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

VEGA HISSI, ESTEBAN G.; GARRO, ADRIANA; ZURITA, ADOLFO; YANEFF, A.; DI SIERVI, N.; ENRIZ, DANIEL R.

San Luis

Congreso; XLVIII Reunión Anual de la Sociedad Argentina de Biofísica (SAB); 2019

Sociedad Argentina de Biofísica (SAB)

Giardia lamblia (G. lamblia) is a protozoan intestinal parasite responsible for an infectionof great epidemiological and clinical importance known as giardiasis. This disease is themost frequent cause of diarrhea and bad absorption in the world, affecting millions ofpeople every year and that is mainly caused by the ingestion of water contaminated withparasite cysts. There is evidence linking the adaptive differentiation processes of G.lamblia with signal transduction mechanisms mediated by cyclic AMP (cAMP). Thissecond messenger would be synthesized by the enzyme adenylyl cyclase (AC: gAC1 andgAC2) which possess very low identity (~ 30%) with respect to their mammaliancounterparts. Therefore, they become molecular targets for the development of specificpharmacological agents. As a starting point, we managed to clone, purify anddemonstrate the adenylyl cyclase activity in enzymatic assays of the catalytic domain ofthe enzyme gAC1. In addition, we performed homology modeling, which used the solubleAC of the cyanobacteria S. platensis as the best template.In this work we present enzymatic inhibition assays and theoretical models ofinteractions between a known S. platensis AC inhibitor, 2-catechol estrogen (2CE) and aseries of new G. lamblia gAC1 inhibitors with novel structural scaffolds. In this way wepresent a new series of piperidine carboxamide based core derivatives obtained bychemical synthesis. Among these compounds, one stands out (Amj147) that has in itsstructure a catechol group similar to that of 2CE. This compound shows an inhibitoryeffect at the μM level, being the most active in the series. Our molecular modeling studyreveals that although the catechol group of Amj147 actively participates throughinteractions with active site ions, the molecular size would result in a mechanism ofinhibition different from that of 2CE. This new compound is an excellent startingstructure for the design of new specific inhibitors of the gAC1 enzyme.