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Journal ArticleDOI: 10.1080/07391102.2020.1731602

Discovery of small molecule inhibitors of chikungunya virus proteins (nsP2 and E1) using in silico approaches.

04 Mar 2021-Journal of Biomolecular Structure & Dynamics (Taylor & Francis)-Vol. 39, Iss: 4, pp 1373-1385
Abstract: Chikungunya virus (CHIKV) has emerged as a major viral threat, affecting over a million people worldwide per year. It is a vector borne disease transmitted to the human by Ades mosquitoes and prima...

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Topics: Chikungunya (56%)
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Journal ArticleDOI: 10.1080/13543776.2020.1751817
Ritu Ghildiyal1, Reema Gabrani1Institutions (1)
Abstract: Introduction: Chikungunya virus (CHIKV), a reemerging human arthropod borne virus, can causes global epidemic outbreaks and has become a serious health concern due to the unavailability of any antiviral therapy/vaccine. Extensive research has been conducted to target different proteins from CHIKV to curtail the spread of virus.Areas covered: This review provides an overview of the granted patents including the current status of antiviral strategies targeting CHIKV.Expert opinion: Under the current scenario, potential molecules and different approaches have been utilized to suppress CHIKV infection. MV-CHIKV and VRC-CHKVLP059-00-VP vaccine candidates have successfully completed phase I clinical trials and ribavirin (inhibitor) has shown significant inhibition of CHIKV replication and could be the most promising candidates. The drug resistance and toxicity can be modulated by using the inhibitors/drugs in combination. Moreover, nanoparticle formulations can improve the efficacy and bioavailability of drugs.

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Topics: Chikungunya (51%)

14 Citations


Journal ArticleDOI: 10.1016/J.SCITOTENV.2021.145168
Abstract: Microbes broadly constitute several organisms like viruses, protozoa, bacteria, and fungi present in our biosphere. Fast-paced environmental changes have influenced contact of human populations with newly identified microbes resulting in diseases that can spread quickly. These microbes can cause infections like HIV, SARS-CoV2, malaria, nosocomial Escherichia coli, methicillin-resistant Staphylococcus aureus (MRSA), or Candida infection for which there are no available vaccines/drugs or are less efficient to prevent or treat these infections. In the pursuit to find potential safe agents for therapy of microbial infections, natural biflavonoids like amentoflavone, tetrahydroamentoflavone, ginkgetin, bilobetin, morelloflavone, agathisflavone, hinokiflavone, Garcinia biflavones 1 (GB1), Garcinia biflavones 2 (GB2), robustaflavone, strychnobiflavone, ochnaflavone, dulcisbiflavonoid C, tetramethoxy-6,6″-bigenkwanin and other derivatives isolated from several species of plants can provide effective starting points and become a source of future drugs. These biflavonoids show activity against influenza, severe acute respiratory syndrome (SARS), dengue, HIV-AIDS, coxsackieviral, hepatitis, HSV, Epstein-Barr virus (EBV), protozoal (Leishmaniasis, Malaria) infections, bacterial and fungal infections. Some of the biflavonoids can provide antiviral and protozoal activity by inhibition of neuraminidase, chymotrypsin-like protease, DV-NS5 RNA dependant RNA polymerase, reverse transcriptase (RT), fatty acid synthase, DNA polymerase, UL54 gene expression, Epstein-Barr virus early antigen activation, recombinant cysteine protease type 2.8 (r-CPB2.8), Plasmodium falciparum enoyl-acyl carrier protein (ACP) reductase or cause depolarization of parasitic mitochondrial membranes. They may also provide anti-inflammatory therapeutic activity against the infection-induced cytokine storm. Considering the varied bioactivity of these biflavonoids against these organisms, their structure-activity relationships are derived and wherever possible compared with monoflavones. Overall, this review aims to highlight these natural biflavonoids and briefly discuss their sources, reported mechanism of action, pharmacological uses, and comment on resistance mechanism, flavopiridol repurposing and the bioavailability aspects to provide a starting point for anti-microbial research in this area.

