Development of new ligands for Peroxisome Proliferator-Activated Receptor by an approach of fragment based drug discovery

• Grant number: 13/26485-0
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: May 01, 2014
• End date: May 13, 2018
• Field of knowledge: Health Sciences - Pharmacy
• Principal Investigator: Flavio da Silva Emery
• Grantee: Paulo Eliandro da Silva Júnior
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated scholarship(s): 16/24817-4 - Development of selective functionalization of novel heterocycles, BE.EP.DR

Abstract

Fragment-based drug discovery (FBDD) is a strategy that has emerged in recent years as an additional and contrasting approach to other drug discovery strategies. This approach involves constructing fragments, small molecules with low molecular weight, which are potent ligands for a specific target. Currently, a class of receptors known as Activated Receptors peroxisome proliferators (PPAR) has aroused the interest of pharmaceutical industries due to its relation with lipid metabolism regulation. Considering that PPARs are promising targets for drug discovery, this project proposes the development of a compound library by fragment-based drug discovery, applying fragment merging and fragment growing. Regarding fragment merging, novel compounds will be obtained from the substitution of the bicyclic core of know PPAR agonists by selected fragments, 2,6-naphthyridin-3-ol and 1H-pyrazolo[3,4-c]pyridin-5-ol. The fragment growing approach aims at fragment elaboration to explore new receptor/ligand interactions. Concomitantly to the synthetic process, the library will be target to virtual screening - Docking - as well as biochemical assays - FRET - in order to evaluate the ligand efficiency of these novel fragments. Obtained data will be used to continue the fragment elaboration cycle, as well as tp better understand the PPAR receptors.

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)

SILVA JUNIOR, P. E.; REZENDE, L. C. D.; GIMENES, JULIA POSSAMAI; MALTAROLLO, VINICIUS GONCALVES; DALE, JAMES; TROSSINI, G. H. G.; EMERY, F. S.; GANESAN, A.. Synthesis of two `heteroaromatic rings of the future' for applications in medicinal chemistry. RSC ADVANCES, v. 6, n. 27, p. 22777-22780, 2016. (11/23342-9, 12/20990-2, 13/26485-0)

SILVA JUNIOR, P. E.; REZENDE, L. C. D.; GIMENES, JULIA POSSAMAI; MALTAROLLO, VINICIUS GONCALVES; DALE, JAMES; TROSSINI, G. H. G.; EMERY, F. S.; GANESAN, A.. Synthesis of two 'heteroaromatic rings of the future' for applications in medicinal chemistry. RSC ADVANCES, v. 6, n. 27, p. 4-pg., 2016-01-01. (11/23342-9, 13/26485-0, 12/20990-2)

DA SILVA JUNIOR, PAULO ELIANDRO; GIL DE MELO, SHAIANI MARIA; DE PAULA, MURILO HELDER; VESSECCHI, RICARDO; OPATZ, TILL; DAY, JAMES E. H.; GANESAN, A.; EMERY, FLAVIO DA SILVA. Growth vector elaboration of fragments: regioselective functionalization of 5-hydroxy-6-azaindazole and 3-hydroxy-2,6-naphthyridine. ORGANIC & BIOMOLECULAR CHEMISTRY, v. 20, n. 37, p. 8-pg., 2022-08-26. (16/24817-4, 13/26485-0)

Academic Publications

(References retrieved automatically from State of São Paulo Research Institutions)

SILVA JÚNIOR, Paulo Eliandro da. Synthesis and exploration of multiple synthetic vectors in \future heteroaromatic\ fragments. 2018. Doctoral Thesis - Universidade de São Paulo (USP). Faculdade de Ciências Farmacêuticas de Ribeirão Preto (PCARP/BC) Ribeirão Preto.