The Identification of Binding Mode for Arabidopsis thaliana 7-Keto-8-aminopelargonic Acid Synthase (AtKAPAS) Inhibitors

Abstract

In this study, we determined the 3D-structure of Arabidopsis thaliana KAPAS by homology modeling. We then investigated the binding mode of compounds obtained from in-house library using computational docking methods. From the flexible docking study, we achieved high dock scores for the active compounds denoted in this study as compound 3 and compound 4. Thus, we highlight the flexibility of specific residues, Lys 312 and Phe 172, when used in active sites. While the traditional approach to discover lead compounds heavily depends on serendipity given the poor understanding of biological modes of actions, the structure-based approach utilizes the structure of appropriate target proteins which have well-known binding sites for possible rational designs. The structure-based approach uses only appropriate target proteins instead of the entire plant for in vivo testing. 2 In order to perform a structure-based assay, it is necessary to determine a potent target with a thorough understanding of the mechanism of action of the target. Several enzymes in plants are known to be essential enzymes, meaning that they are crucial for the plant's sur- vival. Disrupting a single essential enzyme leads to severe disorder in the metabolism of the plant, ultimately causing a lethal phenotype to arise. 7-keto-8-aminopelargonic acid synthase from Arabidopsis thaliana plants (AtKAPAS), introduced in this research, is a new potent herbicide target which is involved in the early steps of the creation of the biotin biosynthesis pathway. AtKAPAS as pyridoxal 5'-phos- phate-dependent enzyme catalyzes the decarboxylative con- densation of L-alanine with pimeloyl-CoA in a stereo specific manner to form KAPA, coenzyme A, and carbon dioxide in the first committed step ofbiotin biosynthesis. Inhibiting AtKAPAS leads to significant changes in the phenotype, such as growth inhibition, severe growth retarda- tion, and the creation of lethal phenotypes. 3