights into the mechanism of inhibition, and let us develop new therapeutic antiviral approaches against novel SARS-CoV-2 coronavirus. Conclusion: In conclusion, this review summarizes recent progress in developing protease inhibitors for SARS-CoV-2.

scholarly journals Protease Inhibitors as Antiviral Agents

1998 ◽  
Vol 11 (4) ◽  
pp. 614-627 ◽  
Author(s):  
A. K. Patick ◽  
K. E. Potts
Keyword(s):  
Protease Inhibitors ◽  
Viral Infections ◽  
Critical Role ◽  
Antiviral Agents ◽  
Antiviral Agent ◽  
Structural Proteins ◽  
Viral Protease ◽  
Virus Particles ◽  
Viral Proteases ◽  
Viral Polyprotein

SUMMARY Currently, there are a number of approved antiviral agents for use in the treatment of viral infections. However, many instances exist in which the use of a second antiviral agent would be beneficial because it would allow the option of either an alternative or a combination therapeutic approach. Accordingly, virus-encoded proteases have emerged as new targets for antiviral intervention. Molecular studies have indicated that viral proteases play a critical role in the life cycle of many viruses by effecting the cleavage of high-molecular-weight viral polyprotein precursors to yield functional products or by catalyzing the processing of the structural proteins necessary for assembly and morphogenesis of virus particles. This review summarizes some of the important general features of virus-encoded proteases and highlights new advances and/or specific challenges that are associated with the research and development of viral protease inhibitors. Specifically, the viral proteases encoded by the herpesvirus, retrovirus, hepatitis C virus, and human rhinovirus families are discussed.

scholarly journals A possible interaction between favipiravir and methotrexate: Drug-induced hepatotoxicity in a patient with osteosarcoma

2021 ◽  
pp. 107815522110313
Author(s):  
Emre Demir ◽  
Osman Sütcüoğlu ◽  
Beril Demir ◽  
Oktay Ünsal ◽  
Ozan Yazıcı
Keyword(s):  
Drug Interactions ◽  
Toxic Hepatitis ◽  
Antiviral Agents ◽  
Antiviral Agent ◽  
Aldehyde Oxidase ◽  
Chemotherapeutic Agents ◽  
High Dose ◽  
Drug Induced ◽  
Metastatic Osteosarcoma ◽  
Grade 3

Introduction Favipiravir is an antiviral agent that is recently used for SARS-CoV2 infection. The drug-drug interactions of favipiravir especially with chemotherapeutic agents in a patient with malignancy are not well known. Case report The patient diagnosed with metastatic osteosarcoma was given high dose methotrexate treatment, and favipiravir was started on the third day of the treatment with suspicion of SARS-CoV2 infection. Grade 3 hepatotoxicity developed after favipiravir. Management & outcome: The acute viral hepatitis panel and autoimmune liver disease panel were negative. The ultrasound of the abdomen was unremarkable for any hepatobiliary pathology. The all viral and hepatobiliary possible etiological factors were ruled out. The patient’s liver enzymes increased just after (12 hours later) the initiation of favipiravir, and we diagnosed toxic hepatitis caused by favipiravir-methotrexate interaction. Therefore, methylprednisolone 1 mg/kg dose was started for a presumed diagnosis of toxic hepatitis. Hepatotoxicity completely regressed after favipiravir was discontinued. Discussion Favipiravir may inhibit methotrexate elimination by inhibiting aldehyde oxidase and its sequential use may cause hepatotoxicity in this case. The clinicians should keep in mind possible drug interactions while using new antiviral agents against SARS-CoV2 like favipiravir.

scholarly journals Dynamical strengthening of covalent and non-covalent molecular interactions by nuclear quantum effects at finite temperature

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Huziel E. Sauceda ◽  
Valentin Vassilev-Galindo ◽  
Stefan Chmiela ◽  
Klaus-Robert Müller ◽  
Alexandre Tkatchenko
Keyword(s):  
Finite Temperature ◽  
Electrostatic Interactions ◽  
Zero Point ◽  
Quantum Effects ◽  
Van Der Waals Interactions ◽  
Interatomic Distances ◽  
Point Energy ◽  
Molecular Bond ◽  
Energy Surfaces ◽  
Nuclear Quantum Effects

