Design, computational studies and synthesis of sulfonamide derivatives targeting DAGL-α enzyme for the treatment of obesity

The endocannabinoid system is a proven signaling pathway for appetite control, indirectly influencing the energy balance and therefore straight involved with obesity. An alternative for the modulation of this system would be sn-1-diacylglicerol lipase α inhibition, generating a signaling cannabinergic decrease and consequent orexia inhibition.1 Aiming to understand how substances with inhibitory activity towards the enzyme interact, the crystal structure of the PCL enzyme was obtained from PDB (PDB ID: 5CH8),2 considering there are no crystal structures available for DAGL-α. Thus, the rigid molecular docking was carried out between the constructed substances gathered from the scientific literature and the in silico model, where the interactions between the amino acid residues and the previously designed molecules were observed through careful analysis.3 After validation, the model was applied to the virtual screening of 8 novel compounds designed as inhibitors of DAGL-α, which were synthesized using methodologies described in the literature.