Computational Determination of Binding Structures and Free Energies of Phosphodiesterase-2 with Benzo[1,4]diazepin-2-one Derivatives

Abstract

Phosphodiesterase-2 (PDE2) is a key enzyme catalyzing hydrolysis of both cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) that serve as intracellular second messengers. PDE2 has been recognized as an attractive drug target, and selective inhibitors of PDE2 are expected to be promising candidates for the memory enhancer, anti-depressant, and anxiolytic agent. In the present study, we examined the detailed binding structures and free energies for PDE2 interacting with a promising series of inhibitors, i.e. benzo[1,4]diazepin-2-one derivatives, by carrying out molecular docking, molecular dynamics (MD) simulations, binding free energy calculations, and binding energy decompositions. The computational results provide valuable insights into the detailed enzyme-inhibitor binding modes including important intermolecular interactions, e.g. the π-π stacking interactions with the common benzo[1,4]diazepin-2-one scaffold of the inhibitors, hydrogen bonding and hydrophobic interactions with the substituents on the benzo[1,4]diazepin-2-one scaffold. Future rational design of new, more potent inhibitors of PDE2 should carefully account for all of these favorable intermolecular interactions. By use of the MD-simulated binding structures, the calculated binding free energies are in good agreement with the experimental activity data for all of the examined benzo[1,4]diazepin-2-one derivatives. The enzyme-inhibitor binding modes determined and the agreement between the calculated and experimental results are expected to be valuable for future rational design of more potent inhibitors of PDE2.

Computational Approaches in the Development of Phosphodiesterase Inhibitors

“…The estimated PDE2A-inhibitor binding paterns and the agreement between theoretical and experimental outcomes provided a irm base for further design of new, selective, and more potent PDE2A inhibitors [57].…”

“…Bo Yang and coworkers examined the binding structures and free energies for PDE2 and benzo [1,4]diazepin-2-one derivatives (PDE2 inhibitors) by combining the molecular docking, molecular dynamics (MD), calculations of binding free energy, and binding energy decompositions [57,58]. Molecular docking was performed followed by energy minimization.…”

Exhaustive search and solvated interaction energy (SIE) for virtual screening and affinity prediction

“…The SIE function has also been applied retrospectively as well as prospectively in several other independent laboratories that have reported SIE predictions versus actual binding affinities [18][19][20][21][22][23][24][25][26][27][28][29][30][31]. Collectively, these data indicate an MUE of 1.30 kcal/mol and an r 2 of 0.47 between the predicted and actual absolute binding affinities (Fig.…”

“…Calibration of several physical parameters, including the dielectric constant, Born radii, surface tension coefficient, and enthalpy-entropy compensation scaling factor, was based on a diverse dataset of 99 protein-ligand complexes [15]. The SIE scoring function parametrized in this manner achieves a reasonable transferability across a wide variety of protein-ligand systems, consistently returning absolute binding affinities within the experimental range, as demonstrated by test cases published in the literature [18][19][20][21][22][23][24][25][26][27][28][29][30][31]. External testing of the standard SIE parametrization in the CSAR-2010 scoring challenge consisting in a curated dataset of 343 protein-ligand complexes diverse with respect to ligands and targets [32,33], afforded binding affinity predictions with a mean-unsigned-error (MUE) of about 2 kcal/mol [34].…”

Binding sensitivity of adefovir to the polymerase from different genotypes of HBV: molecular modeling, docking and dynamics simulation studies

“…The LCPO method [46] was used to estimate the non-polar contribution as follows: ΔG SA =0.0072·Δ SASA , where a probe radium of 1.4 Å was set for the SASA (solvent-accessible surface area) calculation [35] . Because of the high computational demand for large molecules, such as proteins, and the rough estimate of the entropic contribution (-TΔS) [47,48] and because we are comparing the relative binding affinities of two similar systems (ie, HBV polymerase genotypes B and C complexed with the same inhibitor, ADV-DP), the entropic contribution of both systems is disregarded in this study. The energy difference between the two systems (ΔΔG C-B ) is as follows:…”