Exploring binding site of human RBP4 towards discovery of novel inhibitor for treatment of cardiovascular diseases

Abstract Retinol binding proteins (RBPs) are transport proteins that act by solubilizing and protecting their labile ligands in aqueous spaces. In addition, RBPs have diverse and specific functions in regulating the disposition, metabolism and activities of retinoids. Elevated levels of retinol-binding protein 4 (RBP4) are observed in cardiovascular disease conditions, which prompts it as a potential drug target. Therefore, computational approach methods were implemented herein to design a novel inhibitor for RBP4. Crystal structure (2wq9) of RBP4 was retrieved and investigated to locate retinol binding site residues (Lys29, Pro32, Leu35, Phe36, Leu37, Phe45, Ala55, Ala57, Met73, Val74, Gly75, Met88, Try90, His104, Gln117, Arg121, Try133, Phe135, Phe137). Five existing inhibitors of RBP4 were explored against more than one million entries of the Ligand.Info metadatabase to create an in-house library of 2000 compounds. A ligand dataset was prepared using LigPrep and filtered based on Lipinski’s rule of five and reactive group constraints. The crystal structure was optimized and energy minimized applying OPLS force field in Maestro v9.2. Thirteen leads were found to have good binding affinity towards RBP4 through virtual screening workflow of Maestro. Lead 1, namely equilenin (-12.87 kcal/mol) which showed better XPG score was proposed as a potential RBP4 inhibitor. Analysis of docking complexes for the proposed lead revealed a stable hydrogen bond network with good van der Waal interactions and binding orientations. Thus, equilenin would be useful for developing potential drug molecules for cardiovascular diseases.