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

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Swiss Institute of Bioinformatics and Biozentrum, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland
Novartis Institute for Tropical Diseases, 10 Biopolis Road, Chromos #05-01, 138670 Singapore
§ Schrödinger LLC, 120 West 45th Street, 29th Floor, New York, New York 10036-4041
*To whom correspondence should be addressed: Swiss Institute of Bioinformatics and Biozentrum, University of Basel, Klingelbergstrasse 50, CH-4056 Basel, Switzerland. Telephone: +41 61 267 15 81. Fax: +41 61 267 15 84. E-mail: [email protected]
Cite this: J. Med. Chem. 2010, 53, 4, 1483–1495
Publication Date (Web):January 28, 2010
Copyright © 2010 American Chemical Society

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    Dengue fever is a viral disease that affects 50−100 million people annually and is one of the most important emerging infectious diseases in many areas of the world. Currently, neither specific drugs nor vaccines are available. Here, we report on the discovery of new inhibitors of the viral NS5 RNA methyltransferase, a promising flavivirus drug target. We have used a multistage molecular docking approach to screen a library of more than 5 million commercially available compounds against the two binding sites of this enzyme. In 263 compounds chosen for experimental verification, we found 10 inhibitors with IC50 values of <100 μM, of which four exhibited IC50 values of <10 μM in in vitro assays. The initial hit list also contained 25 nonspecific aggregators. We discuss why this likely occurred for this particular target. We also describe our attempts to use aggregation prediction to further guide the study, following this finding.

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    Implementation of decision tree and random forest aggregation predictors, and structures of tested compounds (Tables S1−S4). This material is available free of charge via the Internet at

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    2. Matthew Brecher, Hui Chen, Zhong Li, Nilesh K. Banavali, Susan A. Jones, Jing Zhang, Laura D. Kramer, and Hongmin Li . Identification and Characterization of Novel Broad-Spectrum Inhibitors of the Flavivirus Methyltransferase. ACS Infectious Diseases 2015, 1 (8) , 340-349.
    3. Xuben Hou, Rong Li, Kangshuai Li, Xiao Yu, Jin-Peng Sun, and Hao Fang . Fast Identification of Novel Lymphoid Tyrosine Phosphatase Inhibitors Using Target–Ligand Interaction-Based Virtual Screening. Journal of Medicinal Chemistry 2014, 57 (22) , 9309-9322.
    4. Jacob D. Durrant, Aaron J. Friedman, Kathleen E. Rogers, and J. Andrew McCammon . Comparing Neural-Network Scoring Functions and the State of the Art: Applications to Common Library Screening. Journal of Chemical Information and Modeling 2013, 53 (7) , 1726-1735.
    5. Francesca Curreli, Spreeha Choudhury, Ilya Pyatkin, Victor P. Zagorodnikov, Anna Khulianova Bulay, Andrea Altieri, Young Do Kwon, Peter D. Kwong, and Asim K. Debnath . Design, Synthesis, and Antiviral Activity of Entry Inhibitors That Target the CD4-Binding Site of HIV-1. Journal of Medicinal Chemistry 2012, 55 (10) , 4764-4775.
    6. Bo Chao, Xian-Kun Tong, Wei Tang, De-Wen Li, Pei-Lan He, Jean-Michel Garcia, Li-Min Zeng, An-Hui Gao, Li Yang, Jia Li, Fa-Jun Nan, Michael Jacobs, Ralf Altmeyer, Jian-Ping Zuo, and You-Hong Hu . Discovery and Optimization of 2,4-Diaminoquinazoline Derivatives as a New Class of Potent Dengue Virus Inhibitors. Journal of Medicinal Chemistry 2012, 55 (7) , 3135-3143.
    7. Luke R. Odell, Dian Howan, Christopher P. Gordon, Mark J. Robertson, Ngoc Chau, Anna Mariana, Ainslie E. Whiting, Ruben Abagyan, James A. Daniel, Nick N. Gorgani, Phillip J. Robinson and Adam McCluskey . The Pthaladyns: GTP Competitive Inhibitors of Dynamin I and II GTPase Derived from Virtual Screening. Journal of Medicinal Chemistry 2010, 53 (14) , 5267-5280.
    8. Abdullah R. Alanzi, Mohammed F. Alajmi, Moneerah J. Alqahtani. Molecular docking and ADMET studies of halogenated metabolites from marine sponges as inhibitors of wild-type and mutants PBP2 in Neisseria gonorrhoeae. Journal of Biomolecular Structure and Dynamics 2023, 51 , 1-13.
