In Vitro and In Silico Analyses of New Cinnamid and Rosmarinic Acid-Derived Compounds Biosynthesized in As Arginase Inhibitors

Overview

Journal Pathogens

Date 2022 Sep 23

PMID 36145452

Authors

Julio Abel Alfredo Dos Santos Simone Come

Yibin Zhuang

Tianzhen Li

Simone Brogi

Sandra Gemma

Tao Liu

Edson Roberto da Silva

Affiliations

Soon will be listed here.

Abstract

Arginase is a metalloenzyme that plays a central role in infections. Previously, rosmarinic and caffeic acids were described as antileishmanial agents and as arginase inhibitors. Here, we describe the inhibition of arginase in by rosmarinic acid analogs () and new caffeic acid-derived amides (). Caffeic acid esters and amides were produced by means of an engineered synthesis in and tested against arginase. New amides () were biosynthesized in cultured with 2 mM of different combinations of feeding substrates. The most potent arginase inhibitors showed Ki(s) ranging from 2 to 5.7 μM. Compounds and inhibited arginase (L-ARG) through a noncompetitive mechanism whilst compound showed a competitive inhibition. By applying an in silico protocol, we determined the binding mode of compound . The competitive inhibitor of L-ARG targeted the key residues within the binding site of the enzyme, establishing a metal coordination bond with the metal ions and a series of hydrophobic and polar contacts supporting its micromolar inhibition of L-ARG. These results highlight that dihydroxycinnamic-derived compounds can be used as the basis for developing new drugs using a powerful tool based on the biosynthesis of arginase inhibitors.

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