Identification and molecular characterization of the tubulin‐podophyllotoxin‐type lignans binding site on Giardia lamblia

• Published in: Chemical biology & drug design 2019-12, Vol.94 (6), p.2031-2040
• Main Authors: Gutiérrez‐Gutiérrez, Filiberto, Romo‐Mancillas, Antonio, Puebla‐Pérez, Ana María, Hernández‐Hernández, José Manuel, Castillo‐Romero, Araceli
• Format: Article
• Language: English
• Subjects: antiparasitic; drugs; Giardia lamblia; lignans; microtubules; podophyllotoxin; tubulin
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.13605

There are several drugs for the treatment of giardiasis; however, there is a tendency for patients to abandon treatment because of drug‐related adverse effects, resulting in relapses, acquired resistance, and higher rates of treatment failure. Recently, we reported some podophyllotoxin‐type lignans from Bursera fagaroides var. fagaroides showing antigiardial activity. In the present work, we demonstrated that 5′‐desmethoxy‐peltatin‐A‐methylether (5‐DES), acetylpodophyllotoxin (APOD), and podophyllotoxin (POD) affect the distribution and staining pattern of microtubular structures on Giardia trophozoites. Virtual screening results revealed that the lignans act via binding in a hydrophobic pocket in the heterodimer interface of tubulin in Giardia. This study provides useful insight to understand the action mechanism of 5DES, APOD, and POD on Giardia lamblia. The optimization of these podophyllotoxin‐type lignans will lead to promising candidates for antigiardial drugs. Podophyllotoxin‐type lignans from Bursera fagaroides var. fagaroides (5′‐desmethoxypeltatin‐A‐methylether, acetylpodophyllotoxin, and podophyllotoxin) affect the distribution and staining pattern of microtubular structures on Giardia trophozoites via binding in a hydrophobic pocket in the heterodimer interface of tubulin.