    9. Van Cao, I Putu Sukanadi, Naphat Loeanurit, Aphinya Suroengrit, Wattamon Paunrat, Vipanee Vibulakhaopan, Kowit Hengphasatporn, Yasuteru Shigeta, Warinthorn Chavasiri, Siwaporn Boonyasuppayakorn. A sulfonamide chalcone inhibited dengue virus with a potential target at the SAM-binding site of viral methyltransferase.. Antiviral Research 2023, 220 , 105753.
    10. Xiaoyang Chen, Lijuan Yang, Muhammad Farhan Aslam, Jing Tao, Xueqin Zhang, Peng Ren, Yong Wang, Peng Chao. Functional analysis, virtual screening, and molecular dynamics revealed potential novel drug targets and their inhibitors against cardiovascular disease in human. Journal of Biomolecular Structure and Dynamics 2023, 14 , 1-15.
    11. Navaneetha Nambigari. Cancer Therapeutics: Structure-Based Drug Design of Inhibitors for a Novel Angiogenic Growth Factor. Mathematical Biology and Bioinformatics 2023, 18 (1) , 72-88.
    12. Olga Bobileva, Raitis Bobrovs, Evelina Elva Sirma, Iveta Kanepe, Anna L. Bula, Liene Patetko, Anna Ramata-Stunda, Solveiga Grinberga, Aigars Jirgensons, Kristaps Jaudzems. 3-(Adenosylthio)benzoic Acid Derivatives as SARS-CoV-2 Nsp14 Methyltransferase Inhibitors. Molecules 2023, 28 (2) , 768.
    13. Israr Fatima, Sajjad Ahmad, Mubarak A. Alamri, Muhammad Usman Mirza, Muhammad Tahir ul Qamar, Abdur Rehman, Farah Shahid, Eid A. Alatawi, Faris F. Aba Alkhayl, Wafa Abdullah Al-Megrin, Ahmad Almatroudi. Discovery of Rift Valley fever virus natural pan-inhibitors by targeting its multiple key proteins through computational approaches. Scientific Reports 2022, 12 (1)
    14. Nor Nadirah Abdullah, Syahrul Imran, Kok Wai Lam, Nor Hadiani Ismail. Computational Screening of Styryl Lactone Compounds Isolated from Goniothalamus Species to Identify Potential Inhibitors for Dengue Virus. Journal of Computational Biophysics and Chemistry 2022, 21 (07) , 821-843.
    15. Tim R Fischer, Laurenz Meidner, Marvin Schwickert, Marlies Weber, Robert A Zimmermann, Christian Kersten, Tanja Schirmeister, Mark Helm. Chemical biology and medicinal chemistry of RNA methyltransferases. Nucleic Acids Research 2022, 50 (8) , 4216-4245.
    16. Shikha Joon, Rajeev K. Singla, Bairong Shen. In Silico Drug Discovery for Treatment of Virus Diseases. 2022, 73-93.
    17. Ahmad Mohajja Alshammari. Screening of Phytochemicals Against Snake Venom Metalloproteinase: Molecular Docking and Simulation Based Computational Approaches. Archives of Pharmacy Practice 2022, 13 (3) , 76-84.
    18. Bandar Hamad Aloufi. Structure-based Multi-targeted Molecular Docking and Molecular Dynamic Simulation Analysis to Identify Potential Inhibitors against Ovarian Cancer. Journal Of Biochemical Technology 2022, 13 (2) , 29-39.
    19. K. Eurídice Juárez-Mercado, Fernando D. Prieto-Martínez, Norberto Sánchez-Cruz, Andrea Peña-Castillo, Diego Prada-Gracia, José L. Medina-Franco. Expanding the Structural Diversity of DNA Methyltransferase Inhibitors. Pharmaceuticals 2021, 14 (1) , 17.
    20. Xiao-huan Liu, Xiao Zhang, Zhen-hua Lu, You-shuang Zhu, Tao Wang. Potential molecular targets of nonstructural proteins for the development of antiviral drugs against SARS-CoV-2 infection. Biomedicine & Pharmacotherapy 2021, 133 , 111035.
