Molecular modeling study of binding to the catalytic site of PDE4 enzymes by a novel class of inhibitors

Lawrenz, Morgan; Salter, E. Alan; Wierzbicki, Andrzej; Thompson, W. J.

doi:10.1002/qua.20716

Cited by 3 publications

(4 citation statements)

References 12 publications

(18 reference statements)

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“…Computational studies on PDEs have also been reported in the literature. − For example, molecular dynamics (MD) simulations and hybrid quantum mechanics/molecular mechanics (QM/MM) calculations have been employed to characterize the bridging ligand between the two metal ions and other structural problems in the PDE active site. ,,, Zagrovic et al have employed thermodynamic integration to study the binding affinities of several inhibitors toward PDE5. , …”

Section: Introductionmentioning

confidence: 99%

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

et al. 2010

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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.

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Section: Introductionmentioning

confidence: 99%

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

et al. 2010

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“…This is to attain the most stable conformations, and then saved as pdbqt files to be used for in silico study. Recently, several studies have been reported that the active site region of PDE4 enzyme is Tyr233, His234, Asp275, Asn283, Gln284, Glu304, Thr345, Met347, Asp392, Leu393, Asn395, Thr407, Gln433, Ile410, and Phe446 [32,35–38]. The docking approach [2,39] was performed by launching the PyRx—virtual screening software to compute the binding energy score (kcal/mol).…”

Section: Resultsmentioning

confidence: 99%

A search for antiinflammatory therapies: Synthesis, in silico investigation of the mode of action, and in vitro analyses of new quinazolin‐2,4‐dione derivatives targeting phosphodiesterase‐4 enzyme

Abdelmonsef

Abd-Elhakeem

Mosallam

et al. 2021

Journal of Heterocyclic Chem

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Inflammation is the response of the body's immune system to harmful stimuli. The expression of phosphodiesterase 4 enzyme (PDE4) was demonstrated in many inflammatory cells. Thus, it was considered an attractive therapeutic target for combating inflammatory disorders. In the present study, a novel class of quinazolin‐2,4‐dione analogues 1‐17a,b was synthesized. Structures of the newly synthesized compounds were characterized by means of spectral and elemental analysis. Additionally, molecular docking studies for the new synthetic compounds were performed using PyRx—virtual screening tool to demonstrate the possible binding pattern mode of interactions within the active site region of the PDE4 enzyme. The antiinflammatory activity of the synthesized compounds was also in vitro examined using inhibition of protein denaturation, anti‐proteinase effect, and membrane stabilization assay. The in silico docking studies revealed that the newly synthesized compounds were well accommodated by the active site region of the target protein through a network of noncovalent interactions such as hydrogen bonds and pi‐stacking, which contributed to the enhancement of affinity and stability between the compounds and the target protein. They exhibited better docking scores when compared with reference drugs diclofenac and coumarin. In addition, in vitro testing revealed that the compounds had moderate to good antiinflammatory effects. The biological study agreed with in silico approach, which revealed that the compounds had promising antiinflammatory activity. Hence, our detailed results can facilitate the rational drug design targeting PDE4 enzyme.

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“…10 There exists quite a few recent computational studies covering several important aspects of PDEs. 19,20,[35][36][37][38][39][40][41] For example, molecular dynamics (MD) simulations and hybrid quantum mechanics/molecular mechanics (QM/MM) calculations have been employed in characterizing the bridging ligand between the two metal ions in PDE. 19,20 Wierzbicki et al have also applied the QM/MM method to study the hydrolysis of cAMP in PDE4 37 and the cyclic nucleotide recognition in different PDEs by using truncated models derived from crystal structures.…”

Section: Introductionmentioning

confidence: 99%

“…There exists quite a few recent computational studies covering several important aspects of PDEs. ,,– For example, molecular dynamics (MD) simulations and hybrid quantum mechanics/molecular mechanics (QM/MM) calculations have been employed in characterizing the bridging ligand between the two metal ions in PDE. , Wierzbicki et al have also applied the QM/MM method to study the hydrolysis of cAMP in PDE4 and the cyclic nucleotide recognition in different PDEs by using truncated models derived from crystal structures. , Zagrovic et al have employed thermodynamic integration to study the binding affinities of several inhibitors toward PDE5 . More recently, Zhan et al have compared the binding affinities of several inhibitors toward PDE2 by using MD simulations and molecular mechanics/Poisson−Boltzmann surface area (MM/PBSA) methods .…”

Section: Introductionmentioning

confidence: 99%

A Substrate Selectivity and Inhibitor Design Lesson from the PDE10−cAMP Crystal Structure: A Computational Study

Lau

Cheng

2010

J. Phys. Chem. B

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Phosphodiesterases (PDEs) catalyze the hydrolysis of second messengers cAMP and cGMP in regulating many important cellular signals and have been recognized as important drug targets. Experimentally, a range of specificity/selectivity toward cAMP and cGMP is well-known for the individual PDE families. The study reported here reveals that PDEs might also exhibit selectivity toward conformations of the endogenous substrates cAMP and cGMP. Molecular dynamics simulations and free energy study have been applied to study the binding of the cAMP torsional conformers about the glycosyl bond in PDE10A2. The computational results elucidated that PDE10A2 is energetically more favorable in complex with the syn cAMP conformer (as reported in the crystal structure) and the binding of anti cAMP to PDE10A2 would lead to either a nonreactive configuration or significant perturbation on the catalytic pocket of the enzyme. This experimentally inaccessible information provides important molecular insights for the development of effective PDE10 ligands.

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Molecular modeling study of binding to the catalytic site of PDE4 enzymes by a novel class of inhibitors

Cited by 3 publications

References 12 publications

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

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

A search for antiinflammatory therapies: Synthesis, in silico investigation of the mode of action, and in vitro analyses of new quinazolin‐2,4‐dione derivatives targeting phosphodiesterase‐4 enzyme

A Substrate Selectivity and Inhibitor Design Lesson from the PDE10−cAMP Crystal Structure: A Computational Study

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