Novel Inhibitors of Dengue Virus Methyltransferase: Discovery by in Vitro-Driven Virtual Screening on a Desktop Computer Grid

Podvinec, Michael; Lim, Siew Pheng; Schmidt, Tobias; Scarsi, Marco; Wen, Daying; Sonntag, Louis‐Sebastian; Sanschagrin, Paul C.; Shenkin, Peter S.; Schwede, Torsten

doi:10.1021/jm900776m

Cited by 70 publications

(54 citation statements)

References 49 publications

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“…Nevertheless, Podvinec et al reported that two compounds with no guanosine moiety bound to the SAM binding site (IC 50 of 4.4 and 9.5 µM) [31]. Our results confirm the findings by Podvinec et al in that none of the compounds we discovered contain a guanosine moiety.…”

Section: Discussionsupporting

confidence: 90%

“…Research institutions in developed countries have launched a number of grid-based drug discovery efforts [29-31]; however, similar facilities often do not exist in developing countries. This fact motivated us to utilize two web-based drug-like compound databases (EDULISS and LIDAEUS) for the screening of commercially available chemical compounds as potential inhibitors of dengue NS5 MTase.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, this compound binds to the two binding sites on NS5 MTase (RNA cap site and SAM binding site) with different IC 50 values (2.3 and 127 µM, respectively) [37]. Podvinec et al also suggested two non-nucleoside analogues that act as potential inhibitors of NS5 MTase by binding to the RNA cap site with IC 50 values of 4.9 and 7.1 µM [31]. …”

Section: Discussionmentioning

confidence: 99%

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Structure-based and ligand-based virtual screening of novel methyltransferase inhibitors of the dengue virus

2011

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BackgroundThe dengue virus is the most significant arthropod-borne human pathogen, and an increasing number of cases have been reported over the last few decades. Currently neither vaccines nor drugs against the dengue virus are available. NS5 methyltransferase (MTase), which is located on the surface of the dengue virus and assists in viral attachment to the host cell, is a promising antiviral target. In order to search for novel inhibitors of NS5 MTase, we performed a computer-aided virtual screening of more than 5 million commercially available chemical compounds using two approaches: i) structure-based screening using the crystal structure of NS5 MTase and ii) ligand-based screening using active ligands of NS5 MTase. Structure-based screening was performed using the LIDAEUS (LIgand Discovery At Edinburgh UniverSity) program. The ligand-based screening was carried out using the EDULISS (EDinburgh University LIgand Selection System) program.ResultsThe selection of potential inhibitors of dengue NS5 MTase was based on two criteria: the compounds must bind to NS5 MTase with a higher affinity than that of active NS5 MTase ligands, such as ribavirin triphosphate (RTP) and S-adenosyl-L-homocysteine (SAH); and the compounds must interact with residues that are catalytically important for the function of NS5 MTase. We found several compounds that bind strongly to the RNA cap site and the S-adenosyl-L-methionine (SAM) binding site of NS5 MTase with better binding affinities than that of RTP and SAH. We analyzed the mode of binding for each compound to its binding site, and our results suggest that all compounds bind to their respective binding sites by interacting with, and thus blocking, residues that are vital for maintaining the catalytic activity of NS5 MTase.ConclusionsWe discovered several potential compounds that are active against dengue virus NS5 MTase through virtual screening using structure-based and ligand-based methods. These compounds were predicted to bind into the SAM binding site and the RNA cap site with higher affinities than SAH and RTP. These compounds are commercially available and can be purchased for further biological activity tests.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Structure-based and ligand-based virtual screening of novel methyltransferase inhibitors of the dengue virus

2011

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“…We used the metric of early performance to compare the Vina-, NNScore-, and HTVS-based protocols to a common multi-tiered Glide protocol (HTVS–SP–XP) 34 that has been used extensively in the literature (see, for example, refs (52), (55), (56), and (57)). The top 50% best ligands as judged by the HTVS–HTVS protocol were subsequently redocked with Glide SP.…”

Section: Resultsmentioning

confidence: 99%

Comparing Neural-Network Scoring Functions and the State of the Art: Applications to Common Library Screening

Durrant

Friedman

Rogers

et al. 2013

J. Chem. Inf. Model.

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We compare established docking programs, AutoDock Vina and Schrödinger’s Glide, to the recently published NNScore scoring functions. As expected, the best protocol to use in a virtual-screening project is highly dependent on the target receptor being studied. However, the mean screening performance obtained when candidate ligands are docked with Vina and rescored with NNScore 1.0 is not statistically different than the mean performance obtained when docking and scoring with Glide. We further demonstrate that the Vina and NNScore docking scores both correlate with chemical properties like small-molecule size and polarizability. Compensating for these potential biases leads to improvements in virtual screen performance. Composite NNScore-based scoring functions suited to a specific receptor further improve performance. We are hopeful that the current study will prove useful for those interested in computer-aided drug design.

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“…This group includes curcumin [31][32][33], parthenolide [34][35][36][37][38], and RG108-1 [39], a maleimide analogue of RG108 (vide infra); (3) non-nucleoside and non-covalent blockers such as hydralazine [40][41][42][43][44], procaine [45][46][47], procainamide [41,48], (-)-epigallocatechin-3-gallate (EGCG) [49][50][51][52][53], and mahanine [54,55]; and (4) non-covalent blockers identified from virtual screening such as RG108 [56][57][58] and NSC14778 [59,60]. Some of these compounds are drugs approved for other indications such as hydralazine, procaine, and procainamide (vide infra).…”

Section: Introductionmentioning

confidence: 99%

Homology modeling, docking and structure-based pharmacophore of inhibitors of DNA methyltransferase

Yoo

Medina‐Franco

2011

J Comput Aided Mol Des

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DNA methyltransferase 1 (DNMT1) is an emerging epigenetic target for the treatment of cancer and other diseases. To date, several inhibitors from different structural classes have been published. In this work, we report a comprehensive molecular modeling study of 14 established DNTM1 inhibitors with a herein developed homology model of the catalytic domain of human DNTM1. The geometry of the homology model was in agreement with the proposed mechanism of DNA methylation. Docking results revealed that all inhibitors studied in this work have hydrogen bond interactions with a glutamic acid and arginine residues that play a central role in the mechanism of cytosine DNA methylation. The binding models of compounds such as curcumin and parthenolide suggest that these natural products are covalent blockers of the catalytic site. A pharmacophore model was also developed for all DNMT1 inhibitors considered in this work using the most favorable binding conformations and energetic terms of the docked poses. To the best of our knowledge, this is the first pharmacophore model proposed for compounds with inhibitory activity of DNMT1. The results presented in this work represent a conceptual advance for understanding the protein-ligand interactions and mechanism of action of DNMT1 inhibitors. The insights obtained in this work can be used for the structure-based design and virtual screening for novel inhibitors targeting DNMT1.

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Novel Inhibitors of Dengue Virus Methyltransferase: Discovery by in Vitro-Driven Virtual Screening on a Desktop Computer Grid

Cited by 70 publications

References 49 publications

Structure-based and ligand-based virtual screening of novel methyltransferase inhibitors of the dengue virus

Structure-based and ligand-based virtual screening of novel methyltransferase inhibitors of the dengue virus

Comparing Neural-Network Scoring Functions and the State of the Art: Applications to Common Library Screening

Homology modeling, docking and structure-based pharmacophore of inhibitors of DNA methyltransferase

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