    21. Adib Afandi Abdullah, Yean Kee Lee, Sek Peng Chin, See Khai Lim, Vannajan Sanghiran Lee, Rozana Othman, Shatrah Othman, Noorsaadah Abdul Rahman, Rohana Yusof, Choon Han Heh. Discovery of Dengue Virus Inhibitors. Current Medicinal Chemistry 2020, 27 (30) , 4945-5036.
    22. Renata Kasprzyk, Mateusz Fido, Adam Mamot, Przemyslaw Wanat, Miroslaw Smietanski, Michal Kopcial, Victoria H. Cowling, Joanna Kowalska, Jacek Jemielity. Direct High‐Throughput Screening Assay for mRNA Cap Guanine‐N7 Methyltransferase Activity. Chemistry – A European Journal 2020, 26 (49) , 11266-11275.
    23. Varun Gejji, Pavel Svoboda, Michal Stefanik, Haoqi Wang, Jiri Salat, Ludek Eyer, Daniel Ruzek, Sandun Fernando. An RNA-dependent RNA polymerase inhibitor for tick-borne encephalitis virus. Virology 2020, 546 , 13-19.
    24. Subrata Pramanik, Manisha Thaker, Ananda Gopu Perumal, Rajasekaran Ekambaram, Naresh Poondla, Markus Schmidt, Pok‐Son Kim, Arne Kutzner, Klaus Heese. Proteomic Atomics Reveals a Distinctive Uracil‐5‐Methyltransferase. Molecular Informatics 2020, 39 (5)
    25. Shane M. Buker, Zachary A. Gurard-Levin, Benjamin D. Wheeler, Michael D. Scholle, April W. Case, Jeffrey L. Hirsch, Scott Ribich, Robert A. Copeland, P. Ann Boriack-Sjodin. A Mass Spectrometric Assay of METTL3/METTL14 Methyltransferase Activity. SLAS Discovery 2020, 25 (4) , 361-371.
    26. Megan Chesnut, Laura S. Muñoz, Georgina Harris, Dana Freeman, Lucio Gama, Carlos A. Pardo, David Pamies. In vitro and in silico Models to Study Mosquito-Borne Flavivirus Neuropathogenesis, Prevention, and Treatment. Frontiers in Cellular and Infection Microbiology 2019, 9
    27. Beow Keat Yap, Chong-Yew Lee, Sy Bing Choi, Ezatul E. Kamarulzaman, Maywan Hariono, Habibah A. Wahab. In Silico Identification of Novel Inhibitors. 2019, 761-779.
    28. Camyla Alves Leonel, William Gustavo Lima, Michelli dos Santos, Ariane Coelho Ferraz, Alex Gutterres Taranto, José Carlos de Magalhães, Luciana Lara dos Santos, Jaqueline Maria Siqueira Ferreira. Pharmacophoric characteristics of dengue virus NS2B/NS3pro inhibitors: a systematic review of the most promising compounds. Archives of Virology 2018, 163 (3) , 575-586.
    29. M A F Nasution, R N Aini, U S F Tambunan. Virtual screening of commercial cyclic peptides as NS2B-NS3 protease inhibitor of dengue virus serotype 2 through molecular docking simulation. IOP Conference Series: Materials Science and Engineering 2017, 188 , 012017.
    30. R D Puspitasari, U S F Tambunan. In silico mutation analysis of non-structural protein-5 (NS5) dengue virus. IOP Conference Series: Materials Science and Engineering 2017, 188 , 012043.
    31. Usman Sumo Friend Tambunan, Mochammad Arfin Fardiansyah Nasution, Fauziah Azhima, Arli Aditya Parikesit, Erwin Prasetya Toepak, Syarifuddin Idrus, Djati Kerami. Modification of S -Adenosyl- l -Homocysteine as Inhibitor of Nonstructural Protein 5 Methyltransferase Dengue Virus Through Molecular Docking and Molecular Dynamics Simulation. Drug Target Insights 2017, 11 , 117739281770172.
    32. Dhiraj Acharya, Fengwei Bai. An Overview of Current Approaches Toward the Treatment and Prevention of West Nile Virus Infection. 2016, 249-291.
    33. Matthew Brecher, Hui Chen, Binbin Liu, Nilesh K. Banavali, Susan A. Jones, Jing Zhang, Zhong Li, Laura D. Kramer, Hongmin Li, . Novel Broad Spectrum Inhibitors Targeting the Flavivirus Methyltransferase. PLOS ONE 2015, 10 (6) , e0130062.