AbstractNuclear quantum effects (NQE) tend to generate delocalized molecular dynamics due to the inclusion of the zero point energy and its coupling with the anharmonicities in interatomic interactions. Here, we present evidence that NQE often enhance electronic interactions and, in turn, can result in dynamical molecular stabilization at finite temperature. The underlying physical mechanism promoted by NQE depends on the particular interaction under consideration. First, the effective reduction of interatomic distances between functional groups within a molecule can enhance the n → π* interaction by increasing the overlap between molecular orbitals or by strengthening electrostatic interactions between neighboring charge densities. Second, NQE can localize methyl rotors by temporarily changing molecular bond orders and leading to the emergence of localized transient rotor states. Third, for noncovalent van der Waals interactions the strengthening comes from the increase of the polarizability given the expanded average interatomic distances induced by NQE. The implications of these boosted interactions include counterintuitive hydroxyl–hydroxyl bonding, hindered methyl rotor dynamics, and molecular stiffening which generates smoother free-energy surfaces. Our findings yield new insights into the versatile role of nuclear quantum fluctuations in molecules and materials.

scholarly journals An Intramolecular Salt Bridge in Bacillus thuringiensis Cry4Ba Toxin Is Involved in the Stability of Helix α-3, Which Is Needed for Oligomerization and Insecticidal Activity

2017 ◽  
Vol 83 (20) ◽  
Author(s):  
Sabino Pacheco ◽  
Isabel Gómez ◽  
Jorge Sánchez ◽  
Blanca-Ines García-Gómez ◽  
Mario Soberón ◽  
...  
Keyword(s):  
Bacillus Thuringiensis ◽  
Double Point ◽  
Single Point ◽  
Three Dimensional ◽  
Point Mutations ◽  
Salt Bridge ◽  
Dimensional Structure ◽  
Cry Toxins ◽  
Content Type ◽  
Domain I

ABSTRACT Bacillus thuringiensis three-domain Cry toxins kill insects by forming pores in the apical membrane of larval midgut cells. Oligomerization of the toxin is an important step for pore formation. Domain I helix α-3 participates in toxin oligomerization. Here we identify an intramolecular salt bridge within helix α-3 of Cry4Ba (D111-K115) that is conserved in many members of the family of three-domain Cry toxins. Single point mutations such as D111K or K115D resulted in proteins severely affected in toxicity. These mutants were also altered in oligomerization, and the mutant K115D was more sensitive to protease digestion. The double point mutant with reversed charges, D111K-K115D, recovered both oligomerization and toxicity, suggesting that this salt bridge is highly important for conservation of the structure of helix α-3 and necessary to promote the correct oligomerization of the toxin. IMPORTANCE Domain I has been shown to be involved in oligomerization through helix α-3 in different Cry toxins, and mutations affecting oligomerization also elicit changes in toxicity. The three-dimensional structure of the Cry4Ba toxin reveals an intramolecular salt bridge in helix α-3 of domain I. Mutations that disrupt this salt bridge resulted in changes in Cry4Ba oligomerization and toxicity, while a double point reciprocal mutation that restored the salt bridge resulted in recovery of toxin oligomerization and toxicity. These data highlight the role of oligomer formation as a key step in Cry4Ba toxicity.

Theoretical study on NO3-initiated oxidation of acenaphthene in the atmosphere

2008 ◽  
Vol 86 (2) ◽  
pp. 129-137 ◽  
Author(s):  
Xiaohui Qu ◽  
Qingzhu Zhang ◽  
Wenxing Wang
Keyword(s):  
Product Information ◽  
Environmental Concern ◽  
Single Point ◽  
Basis Set ◽  
Orbital Theory ◽  
Night Time ◽  
Point Energy ◽  
Secondary Reactions ◽  
Favorable Reaction ◽  
High Level

Acenaphthene is widespread and toxic, and thus of substantial environmental concern. The reaction with NO3 radicals is an important atmospheric loss process of acenaphthene at night time. In this work, the mechanism for the NO3-initiated atmospheric oxidation reaction of acenaphthene has been studied using high level molecular orbital theory. Geometries of all the related species have been optimized at the MPWB1K level with the 6–31G(d,p) basis set. The single-point energy calculations have been carried out at the MPWB1K/6–311+G(3df,2p) level. The possible secondary reactions were also studied. Several energetically favorable reaction pathways were revealed for the first time.Key words: acenaphthene, NO3 radicals, reaction mechanism, product information, oxidation degradation.

scholarly journals Statin (3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor)-based therapy for hepatitis C virus (HCV) infection-related diseases in the era of direct-acting antiviral agents

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 223 ◽  
Author(s):  
Sara Sobhy Kishta ◽  
Reem El-Shenawy ◽  
Sobhy Ahmed Kishta
Keyword(s):  
Clinical Trials ◽  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Antiviral Agents ◽  
Antiviral Agent ◽  
Viral Clearance ◽  
Hcv Infection ◽  
Direct Acting Antiviral ◽  
Direct Acting ◽  
Direct Acting Antiviral Agents

