Rational Discovery of Dengue Type 2 Non‐Competitive Inhibitors

Heh, Choon Han; Othman, Rozana; Buckle, Michael J. C.; Sharifuddin, Yusrizam; Yusof, Rohana; Rahman, Noorsaadah Abdul

doi:10.1111/cbdd.12122

Cited by 38 publications

(33 citation statements)

References 47 publications

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“…In silico molecular docking is a good tool to predict and match the desired binding site, understanding possible conformation of the compounds and further clarifies the binding interactions in the binding pocket (Grinter & Zou 2014). Structural homology model built by Heh et al (2013), namely DH-1, was utilized instead of its crystal structure, due to the missing loop between Ile76 and Ser85 of the NS2B region (Erbel et al 2006). DH-1 was previously modelled based on the crystal structure of dengue (PDBid: 2FOM) and West Nile (2FP7) viruses with 89% of its residues were located in the most favored region of the Ramachandran plot (Heh et al 2013).…”

Section: Resultsmentioning

confidence: 99%

“…Structural homology model built by Heh et al (2013), namely DH-1, was utilized instead of its crystal structure, due to the missing loop between Ile76 and Ser85 of the NS2B region (Erbel et al 2006). DH-1 was previously modelled based on the crystal structure of dengue (PDBid: 2FOM) and West Nile (2FP7) viruses with 89% of its residues were located in the most favored region of the Ramachandran plot (Heh et al 2013). By using 2FP7 as the template, Thr77, Ile78, Ser79, Glu80 Asp81, Gly82, Ser83 and Met84 were added to merge the existing gap.…”

Section: Resultsmentioning

confidence: 99%

“…Coordinate file for the 3D homology model of NS2B-NS3 protease of DENV-2, namely DH-1, was retrieved from Heh et al (2013). This model had been previously minimized, water molecules were removed, non-polar hydrogen atoms were merged, Kollman charges were assigned and the solvation parameters were added.…”

Section: Structurementioning

confidence: 99%

“…Keeping this in view, in silico molecular docking was performed using Autodock 4.2.6 software to study the interactions of these small molecule compounds (also termed as ligands) with NS2B-NS3 protease of DENV-2. The structural model of the protease, namely DH-1 (Heh et al 2013), was used as the target protein. Pinostrobin (1) and 4-hydroxypanduratin A (2) were utilized as standard ligands, each representing the non-competitive and competitive inhibitors of NS2B-NS3 protease of DENV-2, respectively (Frimayanti et al 2011;Heh et al 2013;Kiat et al 2006;Othman et al 2008).…”

Section: Introductionmentioning

confidence: 99%

“…The structural model of the protease, namely DH-1 (Heh et al 2013), was used as the target protein. Pinostrobin (1) and 4-hydroxypanduratin A (2) were utilized as standard ligands, each representing the non-competitive and competitive inhibitors of NS2B-NS3 protease of DENV-2, respectively (Frimayanti et al 2011;Heh et al 2013;Kiat et al 2006;Othman et al 2008). Therefore, this study aimed to investigate the binding interactions and search for the best orientation of ligandprotease complex with the lowest binding energy involving the selected antibiotics and NSAID.…”

Section: Introductionmentioning

confidence: 99%

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Molecular Docking Studies of Selected Medicinal Drugs as Dengue Virus-2 Protease Inhibitors

Othman¹,

Othman²,

Baharuddin³

et al. 2017

JSM

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Dengue is a potentially deadly disease with no effective drug. An in silico molecular docking was performed using Autodock 4.2.6 to investigate the molecular interactions between protease inhibitors, comprising antibiotic derivatives namely doxycycline (3), rolitetracycline (5) and a non-steroidal anti-inflammatory drug (NSAID), meclofenamic acid (4), against the NS2B-NS3 protease from dengue virus-2 (DENV-2). The non-competitive inhibitor (3) showed lower binding energy (-5.15 kcal/mol) than the predicted competitive inhibitors 4 and 5 (-3.64 and -3.21 kcal/mol, respectively (-5.15 kcal/mol) berbanding sebatian 4 dan 5 (masing-masing -3.64 dan -3.21 kcal/mol). Analisis struktur menunjukkan sebatian 3 yang terikat pada kawasan alosterik, berinteraksi dengan Lys74, iaitu residu asid amino yang terikat dengan salah satu daripada residu triad pemangkinan, Asp75. Sebatian 4 dan 5 pula menunjukkan ikatan langsung dengan dua triad pemangkinan iaitu His51 dan Ser135, justeru diramalkan sebagai perencat kompetitif. Kata kunci: Mengedok; perencat; Denggi adalah sejenis penyakit yang boleh membawa maut dan sehingga kini tiada sebarang ubat untuk merawat penyakit tersebut. Mengedok molekul secara in silico menggunakan Autodock 4.2.6 telah dijalankan untuk mengkaji interaksi molekul antara perencat protease yang terdiri daripada derivatif antibiotik iaitu doxycycline (3) dan rolitetracycline (5) dan dadah anti-radang bukan steroid (NSAID), asid meklofenamik (4), terhadap NS2B-NS3 daripada virus denggi-2 (DENV-2). Perencat tidak-kompetitif (3) menunjukkan tenaga ikatan yang lebih rendah