    34. Matthew B. Brecher, Zhong Li, Jing Zhang, Hui Chen, Qishan Lin, Binbin Liu, Hongmin Li. Refolding of a fully functional flavivirus methyltransferase revealed that S‐adenosyl methionine but not S‐adenosyl homocysteine is copurified with flavivirus methyltransferase. Protein Science 2015, 24 (1) , 117-128.
    35. Magdalena Byszewska, Mirosław Śmietański, Elżbieta Purta, Janusz M Bujnicki. RNA methyltransferases involved in 5′ cap biosynthesis. RNA Biology 2014, 11 (12) , 1597-1607.
    36. Yohko Nakamura, Akiko Suganami, Mayu Fukuda, Md. Kamrul Hasan, Tomoki Yokochi, Atsushi Takatori, Shunpei Satoh, Tyuji Hoshino, Yutaka Tamura, Akira Nakagawara. Identification of novel candidate compounds targeting TrkB to induce apoptosis in neuroblastoma. Cancer Medicine 2014, 3 (1) , 25-35.
    37. Zhihui Yan, Lijie Zhang, Haiyang Fu, Zhonghua Wang, Jianping Lin. Design of the influenza virus inhibitors targeting the PA endonuclease using 3D-QSAR modeling, side-chain hopping, and docking. Bioorganic & Medicinal Chemistry Letters 2014, 24 (2) , 539-547.
    38. Siew Lim, Pei-Yong Shi. West Nile Virus Drug Discovery. Viruses 2013, 5 (12) , 2977-3006.
    39. Jessica L. Childs-Disney, Ewa Stepniak-Konieczna, Tuan Tran, Ilyas Yildirim, HaJeung Park, Catherine Z. Chen, Jason Hoskins, Noel Southall, Juan J. Marugan, Samarjit Patnaik, Wei Zheng, Chris P. Austin, George C. Schatz, Krzysztof Sobczak, Charles A. Thornton, Matthew D. Disney. Induction and reversal of myotonic dystrophy type 1 pre-mRNA splicing defects by small molecules. Nature Communications 2013, 4 (1)
    40. Hui Chen, Bing Zhou, Matthew Brecher, Nilesh Banavali, Susan A. Jones, Zhong Li, Jing Zhang, Dilip Nag, Laura D. Kramer, Arun K. Ghosh, Hongmin Li, . S-Adenosyl-Homocysteine Is a Weakly Bound Inhibitor for a Flaviviral Methyltransferase. PLoS ONE 2013, 8 (10) , e76900.
    41. Ryan G. Coleman, Michael Carchia, Teague Sterling, John J. Irwin, Brian K. Shoichet, . Ligand Pose and Orientational Sampling in Molecular Docking. PLoS ONE 2013, 8 (10) , e75992.
    42. K. Barral, C. Sallamand, C. Petzold, B. Coutard, A. Collet, Y. Thillier, J. Zimmermann, J.-J. Vasseur, B. Canard, J. Rohayem, F. Debart, E. Decroly. Development of specific dengue virus 2′-O- and N7-methyltransferase assays for antiviral drug screening. Antiviral Research 2013, 99 (3) , 292-300.
    43. Marcin Ziemniak, Malwina Strenkowska, Joanna Kowalska, Jacek Jemielity. Potential Therapeutic Applications of Rna Cap Analogs. Future Medicinal Chemistry 2013, 5 (10) , 1141-1172.
    44. Hui Chen, Lihui Liu, Susan A. Jones, Nilesh Banavali, Jorden Kass, Zhong Li, Jing Zhang, Laura D. Kramer, Arun K. Ghosh, Hongmin Li. Selective inhibition of the West Nile virus methyltransferase by nucleoside analogs. Antiviral Research 2013, 97 (3) , 232-239.
    45. Victor Luzhkov, Etienne Decroly, Bruno Canard, Barbara Selisko, Johan Åqvist. Evaluation of Adamantane Derivatives as Inhibitors of Dengue Virus mRNA Cap Methyltransferase by Docking and Molecular Dynamics Simulations. Molecular Informatics 2013, 32 (2) , 155-164.
    46. Huiguo Lai, Dengfeng Dou, Sridhar Aravapalli, Tadahisa Teramoto, Gerald H. Lushington, Tom M. Mwania, Kevin R. Alliston, David M. Eichhorn, Radhakrishnan Padmanabhan, William C. Groutas. Design, synthesis and characterization of novel 1,2-benzisothiazol-3(2H)-one and 1,3,4-oxadiazole hybrid derivatives: Potent inhibitors of Dengue and West Nile virus NS2B/NS3 proteases. Bioorganic & Medicinal Chemistry 2013, 21 (1) , 102-113.
