In silico studies, design, synthesis, and biological evaluation of kinetoplastid GSK-3 inhibitors

Abstract

Neglected Tropical Diseases (NTDs) disproportionately affect the poorest regions of the world. The scenario is gradually changing, with better understanding of the molecular targets involved in diseases progression in both hosts and parasites, opening new opportunities for research through public-private partnerships. Since 2013, the Laboratory of Synthetic Organic Chemistry at UNICAMP (LQOS) has entered a partnership coordinated by DNDi and has become one of the centers dedicated to the design and synthesis of drug candidates within the Lead Optimization Latin America (LOLA) consortium. Protein kinases (PK) represent approximately 30% of current drug discovery programs, and among them, glycogen synthase kinase 3 (GSK-3) stands out, being related to the progression of several human diseases, including the pathogenesis of NTDs. In this sense, we propose a twelve-month internship (09/1/2022 to 08/31/2022) to be carried out at the Laboratory for Neglected Disease Drug Discovery at Northeastern University in Boston, under the supervision of Prof. Lori Ferrins, whose objective is the rational design, synthesis, and pharmacological evaluation of new kinetoplastid GSK-3 inhibitors aided by in silico studies. The assessment of inhibitory activity on the targets and phenotypic assays will be conducted in collaboration with the Spanish National Research Council (CSIC). In addition, the evaluation of the pharmacokinetic profile of the compounds will be carried out in partnership with the pharmaceutical companies AstraZeneca and Charles River Laboratories. The research group of Prof. Lori Ferrins, whose leader is Professor Michael Pollastri, is recognized for the excellence in the discovery of bioactive compounds targeting NTDs, in particular through the repurposing of human PK inhibitors. The broad spectrum of strategies developed in this laboratory includes the use of modern synthetic routes and purification methods, construction of homology models of proteins which crystallographic structure has not been determined, conformational studies and design of compounds based on the structure of targets, which are highly complementary to the activities developed in LQOS. The researcher will be properly trained in these new techniques and will bring this knowledge to the LQOS, which will be implemented in ongoing research projects by other members of the group. (AU)