Orlistat is the only pancreatic lipase (PL)-inhibitor approved by the FDA as an anti-obesity drug. It can form a covalent bond with Ser152, an important amino acid of the catalytic triad. In search of fragments that can covalently target the serine, many warheads, such as 1,2-diketone, a-keto ester, a-ketoamides, and fluorinated ketones, have been explored. To develop more selective and specific PL-inhibitors, we are aiming to obtain the structure of the PL (PDB ID: 1LPB), and perform structural preparation and minimization. Keeping previously self-synthesized covalent inhibitors as the standard FTrees platform will be used for similarity searching. Followed by FlexX screening, FastGrow, and MedChemesis in SeeSAR Inspirator mode, the Chemical Space will be explored. HYDE score and the docking score will be compared. After filtering the results by AMDE-properties provided by Optibrium, the hit molecule(s) will be considered for molecular dynamics, DFT calculations, and covalent docking.
Arijit intends to achieve the following milestones:
- To obtain the top molecules via HTVS
- To modify promosing candidate molecule(s) by Inspirator mode (Fast Grow, MedChemesis)
- To obtain lead molecule(s) as selective and specific pancreatic lipase inhibitor