Structural analysis of dipeptidyl peptidase 4 and studies of interactions between bioactive ligands and the DPP-4 enzyme

• Grant number: 15/20314-5
• Support type: Scholarships in Brazil - Doctorate
• Effective date (Start): January 01, 2016
• Effective date (End): May 31, 2019
• Field of knowledge: Biological Sciences - Biophysics - Molecular Biophysics
• Principal Investigator: Kathia Maria Honorio
• Grantee: Simone Queiroz Pantaleão
• Home Institution: Centro de Ciências Naturais e Humanas (CCNH). Universidade Federal do ABC (UFABC). Ministério da Educação (Brasil). Santo André , SP, Brazil

Abstract

Seeking to understand the action mechanism of dipeptidyl peptidase-4 (DPP-4) and the main interactions between bioactive ligands and selected target, this project proposes a detailed analysis of the enzyme structure in order to understand the main characteristics of the active site, as well as the influence of structural water in the reaction process and the essential aminoacids into the catalytic triad, the pockets S1 and S2, salt bridge and oxyanion hole. The chosen biological target has high biological importance since it is involved in some important diseases, such as diabetes (currently, the number of people with diabetes is increasing worldwide and strategies for treatment include the use of drugs having side effects). Thus, the study of new DPP-4 is important for the above objective. The methodology to be used in this project consists in using molecular modeling techniques, such as normal modes and molecular dynamics simulations to study the target structure, considering the comparative study of the protein without structural water, with two water molecules described as important in previous studies and all structural water molecules contained in various structures found in PDB (Protein Data Bank). Also, techniques of molecular docking (AutoDock Vina and GOLD programs)and 3D QSAR [CoMFA (Comparative Molecular Field Analysis and CoMSIA (Comparative Molecular Similarity Indices Analysis)] will be used to understand what structural features of the compound series studied are essential for the biological activity. Finally, a virtual screening study will also be conducted collaborating with the search for new bioactive binders of DPP-4. Therefore, this project seeks to understand the main mechanisms involved in the interactions between the biological target and ligands, as well as finding out potential DPP-4 inhibitors that may be candidates for the treatment of type II diabetes.

Scientific publications

(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)

PANTALEAO, SIMONE QUEIROZ; PHILOT, ERIC ALLISON; ALMEIDA, MICHELL DE OLIVEIRA; LIMA, ANGELICA NAKAGAWA; DE SAIRRE, MIRELA INES; SCOTT, ANA LIGIA; HONORIO, KATHIA MARIA. Integrated Protocol to Design Potential Inhibitors of Dipeptidyl Peptidase-4 (DPP-4). CURRENT TOPICS IN MEDICINAL CHEMISTRY, v. 20, n. 3, p. 209-226, 2020. Web of Science Citations: 1.