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Topics: Biflavonoids (59%)

5 Citations


Open accessJournal ArticleDOI: 10.3390/V13071307
05 Jul 2021-Viruses
Abstract: Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that has re-emerged in recent decades, causing large-scale epidemics in many parts of the world. CHIKV infection leads to a febrile disease known as chikungunya fever (CHIKF), which is characterised by severe joint pain and myalgia. As many patients develop a painful chronic stage and neither antiviral drugs nor vaccines are available, the development of a potent CHIKV inhibiting drug is crucial for CHIKF treatment. A comprehensive summary of current antiviral research and development of small-molecule inhibitor against CHIKV is presented in this review. We highlight different approaches used for the identification of such compounds and further discuss the identification and application of promising viral and host targets.

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Topics: Chikungunya (55%)

Open accessJournal ArticleDOI: 10.1016/J.IMU.2021.100753
Abstract: The emerging mosquito-borne Chikungunya virus (CHIKV) infection is a massive threat in tropical areas and is rapidly expanding towards the temperate zones. This virus is causing recent epidemics worldwide, predominantly in Europe and North America. Moreover, CHIKV has a mounting impact on persons with possibly painful arthritis. Millions of positive cases have already been recorded in more than 100 countries worldwide. This virus is also capable of infecting new areas by travelers, which has made it more dreadful. However, for the dearth of approved therapeutics or vaccines to prevent or control the virus, it is essential to identify new and effective medicinal compounds to address this. Therefore, the non-structural protein nsP3 macro domain, nsP2 protease, and envelope proteins responsible for viral replication are the new target sites for therapeutic development. Mushrooms are abundant in bioactive compounds with antiviral properties. Thus, we performed molecular docking (MD) and dynamics simulation to identify the top candidates for nsP3 macro domains, nsP2 protease, and envelope glycoprotein complex inhibitors, as well as to predict possible therapeutic candidates. We then predicted the drug similarity for the best candidates based on higher binding affinity. Our findings suggest that mushroom-derived heliantriol F, semicochliodinol A, and semicochliodinol B are the best inhibitors. Based on the ligand, the predicted drugs allylestrenol (DB01431), calcitriol (DB00136), calcidiol (DB00146), benzonatate (DB02659), and gallamine triethiodide (DB00459) are recommended as alternative therapies for CHIKV.

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Topics: Glycoprotein complex (53%), Chikungunya (51%)

Journal ArticleDOI: 10.1080/07391102.2021.1960195
Meenakshi Chaudhary1, Deepak Sehgal1Institutions (1)
Abstract: Chikungunya Virus (CHIKV) is having a major impact on humans with potentially life-threatening and debilitating arthritis. The lack of a specific antiviral drug against the CHIKV disease has created an alarming situation to identify or develop potent chemical molecules for its remedial measures. Antiviral therapies for viral diseases are generally expensive and have adverse side effects. Plant-based antiviral natural compounds are the most suitable and best alternative of current antiviral drugs because of less toxicity. In the present study, non-structural protein 3 macrodomain (nsP3MD) of the CHIKV that is essential for virus replication has been selected for anti CHIKV drug target. The compounds were identified using molecular docking, virtual screening and further evaluated by molecular dynamics (MD) simulation studies. The binding mechanism of each compound was analyzed considering the stability and energetic parameter. We have found six plant-based natural antiviral compounds Baicalin, Rutaecarpine, Amentoflavone, Apigetrin, Luteoloside, and Baloxavir as strong inhibitors of nsP3MD of CHIKV. ADMET prediction and target analysis of the selected compounds showed drug likeliness of these compounds. MD simulation studies indicated energetically favorable complex formation between nsP3MD and the selected antiviral compounds. Furthermore, the structural effects on these substitutions were analyzed using the principles of each trajectory, which validated the interaction studies. Our analysis suggests a very high probability of these compounds to inhibit nsP3MD of CHIKV and could be evaluated for Chikungunya fever drug development. Communicated by Ramaswamy H. Sarma.

