Discovery of Novel Rhizoctonia solani DHFR Inhibitors as Fungicides Using Virtual Screening

Feng, Ruirui; Sun, Bo; Zhang, Shengkai; Su, Erzheng; Kovalevsky, Andrey Y.; Zhang, Feng; Bennett, Brad C.; Shen, Qirong; Wan, Qun

doi:10.1021/acs.jafc.3c05216

Title: Discovery of Novel Rhizoctonia solani DHFR Inhibitors as Fungicides Using Virtual Screening

Journal Article · 01 December 2023 · Journal of Agricultural and Food Chemistry

DOI: https://doi.org/10.1021/acs.jafc.3c05216 · OSTI ID:2251569

Feng, Ruirui ^[1]; Sun, Bo ^[1]; Zhang, Shengkai ^[2];

^[3];

^[4]; Zhang, Feng ^[1]; Bennett, Brad C. ^[5]; Shen, Qirong ^[1];

^[1]

Nanjing Agricultural University (China)
Institute of Advanced Science Facilities, Shenzhen (China)
Nanjing Forestry Univ. (China)
Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
Samford Univ., Birmingham, AL (United States)

Dihydrofolate reductase (DHFR) is an essential enzyme in the folate pathway and has been recognized as a well-known target for antibacterial and antifungal drugs. We discovered eight compounds from the ZINC database using virtual screening to inhibit Rhizoctonia solani (R. solani), a fungal pathogen in crops. These compounds were evaluated with in vitro assays for enzymatic and antifungal activity. Among these, compound Hit8 is the most active R. solani DHFR inhibitor, with the IC₅₀ of 10.2 μM. The selectivity of inhibition is 22.3 against human DHFR with the IC₅₀ of 227.7 μM. Moreover, Hit8 has higher antifungal activity against R. solani (EC₅₀ of 38.2 mg L^–1) compared with validamycin A (EC₅₀ of 67.6 mg L^–1), a well-documented fungicide. These results suggest that Hit8 may be a potential fungicide. Finally, our study exemplifies a computer-aided method to discover novel inhibitors that could target plant pathogenic fungi.

View Accepted Manuscript (DOE)

Cite

Export

Save

Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 2251569

Journal Information:: Journal of Agricultural and Food Chemistry, Vol. 71, Issue 49; ISSN 0021-8561

Publisher:: American Chemical SocietyCopyright Statement

Country of Publication:: United States

Language:: English

References (49)

