The Octahydroindene Carboxyl Substructure from Dihydrobetulinic Acid is Essential to Inhibit Topoisomerase IB from Leishmania donovani

Author(s)

Camila A. Rocha ^[1] ; Paulo R. S. Sanches ^[2] ; Reinaldo Marchetto ^[3] ; Aderson Zottis ^[4]

Affiliation

^[1] Universidade Estadual Paulista Júlio de Mesquita Filho. Instituto de Química. Departamento de Bioquímica e Tecnologia Química - Brasil

^[2] Universidade Estadual Paulista Júlio de Mesquita Filho. Instituto de Química. Departamento de Bioquímica e Tecnologia Química - Brasil

^[3] Universidade Estadual Paulista Júlio de Mesquita Filho. Instituto de Química. Departamento de Bioquímica e Tecnologia Química - Brasil

^[4] Universidade Estadual Paulista Júlio de Mesquita Filho. Instituto de Química. Departamento de Bioquímica e Tecnologia Química - Brasil

• Document type: Journal article
• Source: Journal of the Brazilian Chemical Society; v. 27, n. 3, p. 591-598, 2016-03-00.

Abstract

The dihydrobetulinic acid is a known competitive inhibitor of topoisomerase IB from Leishmania donovani, a validated target for developing new antileishmanial drugs. However, its binding mode and interaction pocket have not been established yet. We combined docking and molecular dynamics simulations to identify the most probable binding pocket. Our best model strongly suggests a cavity involving the residues arginine 314 and arginine 410 from chain A, and the catalytic tyrosine 222 from chain B as the interaction site and a substructure of this terpene inhibitor as essential for the process of molecular recognition. Then, a new class of inhibitors with increased affinity could be designed by structure-based approaches. (AU)

• FAPESP's process: 12/00360-4 - Antibacterial and Antitumor Drug Design: Applying Advanced Computational Methods for the Identification of New Inhibitor Classes Against Bacterial and Human Topoisomerase Enzyme
• Grantee: Aderson Zottis
• Support Opportunities: Scholarships in Brazil - Post-Doctoral