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

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

doi:10.1021/acs.jafc.3c05216

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

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

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5 Scopus citations

Abstract

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. Our study exemplifies a computer-aided method to discover novel inhibitors that could target plant pathogenic fungi.

Original language	English
Pages (from-to)	19385-19395
Number of pages	11
Journal	Journal of Agricultural and Food Chemistry
Volume	71
Issue number	49
DOIs	https://doi.org/10.1021/acs.jafc.3c05216
State	Published - Dec 13 2023

Funding

We thank the support from Prof. Gang Chen, Prof. Fazhi Qi, and Dr. Yakang Li to use high-performance computation resources, including the National High Energy Physics Science Data Center (NHEPSDC) and China Spallation Neutron Source (CSNS). This work was supported by the National Natural Science Foundation of China (nos. 32071264 and 12005248) and Nanjing Agricultural University (no. XUEKEN2023039).

Funders	Funder number
China Spallation Neutron Source
National High Energy Physics Science Data Center
National Natural Science Foundation of China	12005248, 32071264
Nanjing Agricultural University	XUEKEN2023039

Keywords

dihydrofolate reductase
enzyme inhibition
fungicide
virtual screening

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10.1021/acs.jafc.3c05216

Cite this

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title = "Discovery of Novel Rhizoctonia solani DHFR Inhibitors as Fungicides Using Virtual Screening",

abstract = "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. Our study exemplifies a computer-aided method to discover novel inhibitors that could target plant pathogenic fungi.",

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author = "Ruirui Feng and Bo Sun and Shengkai Zhang and Erzheng Su and Andrey Kovalevsky and Feng Zhang and Bennett, {Brad C.} and Qirong Shen and Qun Wan",

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doi = "10.1021/acs.jafc.3c05216",

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T1 - Discovery of Novel Rhizoctonia solani DHFR Inhibitors as Fungicides Using Virtual Screening

AU - Feng, Ruirui

AU - Sun, Bo

AU - Zhang, Shengkai

AU - Su, Erzheng

AU - Kovalevsky, Andrey

AU - Zhang, Feng

AU - Bennett, Brad C.

AU - Shen, Qirong

AU - Wan, Qun

PY - 2023/12/13

Y1 - 2023/12/13

N2 - 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. Our study exemplifies a computer-aided method to discover novel inhibitors that could target plant pathogenic fungi.

AB - 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. Our study exemplifies a computer-aided method to discover novel inhibitors that could target plant pathogenic fungi.

KW - dihydrofolate reductase

KW - enzyme inhibition

KW - fungicide

KW - virtual screening

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ER -

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

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Keywords

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