Functional screening and optimization of molecules acting on a GPCR target with potential immunotherapeutic application

• Grant number: 22/15994-0
• Support Opportunities: Research Grants - Innovative Research in Small Business - PIPE
• Start date: May 01, 2023
• End date: October 31, 2025
• Field of knowledge: Biological Sciences - Pharmacology - Biochemical and Molecular Pharmacology
• Principal Investigator: Ricardo Di Lazzaro Filho
• Grantee: Ricardo Di Lazzaro Filho
• Company: Naiad Desenvolvimento Computacional de Fármacos Ltda
• CNAE: Desenvolvimento e licenciamento de programas de computador customizáveis ; Pesquisa e desenvolvimento experimental em ciências físicas e naturais
• City: São Caetano do Sul
• Associated researchers: Claudio Miguel da Costa Neto
• Associated scholarship(s): 23/09278-3 - Application of in silico methods in the development of molecules acting in a GPCR with potential application in immunotherapy - an overview of the productive chain in Drug Design., BP.TT; 23/09420-4 - Application of in silico methods in the development of molecules acting in a GPCR with potential application in immunotherapy - an overview of the productive chain in Drug Design., BP.TT

Abstract

G-protein coupled receptors (GPCRs) are important pharmacological targets. Drugs that alter the activity of these receptors can have a therapeutic effect on several diseases, such as cardiovascular, psychological, and immunological diseases. Many drugs were created focusing on the modulation of specific GPCRs, blocking or stimulating their activity. In fact, around 35% of all FDA-approved drugs have a GPCR as the main target. This project focuses on advancing the development of small molecules identified by NAIAD as modulators of a GPCR highly specific for immune cells. Activation of the GPCR in question induces an anti-inflammatory phenotype in macrophages, while its blockade induces a pro-inflammatory phenotype in macrophages. Molecules that activate the GPCR in question have great potential in the treatment of autoimmune conditions, while those with the opposite effect have great potential for development as new immunotherapeutic drugs (first-in-class). There is currently a great demand for new and more effective therapies for immuno-oncology. The market in question should reach US$ 120 billion in 2026, and it is estimated that 1 in every five people alive will die as a result of some type of cancer. The objective here is the use of the computational platform developed at NAIAD, for the generation of small molecules with modulatory activity on the target in question, starting from small molecules already identified as modulators of this GPCR by the company's platform (hits). Our platform integrates classic structure based drug design techniques with deep learning techniques, in order to virtually screen and develop small molecules with high pharmacological potential, focusing on efficiency. The small molecules selected using NAIAD's platform will be synthesized and validated in vitro regarding their modulatory activity on the GPCR in question, and the best ones will be evaluated in vitro with regard to their selectivity. The IP assets to be developed with funding from this project, after being protected by patent, not only represent a high value-added asset to be potentially licensed and co-developed with large pharmaceutical companies but also, have the potential to generate new first-in-class drugs, with the potential to impact the quality of life of billions of people, as new immuno-oncological therapies. (AU)