Computational approach for the design of AP1867 analogs: aiming at new synthetic routes for potential immunosuppressant agents

Molecular modelling and synthetic arguments are valuable tools for the design of potential immunosuppressant agents. In this paper, eight proline-based compounds related to the AP1867 structure are studied and at least one of them is found to be a structurally good candidate for the inhibition of FKBP protein. Theoretical calculations were carried out to locate the most energetically favorable chemical substituent group relative to a core skeleton group on interaction with the FKBP binding cavity. Connolly accessible surface calculations have complemented the molecular mechanics and dynamics approaches. Calculated results were also analyzed on the basis of hydrogen bond interactions, relative energies of interaction, root-mean square deviations of amino acid residues of the crystallized protein, and orientation of the substituent groups within the active site. The results show a significant reduction in the relative interaction energies and very good shape complementarities between our final analog compound and the FKBP binding pocket.