Structural insights into impact of Y134F mutation and identification of fungicidal compounds against CYP51 in Puccinia triticina
Sterol 14?-Demethylase Cytochrome P450 (CYP51) protein involved in ergosterol biosynthesis pathways is a crucial target for efficient fungicidal compounds. However, the recognition mechanism and dynamic behavior of CYP51 in wheat leaf rust pathogen, Puccinia triticina is still obscure. Previously, a mutation at codon 134 (Y134F) was reported in five European isolates of P. triticina, the structural basis of this mutation remain unclear. To address this problem, CYP51 wild type protein and its variant proteins were successfully modeled using I-TASSER, an ab initio based structure prediction pipeline. To gain valuable insights into structure-function behavior for the binding wild-type and mutant-type proteins, individually generated protein models was subjected to 50ns molecular dynamics (MD) simulations run. Observably, this comparative protein-ligand interaction analysis and binding free energy results revealed that impact of mutation on the thermodynamics and conformational stability of the CYP51 protein is negligible. In present study, we carried out structure-based molecular docking 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 XPGlidedocking score of -11.41, -12.52, -7.40 and -7.55 kcal/mol, respectively. These compounds were found to directly bond to heme group of CYP51, subsequently disturbing the stability and survival of fungus and can be used to control leaf rust in wheat.