Structural insights into impact of Y134F mutation and discovery of novel fungicidal compounds against CYP51 in Puccinia triticina.

Abstract:

:Sterol 14α-Demethylase Cytochrome P450 (CYP51) protein involved in ergosterol biosynthesis pathways turn out to be a crucial target for the fungicidal compound. However, the recognition mechanism and dynamic behavior of CYP51 in wheat leaf rust pathogen, Puccinia triticina, is still obscure. Previously, a mutation at position 134 (Y134F) was reported in five European isolates of P. triticina, conversely, structural basis of this mutation remains unclear. To address this problem, three-dimensional structure of CYP51 protein from P. triticina was successfully built using homology modeling approach. To assess the protein structure stability, wild and mutant-type CYP51 proteins bound with azole fungicide was subjected to 50 ns molecular dynamics (MD) simulations run. Observably, the comparative protein-ligand interaction analysis and binding free energy results revealed that impact of the mutation on the thermodynamics and conformational stability of the CYP51 protein was negligible. In addition, we carried out structure-based virtual screening and identified potent novel fungicidal compounds from four different databases and libraries. Consequently, through MD simulation and thermodynamic integration, four novel compounds such as CoCoCo54211 (CoCoCo database), ZINC04089470 (ZINC database), Allyl pyrocatechol 3,4 diacetate (Natural compound library), and 9-octadecenoic acid (Traditional Chinese Medicine database) has been predicted as potent fungicidal compound against CYP51 with XPGlide docking score of -11.41, -13.64, -7.40, and -6.55 kcal/mol, respectively. These compounds were found to form hydrogen bonds with heme group of CYP51, subsequently disturbing the stability and survival of fungus and can be used to control leaf rust in wheat.

journal_name

J Cell Biochem

authors

Pandey B,Sharma P

doi

10.1002/jcb.26422

subject

Has Abstract

pub_date

2018-03-01 00:00:00

pages

2588-2603

issue

3

eissn

0730-2312

issn

1097-4644

journal_volume

119

pub_type

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