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Topics: Antiviral drug (55%), Rutaecarpine (53%)
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55 results found


Open accessJournal ArticleDOI: 10.1093/NAR/28.1.235
Abstract: The Protein Data Bank (PDB; http://www.rcsb.org/pdb/ ) is the single worldwide archive of structural data of biological macromolecules. This paper describes the goals of the PDB, the systems in place for data deposition and access, how to obtain further information, and near-term plans for the future development of the resource.

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30,190 Citations


Journal ArticleDOI: 10.1016/S0169-409X(00)00129-0
Abstract: Experimental and computational approaches to estimate solubility and permeability in discovery and development settings are described In the discovery setting 'the rule of 5' predicts that poor absorption or permeation is more likely when there are more than 5 H-bond donors, 10 H-bond acceptors, the molecular weight (MWT) is greater than 500 and the calculated Log P (CLogP) is greater than 5 (or MlogP > 415) Computational methodology for the rule-based Moriguchi Log P (MLogP) calculation is described Turbidimetric solubility measurement is described and applied to known drugs High throughput screening (HTS) leads tend to have higher MWT and Log P and lower turbidimetric solubility than leads in the pre-HTS era In the development setting, solubility calculations focus on exact value prediction and are difficult because of polymorphism Recent work on linear free energy relationships and Log P approaches are critically reviewed Useful predictions are possible in closely related analog series when coupled with experimental thermodynamic solubility measurements

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12,161 Citations


Open accessJournal ArticleDOI: 10.1002/JCC.21256
Abstract: We describe the testing and release of AutoDock4 and the accompanying graphical user interface AutoDockTools. AutoDock4 incorporates limited flexibility in the receptor. Several tests are reported here, including a redocking experiment with 188 diverse ligand-protein complexes and a cross-docking experiment using flexible sidechains in 87 HIV protease complexes. We also report its utility in analysis of covalently bound ligands, using both a grid-based docking method and a modification of the flexible sidechain technique.

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11,532 Citations


Journal ArticleDOI: 10.1038/NRD1549
Abstract: Computational approaches that 'dock' small molecules into the structures of macromolecular targets and 'score' their potential complementarity to binding sites are widely used in hit identification and lead optimization Indeed, there are now a number of drugs whose development was heavily influenced by or based on structure-based design and screening strategies, such as HIV protease inhibitors Nevertheless, there remain significant challenges in the application of these approaches, in particular in relation to current scoring schemes Here, we review key concepts and specific features of small-molecule-protein docking methods, highlight selected applications and discuss recent advances that aim to address the acknowledged limitations of established approaches

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Topics: Virtual screening (59%), Scoring functions for docking (54%), Lead Finder (53%) ... show more

2,455 Citations


Journal ArticleDOI: 10.1016/J.DDTEC.2004.11.007
Christopher A. Lipinski1Institutions (1)
Abstract: Citations in CAS SciFinder to the rule-of-five (RO5) publication will exceed 1000 by year-end 2004. Trends in the RO5 literature explosion that can be discerned are the further definitions of drug-like. This topic is explored in terms of drug-like physicochemical features, drug-like structural features, a comparison of drug-like and non-drug-like in drug discovery and a discussion of how drug-like features relate to clinical success. Physicochemical features of CNS drugs and features related to CNS blood-brain transporter affinity are briefly reviewed. Recent literature on features of non-oral drugs is reviewed and how features of lead-like compounds differ from those of drug-like compounds is discussed. Most recently, partly driven by NIH roadmap initiatives, considerations have arisen as to what tool-like means in the search for chemical tools to probe biology space. All these topics frame the scope of this short review/perspective.:

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2,384 Citations