Banca de DEFESA: SUELLEN GONÇALVES DA SILVA

Uma banca de DEFESA de MESTRADO foi cadastrada pelo programa.
DISCENTE : SUELLEN GONÇALVES DA SILVA
DATA : 13/11/2019
HORA: 14:00
LOCAL: sala 7
TÍTULO:

Screning of Leishmania major Pteridine Reductase 1 (LmPTR1) inhibitors

PALAVRAS-CHAVES:

LmPTR1. Fragment Screening. FITC. Hotspots. TSA. FTMap.

PÁGINAS: 85
GRANDE ÁREA: Ciências da Saúde
ÁREA: Farmácia
RESUMO:

Leishmaniasis is a protozoosis that presents itself as a public health challenge in many parts of the world. However, drugs available for the treatment of patients with this disease have a low therapeutic index, relatively long treatment period and reduced therapeutic adherence, which may favor the selection of resistant strains. Consequently, the development of new drugs becomes crucial. Although inhibition of the folate pathway has led to drug discovery against numerous diseases, inhibitors of the enzyme dihydrofolate reductase thymidylate synthase (DHFR-TS) are inefficient against Leishmania spp. The low susceptibility of parasites is associated with Pteridine Reductase 1 (PTR1), an enzyme that works as an alternative pathway for the reduction of folic acid and unconjugated pteridines when DHFR-TS is inhibited. For this reason, inhibitors of this enzyme are promising compounds for the development of new drugs against leishmaniasis. In this context, the aim of this study is to identify molecular fragments and / or lead-like compounds that bind to Leishmania major PTR1 (LmPTR1). Thermal displacement assays showed that the evaluated thiazolidine-2,4-dione derivatives were inactive and that an imidazopyrazine derivative interact with the target in a concentration-response manner. Finally, 42 fragments increase the thermal stability of LmPTR1 (ΔTm> 1.5 ° C). Assays with the covalently fluorescein-linked protein suggest the most affinity fragments for LmPTR1 are LBEA0418 (Kd = 11 ± 1.31mM), LBEA0126 (Kd = 11 ± 1.22mM), LBEA0394 (Kd = 7.5 ± 1.14). ) mM, LBEA0111 (Kd = 1.35 ± 2.11 mM) and LBEA0138 (Kd = 6.5 ± 1.46 mM), while the fragments with the highest binding efficiency are LBEA0111 (LE = 0.33 kcal / mol ) LBEA0447 (LE = 0.32 kcal / mol). Additionally, these assays suggest that six fragments (LBEA0463, 0414, 0418, 0405, 0472, 0473, 0401) interact incompetently with the enzyme cofactor, while seven non-competitively interact (LBEA0453, 0126, 0394, 0111, 0138 , 0447, 0125). Two fragments interact competitively with the substrate (LBEA0418 and LBEA0473), one interacting incompetently (LBEA0463) and two non-competitively (LBE0126, 0394). Because most fragments do not compete with the cofactor or substrate, FTMap and Hotspot Fragment Maps (FragMap) servers were used to identify likely hotspots for these fragments. This information was used to guide molecular coupling studies that will be used to develop leader compounds from fragments.

MEMBROS DA BANCA:
Presidente - 1493023 - MARCELO SANTOS CASTILHO
Externo ao Programa - 1507716 - MAURICIO MORAES VICTOR
Externo à Instituição - FRANCO HENRIQUE ANDRADE LEITE