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Structurementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Molecular Docking Studies of Selected Medicinal Drugs as Dengue Virus-2 Protease Inhibitors

Othman¹,

Othman²,

Baharuddin³

et al. 2017

JSM

Self Cite

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Cytochrome P450 reaction phenotyping and inhibition and induction studies of pinostrobin in human liver microsomes and hepatocytes

Tan

Dong

Zhang

et al. 2017

Biomedical Chromatography

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Pinostrobin (PI, 5-hydroxy-7-methoxyflavanone) is a natural flavonoid known for its rich pharmacological activities. The objective of this study was to identify the human liver cytochrome P450 (CYP450) isoenzymes involved in the metabolism of PI. A single hydoxylated metabolite was obtained from PI after an incubation with pooled human liver microsomes (HLMs). The relative contributions of different CYP450s were evaluated using CYP450-selective inhibitors in HLMs and recombinant human CYP450 enzymes, and the results revealed the major involvement of CYP1A2, CYP2C9 and CYP2E1 in PI metabolism. We also evaluated the ability of PI to inhibit and induce human cytochrome P450 enzymes in vitro. High-performance liquid chromatography and liquid chromatography-tandem mass spectrometry analytical techniques were used to estimate the enzymatic activities of seven drug-metabolizing CYP450 isozymes in vitro. In HLMs, PI did not inhibit CYP 1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or CYP3A4 (IC > 100 μm). In the induction studies, PI had minimal effects on CYP1A2, CYP2B6and CYP3A4 activity. Based on these results, PI would not be expected to cause clinically significant CYP450 inhibition or induction.

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Flavonoids as efficient scaffolds: Recent trends for malaria, leishmaniasis, Chagas disease, and dengue

Boniface

Ferreira

2019

Phytotherapy Research

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Endemic in 149 tropical and subtropical countries, neglected tropical diseases (NTDs) affect more than 1 billion people annually with over 500,000 deaths. Among the NTDs, some of the most severe consist of leishmaniasis, Chagas disease, and dengue. The impact of the combined NTDs closely rivals that of malaria. According to the World Health Organization, 216 million cases of malaria were reported in 2016 with 445,000 deaths. Current treatment options are associated with various limitations including widespread drug resistance, severe adverse effects, lengthy treatment duration, unfavorable toxicity profiles, and complicated drug administration procedures. Flavonoids are a class of compounds that has been the subject of considerable scientific interest. New developments of flavonoids have made promising advances for the potential treatment of malaria, leishmaniasis, Chagas disease, and dengue, with less toxicity, high efficacy, and improved bioavailability. This review summarizes the current standings of the use of flavonoids to treat malaria and neglected diseases such as leishmaniasis, Chagas disease, and dengue. Natural and synthetic flavonoids are leading compounds that can be used for developing antiprotozoal and antiviral agents. However, detailed studies on toxicity, pharmacokinetics, and mechanisms of action of these compounds are required to confirm the in vitro pharmacological claims of flavonoids for pharmaceutical applications. Highlights In the current review, we have tried to compile recent discoveries on natural and synthetic flavonoids as well as their implication in the treatment of malaria, leishmaniasis, Chagas disease, and dengue. A total of 373 (220 natural and 153 synthetic) flavonoids have been evaluated for antimalarial, antileishmanial, antichagasic, and antidengue activities. Most of these flavonoids showed promising results against the above diseases. Reports on molecular modeling of flavonoid compounds to the disease target indicated encouraging results. Flavonoids can be prospected as potential leads for drug development; however, more rigorously designed studies on toxicity and pharmacokinetics, as well as the quantitative structure–activity relationship studies of these compounds, need to be addressed.

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Rational Discovery of Dengue Type 2 Non‐Competitive Inhibitors

Cited by 38 publications

References 47 publications

Molecular Docking Studies of Selected Medicinal Drugs as Dengue Virus-2 Protease Inhibitors

Molecular Docking Studies of Selected Medicinal Drugs as Dengue Virus-2 Protease Inhibitors

Cytochrome P450 reaction phenotyping and inhibition and induction studies of pinostrobin in human liver microsomes and hepatocytes

Flavonoids as efficient scaffolds: Recent trends for malaria, leishmaniasis, Chagas disease, and dengue

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