MOLPROBITY: structure validation and all-atom contact analysis for nucleic acids and their complexes Davis, I. W.; Murray, L. W.; Richardson, J. S. Nucleic Acids Research, Vol. 32, Issue Web Server https://doi.org/10.1093/nar/gkh398	journal	July 2004
MMPBSA.py : An Efficient Program for End-State Free Energy Calculations Miller, Bill R.; McGee, T. Dwight; Swails, Jason M. Journal of Chemical Theory and Computation, Vol. 8, Issue 9 https://doi.org/10.1021/ct300418h	journal	August 2012
AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading Trott, Oleg; Olson, Arthur J. Journal of Computational Chemistry https://doi.org/10.1002/jcc.21334	journal	January 2009
A Comparative Study on the Constitutive Properties of Marketed Pesticides Hao, Gefei; Dong, Qingjian; Yang, Guangfu Molecular Informatics, Vol. 30, Issue 6-7 https://doi.org/10.1002/minf.201100020	journal	June 2011
X-ray structure of the ternary MTX·NADPH complex of the anthrax dihydrofolate reductase: A pharmacophore for dual-site inhibitor design Bennett, Brad C.; Wan, Qun; Ahmad, Md Faiz Journal of Structural Biology, Vol. 166, Issue 2 https://doi.org/10.1016/j.jsb.2009.01.001	journal	May 2009
Morphological and Genetical Variability among Rhizoctonia solani Isolates Causing Sheath Blight Disease of Rice Moni, Zakiah Rahman; Ali, Md Ansar; Alam, Md Shahidul Rice Science, Vol. 23, Issue 1 https://doi.org/10.1016/j.rsci.2016.01.005	journal	January 2016
Towards Species-specific Antifolates Chan, D.; Anderson, A. Current Medicinal Chemistry, Vol. 13, Issue 4 https://doi.org/10.2174/092986706775527938	journal	February 2006
Characteristics of Validamycin A in Controlling Rhizoctonia Diseases Matsuura, Kazuho Natural Products https://doi.org/10.1016/B978-0-08-029223-6.50048-3	book	January 1983
The Antifolate Activity of Tea Catechins Lucock, Mark D.; Roach, Paul D. Cancer Research, Vol. 65, Issue 18 https://doi.org/10.1158/0008-5472.CAN-05-1414	journal	September 2005
PyMOL and Inkscape Bridge the Data and the Data Visualization Yuan, Shuguang; Chan, H. C. Stephen; Filipek, Slawomir Structure, Vol. 24, Issue 12 https://doi.org/10.1016/j.str.2016.11.012	journal	December 2016
PROCHECK: a program to check the stereochemical quality of protein structures Laskowski, R. A.; MacArthur, M. W.; Moss, D. S. Journal of Applied Crystallography, Vol. 26, Issue 2 https://doi.org/10.1107/S0021889892009944	journal	April 1993
Dihydrofolate reductase inhibitors for use as antimicrobial agents He, Juan; Qiao, Wenliang; An, Qi European Journal of Medicinal Chemistry, Vol. 195 https://doi.org/10.1016/j.ejmech.2020.112268	journal	June 2020
Toward Broad Spectrum Dihydrofolate Reductase Inhibitors Targeting Trimethoprim Resistant Enzymes Identified in Clinical Isolates of Methicillin Resistant Staphylococcus aureus Reeve, Stephanie M.; Si, Debjani; Krucinska, Jolanta ACS Infectious Diseases, Vol. 5, Issue 11 https://doi.org/10.1021/acsinfecdis.9b00222	journal	September 2019
GROMACS: High performance molecular simulations through multi-level parallelism from laptops to supercomputers Abraham, Mark James; Murtola, Teemu; Schulz, Roland SoftwareX, Vol. 1-2 https://doi.org/10.1016/j.softx.2015.06.001	journal	September 2015
Highly accurate protein structure prediction with AlphaFold Jumper, John; Evans, Richard; Pritzel, Alexander Nature https://doi.org/10.1038/s41586-021-03819-2	journal	July 2021
Morphological similarity: A 3D molecular similarity method correlated with protein-ligand recognition Jain, Ajay N. Journal of Computer-Aided Molecular Design, Vol. 14, Issue 2, p. 199-213 https://doi.org/10.1023/A:1008100132405	journal	January 2000
Tea polyphenol is a potential antifungal agent for the control of obligate biotrophic fungus in plants Yang, Yuheng; Chen, Yingjuan; Chen, Fajing Journal of Phytopathology, Vol. 165, Issue 7-8 https://doi.org/10.1111/jph.12591	journal	June 2017
ESPript: analysis of multiple sequence alignments in PostScript Gouet, P.; Courcelle, E.; Stuart, D. Bioinformatics, Vol. 15, Issue 4 https://doi.org/10.1093/bioinformatics/15.4.305	journal	April 1999
Anticancer Antifolates: Current Status and Future Directions McGuire, John Current Pharmaceutical Design, Vol. 9, Issue 31 https://doi.org/10.2174/1381612033453712	journal	December 2003
Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings 1PII of original article: S0169-409X(96)00423-1. The article was originally published in Advanced Drug Delivery Reviews 23 (1997) 3–25. 1 Lipinski, Christopher A.; Lombardo, Franco; Dominy, Beryl W. Advanced Drug Delivery Reviews, Vol. 46, Issue 1-3 https://doi.org/10.1016/S0169-409X(00)00129-0	journal	March 2001
LigPlot+: Multiple Ligand–Protein Interaction Diagrams for Drug Discovery Laskowski, Roman A.; Swindells, Mark B. Journal of Chemical Information and Modeling, Vol. 51, Issue 10 https://doi.org/10.1021/ci200227u	journal	October 2011
Malarial dihydrofolate reductase as a paradigm for drug development against a resistance-compromised target Yuthavong, Y.; Tarnchompoo, B.; Vilaivan, T. Proceedings of the National Academy of Sciences, Vol. 109, Issue 42 https://doi.org/10.1073/pnas.1204556109	journal	October 2012
Ligand-Induced Conformational Changes in the Crystal Structures of Pneumocystis carinii Dihydrofolate Reductase Complexes with Folate and NADP ⁺ ^† ^, ^‡ Cody, Vivian; Galitsky, Nikolai; Rak, Dawn Biochemistry, Vol. 38, Issue 14 https://doi.org/10.1021/bi982728m	journal	April 1999
Clinical experience with cyclooxygenase-2 inhibitors van Ryn, J.; Pairet, M. Inflammation Research, Vol. 48, Issue 5 https://doi.org/10.1007/s000110050455	journal	May 1999
Baseline sensitivity and efficacy of thifluzamide in Rhizoctonia solani Chen, Y.; Zhang, A. ‐F.; Wang, W. ‐X. Annals of Applied Biology, Vol. 161, Issue 3 https://doi.org/10.1111/j.1744-7348.2012.00569.x	journal	September 2012
Crystal structures of recombinant human dihydrofolate reductase complexed with folate and 5-deazafolate Davies, Jay F.; Delcamp, Tavner J.; Prendergast, Neal J. Biochemistry, Vol. 29, Issue 40 https://doi.org/10.1021/bi00492a021	journal	October 1990
ADMETlab 2.0: an integrated online platform for accurate and comprehensive predictions of ADMET properties Xiong, Guoli; Wu, Zhenxing; Yi, Jiacai Nucleic Acids Research, Vol. 49, Issue W1 https://doi.org/10.1093/nar/gkab255	journal	April 2021
Can we use docking and scoring for hit-to-lead optimization? Enyedy, Istvan J.; Egan, William J. Journal of Computer-Aided Molecular Design, Vol. 22, Issue 3-4 https://doi.org/10.1007/s10822-007-9165-4	journal	January 2008
Virtual screening and fast automated docking methods Schneider, Gisbert; Böhm, Hans-Joachim Drug Discovery Today, Vol. 7 https://doi.org/10.1016/S1359-6446(02)00004-1	journal	January 2002
Assessing the Performance of the MM/PBSA and MM/GBSA Methods. 1. The Accuracy of Binding Free Energy Calculations Based on Molecular Dynamics Simulations Hou, Tingjun; Wang, Junmei; Li, Youyong Journal of Chemical Information and Modeling, Vol. 51, Issue 1 https://doi.org/10.1021/ci100275a	journal	November 2010
Molecular Docking and High-Throughput Screening for Novel Inhibitors of Protein Tyrosine Phosphatase-1B Doman, Thompson N.; McGovern, Susan L.; Witherbee, Bryan J. Journal of Medicinal Chemistry, Vol. 45, Issue 11 https://doi.org/10.1021/jm010548w	journal	May 2002
High-throughput docking for lead generation Abagyan, Ruben; Totrov, Maxim Current Opinion in Chemical Biology, Vol. 5, Issue 4 https://doi.org/10.1016/S1367-5931(00)00217-9	journal	August 2001
ZINC 15 – Ligand Discovery for Everyone Sterling, Teague; Irwin, John J. Journal of Chemical Information and Modeling, Vol. 55, Issue 11 https://doi.org/10.1021/acs.jcim.5b00559	journal	November 2015
gmx_MMPBSA: A New Tool to Perform End-State Free Energy Calculations with GROMACS Valdés-Tresanco, Mario S.; Valdés-Tresanco, Mario E.; Valiente, Pedro A. Journal of Chemical Theory and Computation, Vol. 17, Issue 10 https://doi.org/10.1021/acs.jctc.1c00645	journal	September 2021
Three-dimensional structure of M. tuberculosis dihydrofolate reductase reveals opportunities for the design of novel tuberculosis drugs Li, Rongbao; Sirawaraporn, Rachada; Chitnumsub, Penchit Journal of Molecular Biology, Vol. 295, Issue 2 https://doi.org/10.1006/jmbi.1999.3328	journal	January 2000
Functional significance of evolving protein sequence in dihydrofolate reductase from bacteria to humans Liu, C. T.; Hanoian, P.; French, J. B. Proceedings of the National Academy of Sciences, Vol. 110, Issue 25 https://doi.org/10.1073/pnas.1307130110	journal	June 2013
Analyses of the Temporal Development and Yield Losses due to Sheath Blight of Rice (Rhizoctonia solani AG1.1a) Tan, Wan-zhong; Zhang, Wei; Ou, Zeng-qi Agricultural Sciences in China, Vol. 6, Issue 9 https://doi.org/10.1016/S1671-2927(07)60149-7	journal	September 2007
