Molecular modeling studies of the Penicillium Camembertti Lipase (PCL) enzyme: Docking and validation of bioactive compounds

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. 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). To analyze similarities between crystallographic structure of PCL and DAGL-α, the primary sequence of DAGL- α was obtained through the NCBI proteomic server and after identifying the best correlation between the amino acid residues using the Swiss Model server, it was found that a high structural similarity and the preservation of the catalytic residues could be observed. In parallel, substances with high inhibitory activity against DAGL-α were gathered, as it can be observed for the sulfonamides 1 and 23 (Figure 1). The rigid molecular docking was carried out between the constructed substances and the in silico model, where the interactions between the amino acid residues and the previously designed molecules were observed through careful analysis. From these interactions, were frequently observed the residues R87, V86, K270, D267 also S145 (3), which can be used as markers for future virtual screening of novel compounds.