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Functional screening and optimization of molecules acting on the oxytocin receptor with a focus on therapeutic applications


The oxytocin receptor (OXTR) is a G protein-coupled receptor (GPCR) involved in the modulation of various signaling biological processes. Although its function was initially linked only to its role in the induction of labor and breastfeeding, its role in several other processes has recently been raised, specifically with regard to its potential use as a pharmacological target. OXTR agonists have been identified as potentially useful in the treatment of neurological and psychiatric conditions and diseases (chemical dependence, autism, dementia and others), in addition to conditions related to food and metabolism. OXTR antagonists have been touted as potentially useful in the treatment of prostatic hyperplasia, increased success rates of assisted fertilization, erectile dysfunction, and more recently, cancer subtypes for which treatments are only partially effective. Given that currently only peptide modulators of OXTR are approved for clinical use, the half-life of such compounds prevents them from being used in therapy beyond induction/inhibition of labor and induction of breastfeeding. This project aims to optimize new small molecules acting on OXTR (already developed by NAIAD through FAPESP/PIPE Phase 1 funding 2018/22551-2) and the search for new chemical classes acting on OXTR with different effects (agonism, biased agonism and antagonism). NAIAD's structure-based virtual screening platform based on AI and molecular docking will be used in conjunction with in silico techniques for ADMET prediction and other computer simulation and chemical optimization techniques to efficiently explore a chemical space of billions of molecules in the search and optimization of molecules with adequate pharmacological properties acting on OXTR. The molecules will be synthesized and validated in in vitro tests regarding their effect on OXTR and their ADMET properties in computational chemical search and optimization cycles followed by in vitro validation. Here, it is expected to obtain molecules with high pharmacological potential, sufficient to be tested in animal models for the conditions selected among those mentioned above, and subsequently to be followed by clinical tests and clinical use. It is worth noting that among the conditions and diseases potentially treatable by new small molecules acting on OXTR, several do not have sufficient treatment approved for clinical use today. (AU)

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