Tuning the electronic effects in designing ligands for the inhibition of rotamase activity of FK506 binding protein

Abstract

FK506-binding protein (FKBP) is a cytosolic enzyme, which catalyzes the cis–trans isomerization of prolyl peptides. The twisted amide geometries assist the isomerization process and inhibit the rotamase activity of FKBP. This work reveals the role of electronic effects in ligands to facilitate the twisted amide geometries for efficient inhibition of the rotamase activity of FKBP12. The azirine ligand (5A) lowered the rotation barrier of –C–N amide bond by ~ 14.0 kcal/mol compared to the reference ligand molecule (1A) using M062X/cc-pVDZ//M062X/6-31G(d) level of theory. A significant lowering in rotation barrier has been achieved in (5A) due to the ring's anti-aromatic nature. The ring strain in the 1H-azirine ring pyramidalizes the amide bond's nitrogen center by 78° in the ground state compared to 1A. The natural bond orbital (NBO) analysis confirmed the lowering in the delocalization of electron density from nitrogen lone pair to π*C = O orbital in amide bonds. The designed models (1A-5A) were developed into ligands to mimic the binding domain of FK506 (1B-5B). The binding of these ligands (1B-5B) was examined with the quantum mechanics and molecular mechanics (QM/MM) ONIOM approach in the presence of FKBP12 binding site residues. The calculated results reveal the preferential binding of twisted amide forms with FKBP12 over their planar analogous. The hydrophobic interactions augment the binding affinity of the twisted forms with the FKBP12 binding site in agreement with the experimental observations. These studied ligands could act as potential inhibitors of FKBP12 for their therapeutic application.