Deep Learning-Enabled Screening Of Ultra-Large Libraries To Identify Glycogen Synthase Kinase 3 Beta -Dopamine D3 Receptor Dual-Target-Directed Ligands
Given the complex and mul2factorial nature of bipolar disorder (BD), single-target treatments have typically provided limited symptom relief without disease-modifying benefits. To address these challenges, we recently reported two series of mul2target-directed ligands that act as par2al agonists at the dopamine D3 receptor (D3R) and inhibitors of glycogen synthase kinase 3 beta (GSK-3β). Despite being structurally dis2nct, these targets both independently contribute to cogni2on and mood regula2on. Among our findings, several compounds showed significant promise as mul2target-directed ligands, demonstra2ng nanomolar efficacy at D3R and lowmicromolar inhibi2on of GSK-3β, thus preliminarily suppor2ng the feasibility of our approach (Di Mar2no et al., ChemMedChem 2020). However, these compounds, by design, closely resemble known single-target modulators of the two targets. While star2ng from independently validated targets associated with a disease and building on structures annotated for ac2vity at those targets are both effec2ve strategies for quickly obtaining ac2ve dualtarget compounds, this approach limits the structural novelty typically achievable (Lembo and BoTegoni, J Med Chem 2024). This project aims to iden2fy dual-target-directed ligands (DTDLs) ac2ve at D3R and GSK-3β that feature novel structures, dis2nct from known single-target compounds. To accomplish this, we will u2lize a protocol for virtual screening of ultra-large chemical libraries, enhanced by deep learning techniques.
Objectives
1) Develop predic2ve models using Chemprop to iden2fy poten2al DTDLs targe2ng GSK-3β and D3R.
2) Perform virtual screening of the Enamine Real Diversity set, consis2ng of 48.2 million compounds.
3) Select and experimentally validate top-ranked compounds as poten2al therapeu2c agents for BD.
Importo totale UniUrb: 4.771 £
Periodo: 21/11/2024 - 20/11/2025
Struttura UniUrb di riferimento: Dipartimento Scienze Biomolecolari (DISB)
Referente UniUrb: Prof. Giovanni Bottegoni
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