Recent improvements have been made in the treatment of hepatitis C virus (HCV) infection with the introduction of direct-acting antiviral agents (DAAs). However, despite successful viral clearance, many patients continue to have HCV-related disease progression. Therefore, new treatments must be developed to achieve viral clearance and prevent the risk of HCV-related diseases. In particular, the use of pitavastatin together with DAAs may improve the antiviral efficacy as well as decrease the progression of liver fibrosis and the incidence of HCV-related hepatocellular carcinoma. To investigate the management methods for HCV-related diseases using pitavastatin and DAAs, clinical trials should be undertaken. However, concerns have been raised about potential drug interactions between statins and DAAs. Therefore, pre-clinical trials using a replicon system, human hepatocyte-like cells, human neurons and human cardiomyocytes from human-induced pluripotent stem cells should be conducted. Based on these pre-clinical trials, an optimal direct-acting antiviral agent could be selected for combination with pitavastatin and DAAs. Following the pre-clinical trial, the combination of pitavastatin and the optimal direct-acting antiviral agent should be compared to other combinations of DAAs (e.g., sofosbuvir and velpatasvir) according to the antiviral effect on HCV infection, HCV-related diseases and cost-effectiveness.

scholarly journals Essential Oils as Antiviral Agents, Potential of Essential Oils to Treat SARS-CoV-2 Infection: An In-Silico Investigation

2020 ◽  
Vol 21 (10) ◽  
pp. 3426 ◽  
Author(s):  
Joyce Kelly R. da Silva ◽  
Pablo Luis Baia Figueiredo ◽  
Kendall G. Byler ◽  
William N. Setzer
Keyword(s):  
Essential Oil ◽  
Essential Oils ◽  
Antiviral Agents ◽  
Rna Dependent Rna Polymerase ◽  
Protein Targets ◽  
Docking Analysis ◽  
Main Protease ◽  
Pathogenic Viruses ◽  
Oil Components ◽  
Molecular Docking Analysis

Essential oils have shown promise as antiviral agents against several pathogenic viruses. In this work we hypothesized that essential oil components may interact with key protein targets of the 2019 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A molecular docking analysis was carried out using 171 essential oil components with SARS-CoV-2 main protease (SARS-CoV-2 Mpro), SARS-CoV-2 endoribonucleoase (SARS-CoV-2 Nsp15/NendoU), SARS-CoV-2 ADP-ribose-1″-phosphatase (SARS-CoV-2 ADRP), SARS-CoV-2 RNA-dependent RNA polymerase (SARS-CoV-2 RdRp), the binding domain of the SARS-CoV-2 spike protein (SARS-CoV-2 rS), and human angiotensin−converting enzyme (hACE2). The compound with the best normalized docking score to SARS-CoV-2 Mpro was the sesquiterpene hydrocarbon (E)-β-farnesene. The best docking ligands for SARS−CoV Nsp15/NendoU were (E,E)-α-farnesene, (E)-β-farnesene, and (E,E)−farnesol. (E,E)−Farnesol showed the most exothermic docking to SARS-CoV-2 ADRP. Unfortunately, the docking energies of (E,E)−α-farnesene, (E)-β-farnesene, and (E,E)−farnesol with SARS-CoV-2 targets were relatively weak compared to docking energies with other proteins and are, therefore, unlikely to interact with the virus targets. However, essential oil components may act synergistically, essential oils may potentiate other antiviral agents, or they may provide some relief of COVID-19 symptoms.

scholarly journals Histidine, the less interactive cousin of arginine

2019 ◽  
Vol 25 (2) ◽  
pp. 212-218 ◽  
Author(s):  
Ludovic Muller ◽  
Shelley N Jackson ◽  
Amina S Woods
Keyword(s):  
Electrostatic Interactions ◽  
Noncovalent Complex ◽  
Salt Bridge ◽  
Amino Acid Residues ◽  
Noncovalent Complexes ◽  
Post Translational Modifications ◽  
Noncovalent Bonds ◽  
Esi Mass Spectrometry ◽  
Main Factors ◽  
Biomolecular Conformation

Electrostatic interactions are one of the main factors influencing biomolecular conformation. The formation of noncovalent complexes by electrostatic interactions is governed by certain amino acid residues and post-translational modifications. It has been demonstrated that adjacent arginine forms noncovalent complex with phosphate; however, histidine noncovalent complexes have rarely been investigated. In the present work, we compare the interaction between basic epitopes (NLRRITRVN, SHHGLHSTPD) and diverse acidic and aromatic-rich peptides using both MALDI and ESI Mass spectrometry. We show that adjacent histidines can also form stable noncovalent bonds and that those bonds are probably formed by a salt bridge between the phosphate or the acid residues and the histidines. However, noncovalent complexes with the arginine epitopes form more readily and are stronger than those with histidine-containing epitopes.

Sign in / Sign up

Export Citation Format

Share Document