The neuraminidase (NA) of the influenza virus is the target of antiviral drug, oseltamivir. Recently, cases are reported that Influenza virus becoming resistant to oseltamivir, necessitating the development of new long-acting antiviral compounds. Most importantly, H274Y mutation in neuraminidase exhibits high levels of resistance to oseltamivir. In this report, a novel class of lead molecule with potential NA inhibitory activity was found from the traditional Chinese medicine database (TCMD) using virtual screening approach. Initially ADME properties of the lead compounds were analyzed with respect to the Lipinski rule of five. Subsequently, the data reduction was carried out by employing molecular docking study. Final validation was done by means of molecular dynamic simulations. The toxicity profiles for the screened compound were also analyzed. The result indicates that neoglucobrassicin (a compound derived from TCMD) become a promising lead compound and be effective in treating oseltamivir-resistant influenza virus strains. © 2013 Karthick and Ramanathan.

Ramanathan K

Department of Biotechnology

School of Bio Sciences and Technology

Vellore Campus

Karthick V

Fulltext

Vellore Institute of Technology (VIT) is a private university located in&nbsp;Tamil Nadu, India. Founded in 1984, as Vellore Engineering College, the institution offers 20 undergraduate, 34 postgraduate, four integrated and four research programs. It has campuses in Vellore, Amravati, Bhopal and Chennai.

VIT is one of the top ranked private universities in India according to NIRF, THE and QS Rankings.&nbsp;Govt. of India has recognized&nbsp;VIT, Vellore as an&nbsp;Institution of Eminence. This has allowed VIT to take independent quality initiatives and move up in world ranking.

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Virtual screening for oseltamivir-resistant a (H5N1) influenza neuraminidase from traditional Chinese medicine database: a combined molecular docking with molecular dynamics approach.

SpringerPlus

Introduction: β-Tubulin is an important target for the binding of anti-cancer drugs, in particular, paclitaxel (taxol), vinblastine and epothilone. However, mutations in β-tubulin structure give resistance to chemotherapeutic agents. Notably, mutations at R306C, F270 V, L217R, L228F, A185T and A248V positions in β-tubulin give high resistance for paclitaxel binding. Objective: To discover novel inhibitors of β-tubulin from natural sources, particularly alkaloids, using a virtual screening approach. Methodology: A virtual screening approach was employed to find potent lead molecules from the Naturally-occurring Plant-based Anti-cancer Compound-activity Target (NPACT) database. Alkaloids have great potential to be anti-cancer agents. Therefore, we have screened all alkaloids from a total of 1574 molecules from the NPACT database for our study. Initially, Molinspiration and DataWarrior programs were utilised to calculate pharmacokinetics and toxicity risks of the alkaloids, respectively. Subsequently, AutoDock algorithm was employed to understand the binding efficiency of alkaloids against β-tubulin. The binding affinity of the docked complex was confirmed by means of an intermolecular interaction study. Moreover, oral toxicity was predicted by using ProTox program. Further, metabolising capacity of drugs was studied by using SmartCYP software. Additionally, scaffold analysis was done with the help of scaffold trees and dendrograms, providing knowledge about the building blocks for parent-compound synthesis. Results: Overall, the results of our computational analysis indicate that isostrychnine, obtained from Strychnosnux-vomica, satisfies pharmacokinetic and bioavailability properties, binds efficiently with β-tubulin. Thus, it could be a promising lead for the treatment of paclitaxel resistant cancer types. Conclusion: This is the first observation of inhibitory activity of isostrychnine against β-tubulin and warrants further experimental investigation. Copyright © 2016 John Wiley &amp; Sons, Ltd. Copyright © 2016 John Wiley &amp; Sons, Ltd.

Phytochemical Analysis

Exploring β-Tubulin Inhibitors from Plant Origin using Computational Approach

Background: The Ebola virus is highly pathogenic and destructive to humans and other primates. The Ebola virus encodes viral protein 40 (VP40), which is highly expressed and regulates the assembly and release of viral particles in the host cell. Because VP40 plays a prominent role in the life cycle of the Ebola virus, it is considered as a key target for antiviral treatment. However, there is currently no FDA-approved drug for treating Ebola virus infection, resulting in an urgent need to develop effective antiviral inhibitors that display good safety profiles in a short duration. Methods: This study aimed to screen the effective lead candidate against Ebola infection. First, the lead molecules were filtered based on the docking score. Second, Lipinski rule of five and the other drug likeliness properties are predicted to assess the safety profile of the lead candidates. Finally, molecular dynamics simulations was performed to validate the lead compound. Results: Our results revealed that emodin-8-beta-D-glucoside from the Traditional Chinese Medicine Database (TCMD) represents an active lead candidate that targets the Ebola virus by inhibiting the activity of VP40, and displays good pharmacokinetic properties. Conclusion: This report will considerably assist in the development of the competitive and robust antiviral agents against Ebola infection. © 2016 Karthick et al.

Infectious Diseases of Poverty

Virtual screening of the inhibitors targeting at the viral protein 40 of Ebola virus

Virtual screening for oseltamivir-resistant a (H5N1) influenza neuraminidase from traditional Chinese medicine database: a combined molecular docking with molecular dynamics approach

Oseltamivir (Tamiflu) is the preferred anti-viral drug employed to fight the flu virus in infected individuals. The principal target for this drug is a virus surface glycoprotein, neuraminidase (NA), which facilitates the release of nascent virus and thus spreads infections. Until recently, only a low prevalence of neuraminidase inhibitors (NAIs) resistance (&lt;1 %) had been detected in circulating viruses. However, there have been reports of significant numbers of A (H1N1) influenza strains with a H274Y neuraminidase mutation that was highly resistant to the NAI, oseltamivir. In this study, we highlight the effect of point mutation-induced oseltamivir resistance in H1N1 subtype neuraminidases by molecular docking and molecular dynamics simulation approach. Our results suggested that wild-type NA could be more indispensable for the oseltamivir binding, as characterized by minimum number of H-bonds, high flexibility and largest binding affinity than mutant-type NA. This study throws light on the possible effects of drug-resistant mutations on the large functionally important collective motions in biological systems. © 2012 Springer Science+Business Media, LLC.

Applied Biochemistry and Biotechnology

Exploring the Cause of Oseltamivir Resistance Against Mutant H274Y Neuraminidase by Molecular Simulation Approach

PLoS Computational Biology

Two Birds with One Stone? Possible Dual-Targeting H1N1 Inhibitors from Traditional Chinese Medicine

PLoS ONE

Identifying HER2 Inhibitors from Natural Products Database

BMC Biology

Molecular dynamics simulations and drug discovery

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ISSN	21931801
Open Access	Yes