Characterization of Rhizoctonia solani Associated with Soybean in Brazil Chela Fenille, Roseli; Luiz de Souza, Nilton; Eurya Kuramae, Eiko European Journal of Plant Pathology, Vol. 108, Issue 8, p. 783-792 https://doi.org/10.1023/A:1020811019189	journal	October 2002
Recent Design and Structure-Activity Relationship Studies on the Modifications of DHFR Inhibitors as Anticancer Agents Wróbel, Agnieszka; Drozdowska, Danuta Current Medicinal Chemistry, Vol. 28, Issue 5 https://doi.org/10.2174/0929867326666191016151018	journal	February 2021
Antifungal potential and biochemical effects of monoterpenes and phenylpropenes on plant Marei, Gehan I. Kh.; Abdelgaleil, Samir. A. M. Plant Protection Science, Vol. 54, Issue 1 https://doi.org/10.17221/9/2017-PPS	journal	March 2018
Machine learning classification can reduce false positives in structure-based virtual screening Adeshina, Yusuf O.; Deeds, Eric J.; Karanicolas, John Proceedings of the National Academy of Sciences, Vol. 117, Issue 31 https://doi.org/10.1073/pnas.2000585117	journal	July 2020
Understanding the role of Leu22 variants in methotrexate resistance: comparison of wild-type and Leu22Arg variant mouse and human dihydrofolate reductase ternary crystal complexes with methotrexate and NADPH Cody, Vivian; Luft, Joe R.; Pangborn, Walt Acta Crystallographica Section D Biological Crystallography, Vol. 61, Issue 2 https://doi.org/10.1107/S0907444904030422	journal	January 2005
Tea polyphenol epigallocatechin-3-gallate inhibits ergosterol synthesis by disturbing folic acid metabolism in Candida albicans Navarro-Martinez, M. D. Journal of Antimicrobial Chemotherapy, Vol. 57, Issue 6 https://doi.org/10.1093/jac/dkl124	journal	April 2006
Construction and evaluation of the kinetic scheme associated with dihydrofolate reductase from Escherichia coli Fierke, Carol A.; Johnson, Kenneth A.; Benkovic, Stephen J. Biochemistry, Vol. 26, Issue 13 https://doi.org/10.1021/bi00387a052	journal	June 1987
Simple adjustment of the sequence weight algorithm remarkably enhances PSI-BLAST performance Oda, Toshiyuki; Lim, Kyungtaek; Tomii, Kentaro BMC Bioinformatics, Vol. 18, Issue 1 https://doi.org/10.1186/s12859-017-1686-9	journal	June 2017
Full length amylin oligomer aggregation: insights from molecular dynamics simulations and implications for design of aggregation inhibitors Berhanu, Workalemahu Mikre; Masunov, Artëm E. Journal of Biomolecular Structure and Dynamics, Vol. 32, Issue 10 https://doi.org/10.1080/07391102.2013.832635	journal	September 2013
Structural comparison of Mtb-DHFR and h-DHFR for design, synthesis and evaluation of selective non-pteridine analogues as antitubercular agents Sharma, Kalicharan; Tanwar, Omprakash; Sharma, Shweta Bioorganic Chemistry, Vol. 80 https://doi.org/10.1016/j.bioorg.2018.04.022	journal	October 2018
Antifungal screening of endophytic fungi fromGinkgo bilobafor discovery of potent anti-phytopathogenic fungicides Xiao, Yu; Li, Hong-Xia; Li, Cong FEMS Microbiology Letters, Vol. 339, Issue 2 https://doi.org/10.1111/1574-6968.12065	journal	January 2013
Quo Vadis, Virtual Screening? A Comprehensive Survey of Prospective Applications Ripphausen, Peter; Nisius, Britta; Peltason, Lisa Journal of Medicinal Chemistry, Vol. 53, Issue 24 https://doi.org/10.1021/jm101020z	journal	October 2010

Similar Records

Characterization of genes involved in biosynthesis of a novel antibiotic from Burkholderia cepacia BC11 and their role in biological control of Rhizoctonia solani

Journal Article · 1998 · Applied and Environmental Microbiology · OSTI ID:675511

Kang, Y; Carlson, R; Tharpe, W; +1 more

Investigating the roles of MicroRNAs in biotic stress response induced by Rhizoctonia solani in rice

Journal Article · 2014 · AIP Conference Proceedings · OSTI ID:22308351

Syuhada, O. Nurfarahana; Kalaivani, N.

Mechanism for mercury tolerance in fungi. [Aspergillus niger; Rhizoctonia solani; Pythium ultimum]

Journal Article · 1964 · Phytopathology; (United States) · OSTI ID:5119937

Ashworth, Jr, L J; Amin, J V

Related Subjects

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY
dihydrofolate reductase
virtual screening
fungicide
enzyme inhibition

Title: Discovery of Novel Rhizoctonia solani DHFR Inhibitors as Fungicides Using Virtual Screening

Citation Formats

References (49)

Similar Records

Related Subjects