Molecular modeling study of specific inhibitors for the adenylyl cyclase 1 enzyme of the intestinal parasite Giardia lamblia

ESTEBAN GABRIEL VEGA HISSI ; AGUSTÍN YANEFF; ESTEBAN GABRIEL VEGA HISSI ; AGUSTÍN YANEFF; ADOLFO ZURITA; DANIEL RICARDO ENRIZ; ADOLFO ZURITA; DANIEL RICARDO ENRIZ; ADRIANA GARRO; NICOLÁS DI SIERVI; ADRIANA GARRO; NICOLÁS DI SIERVI

San Luis

Congreso; XLVIII Reunión Anual de la Sociedad Argentina de Biofísica; 2019

Sociedad Argentina de Biofísica

Giardia lamblia (G. lamblia) is a protozoan intestinal parasite responsible for an infection of great epidemiological and clinical importance known as giardiasis. This disease is the most frequent cause of diarrhea and bad absorption in the world, affecting millions of people every year and that is mainly caused by the ingestion of water contaminated with parasite cysts. There is evidence linking the adaptive differentiation processes of G. lamblia with signal transduction mechanisms mediated by cyclic AMP (cAMP). This second messenger would be synthesized by the enzyme adenylyl cyclase (AC: gAC1 and gAC2) which possess very low identity (~ 30%) with respect to their mammalian counterparts. Therefore, they become molecular targets for the development of specific pharmacological agents. As a starting point, we managed to clone, purify and demonstrate the adenylyl cyclase activity in enzymatic assays of the catalytic domain of the enzyme gAC1. In addition, we performed homology modeling, which used the soluble AC of the cyanobacteria S. platensis as the best template.In this work we present enzymatic inhibition assays and theoretical models of interactions between a known S. platensis AC inhibitor, 2-catechol estrogen (2CE) and a series of new G. lamblia gAC1 inhibitors with novel structural scaffolds. In this way we present a new series of piperidine carboxamide based core derivatives obtained by chemical synthesis. Among these compounds, one stands out (Amj147) that has in its structure a catechol group similar to that of 2CE. This compound shows an inhibitory effect at the μM level, being the most active in the series. Our molecular modeling study reveals that although the catechol group of Amj147 actively participates through interactions with active site ions, the molecular size would result in a mechanism of inhibition different from that of 2CE. This new compound is an excellent starting structure for the design of new specific inhibitors of the gAC1 enzyme.