    47. Thangaraju Tamilvanan, Waheeta Hopper. Active site specific pharmacophore-based screening for methyltransferase inhibitors. Journal of Pharmacy Research 2013, 7 (1) , 121-126.
    48. Ori Kalid, Dora Toledo Warshaviak, Sharon Shechter, Woody Sherman, Sharon Shacham. Consensus Induced Fit Docking (cIFD): methodology, validation, and application to the discovery of novel Crm1 inhibitors. Journal of Computer-Aided Molecular Design 2012, 26 (11) , 1217-1228.
    49. François Ferron, Etienne Decroly, Barbara Selisko, Bruno Canard. The viral RNA capping machinery as a target for antiviral drugs. Antiviral Research 2012, 96 (1) , 21-31.
    50. Manuela S. Murgueitio, Marcel Bermudez, Jérémie Mortier, Gerhard Wolber. In silico virtual screening approaches for anti-viral drug discovery. Drug Discovery Today: Technologies 2012, 9 (3) , e219-e225.
    51. Jakyung Yoo, José L. Medina-Franco. Trimethylaurintricarboxylic acid inhibits human DNA methyltransferase 1: insights from enzymatic and molecular modeling studies. Journal of Molecular Modeling 2012, 18 (4) , 1583-1589.
    52. Toan B. Nguyen, Sergio E. Wong, Felice C. Lightstone. Leveraging Structural Information for the Discovery of New Drugs: Computational Methods. 2012, 209-234.
    53. Jeremy Green, Upul Bandarage, Kate Luisi, Rene Rijnbrand. Recent Advances in the Discovery of Dengue Virus Inhibitors. 2012, 297-317.
    54. Jakyung Yoo, Joo Hee Kim, Keith D. Robertson, José L. Medina-Franco. Molecular Modeling of Inhibitors of Human DNA Methyltransferase with a Crystal Structure. 2012, 219-247.
    55. See Ven Lim, Mohd Basyaruddin A Rahman, Bimo A Tejo. Structure-based and ligand-based virtual screening of novel methyltransferase inhibitors of the dengue virus. BMC Bioinformatics 2011, 12 (S13)
    56. Maude Tremblay-Létourneau, Simon Despins, Isabelle Bougie, Martin Bisaillon, . Virtual High-Throughput Screening Identifies Mycophenolic Acid as a Novel RNA Capping Inhibitor. PLoS ONE 2011, 6 (9) , e24806.
    57. Jakyung Yoo, José L. Medina-Franco. Homology modeling, docking and structure-based pharmacophore of inhibitors of DNA methyltransferase. Journal of Computer-Aided Molecular Design 2011, 25 (6) , 555-567.
    58. Chenzhong Liao, Markus Sitzmann, Angelo Pugliese, Marc C Nicklaus. Software and Resources for Computational Medicinal Chemistry. Future Medicinal Chemistry 2011, 3 (8) , 1057-1085.
    59. Moheshwarnath Issur, Frédéric Picard‐Jean, Martin Bisaillon. The RNA capping machinery as an anti‐infective target. WIREs RNA 2011, 2 (2) , 184-192.
    60. Justin G Julander, Stuart T Perry, Sujan Shresta. Important Advances in the Field of Anti-Dengue Virus Research. Antiviral Chemistry and Chemotherapy 2011, 21 (3) , 105-116.
    61. Francesca Curreli, Hongtao Zhang, Xihui Zhang, Ilya Pyatkin, Zagorodnikov Victor, Andrea Altieri, Asim K. Debnath. Virtual screening based identification of novel small-molecule inhibitors targeted to the HIV-1 capsid. Bioorganic & Medicinal Chemistry 2011, 19 (1) , 77-90.
    62. Anil K Agarwal, Colin W. G. Fishwick. Structure‐based design of anti‐infectives. Annals of the New York Academy of Sciences 2010, 1213 (1) , 20-45.
    63. Lihui Liu, Hongping Dong, Hui Chen, Jing Zhang, Hua Ling, Zhong Li, Pei-Yong Shi, Hongmin Li. Flavivirus RNA cap methyltransferase: structure, function, and inhibition. Frontiers in Biology 2010, 5 (4) , 286-303.

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