Repurposing Orlistatanaloges: A Ligand-Based Screening Approach using Morgan Fingerprints for Novel Therapeutic agents for Obesity

Obesity is a universal healthiness topic that necessitates the discovery of novel therapeutic agents. This research focuses on repurposing Orlistat analogs using a ligand-based screening approach with Morgan fingerprints to identify promising candidates for obesity treatment. Orlistat, a lipase inhibitor that reduces fat absorption, was selected as the primary ligand due to its established mechanism of action, clinical efficacy, and well-documented safety profile. A ligand screening process was conducted using the DrugRep platform, which evaluated several compounds based on binding scores and protein interactions. Among the screened compounds, chloramphenicol palmitate (DB14658) demonstrated the highest binding affinity (-7.5), interacting with key residues such as ASP36, TYR38, and ARG100 within the target protein’s binding pockets. The docking studies were further validated by PDB-REDO refinements, which improved the crystallographic model quality, reducing R and R-free values and enhancing the Ramachandran plot and rotamer normality. These improvements indicate better molecular geometry and protein-ligand interactions. The outcomespropose that chloramphenicol palmitate (DB14658) holds potential as a repurposed therapeutic agent for obesity due to its strong binding affinity and favourable interactions with target proteins. Additionally, the study highlights the viability of repurposing Orlistat analogs by optimizing their molecular structures for enhanced efficacy and minimized side effects. This ligand-based screening approach presents a promising strategy for developing novel anti-obesity drugs by repurposing well-characterised compounds.