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Varnavas D. Mouchlis Thomas M. Mavromoustakos George Kokotos 《Journal of computer-aided molecular design》2010,24(2):107-115
Docking calculations that allow the estimation of the binding energy of small ligands in the GIIA sPLA2 active site were used in a structure-based design protocol. Four GIIA sPLA2 inhibitors co-crystallised with the enzyme, were used for examining the enzyme active site and for testing the FlexX in SYBYL
6.8 molecular docking program to reproduce the crystallographic experimental data. The FPL67047XX inhibitor was chosen as
a prototype structure for applying free energy perturbation (FEP) studies. Structural modifications of the initial structure
of the FPL67047XX inhibitor (IC50 0.013 μM) were performed in an effort to optimise the interactions in the GIIA sPLA2 active site. The structural modifications were based on: (1) the exploration of absolute configuration (i.e. comparison of
the binding score of (R)- and (S)-enantiomers); (2) bioisosterism (i.e. replacement of the carboxylate group with the bioisosteric sulphonate and phosphonate
groups); (3) insertion of substituents that fit better in the active site. The generated new structures exhibited higher binding
energy. Such structures may spark off the interest of medicinal chemists for synthesizing potentially more active GIIA sPLA2 inhibitors. 相似文献
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Mouchlis VD Michopoulou V Constantinou-Kokotou V Mavromoustakos T Dennis EA Kokotos G 《Journal of chemical information and modeling》2012,52(1):243-254
The group IVA cytosolic phospholipase A(2) (GIVA cPLA(2)) plays a central role in inflammation. Long chain 2-oxoamides constitute a class of potent GIVA cPLA(2) inhibitors that exhibit potent in vivo anti-inflammatory and analgesic activity. We have now gained insight into the binding of 2-oxoamide inhibitors in the GIVA cPLA(2) active site through a combination of molecular docking calculations and molecular dynamics simulations. Recently, the location of the 2-oxoamide inhibitor AX007 within the active site of the GIVA cPLA(2) was determined using a combination of deuterium exchange mass spectrometry followed by molecular dynamics simulations. After the optimization of the AX007-GIVA cPLA(2) complex using the docking algorithm Surflex-Dock, a series of additional 2-oxoamide inhibitors have been docked in the enzyme active site. The calculated binding affinity presents a good statistical correlation with the experimental inhibitory activity (r(2) = 0.76, N = 11). A molecular dynamics simulation of the docking complex of the most active compound has revealed persistent interactions of the inhibitor with the enzyme active site and proves the stability of the docking complex and the validity of the binding suggested by the docking calculations. The combination of molecular docking calculations and molecular dynamics simulations is useful in defining the binding of small-molecule inhibitors and provides a valuable tool for the design of new compounds with improved inhibitory activity against GIVA cPLA(2). 相似文献
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Mouchlis VD Melagraki G Mavromoustakos T Kollias G Afantitis A 《Journal of chemical information and modeling》2012,52(3):711-723
Molecular docking, classification techniques, and 3D-QSAR CoMSIA were combined in a multistep framework with the ultimate goal of identifying potent pyrimidine-urea inhibitors of TNF-α production. Using the crystal structure of p38α, all the compounds were docked into the enzyme active site. The docking pose of each compound was subsequently used in a receptor-based alignment for the generation of the CoMSIA fields. "Active" and "inactive" compounds were used to build a Random Tree classification model using the docking score and the CoMSIA fields as input parameters. Domain of applicability indicated the compounds for which activity estimations can be accepted with confidence. For the active compounds, a 3D-QSAR CoMSIA model was subsequently built to accurately estimate the IC(50) values. This novel multistep framework gives insight into the structural characteristics that affect the binding and the inhibitory activity of these analogues on p38α MAP kinase, and it can be extended to other classes of small-molecule inhibitors. In addition, the simplicity of the proposed approach provides expansion to its applicability such as in virtual screening procedures. 相似文献
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Tzoupis H Leonis G Durdagi S Mouchlis V Mavromoustakos T Papadopoulos MG 《Journal of computer-aided molecular design》2011,25(10):959-976
The objectives of this study include the design of a series of novel fullerene-based inhibitors for HIV-1 protease (HIV-1
PR), by employing two strategies that can also be applied to the design of inhibitors for any other target. Additionally,
the interactions which contribute to the observed exceptionally high binding free energies were analyzed. In particular, we
investigated: (1) hydrogen bonding (H-bond) interactions between specific fullerene derivatives and the protease, (2) the
regions of HIV-1 PR that play a significant role in binding, (3) protease changes upon binding and (4) various contributions
to the binding free energy, in order to identify the most significant of them. This study has been performed by employing
a docking technique, two 3D-QSAR models, molecular dynamics (MD) simulations and the molecular mechanics Poisson–Boltzmann
surface area (MM–PBSA) method. Our computed binding free energies are in satisfactory agreement with the experimental results.
The suitability of specific fullerene derivatives as drug candidates was further enhanced, after ADMET (absorption, distribution,
metabolism, excretion and toxicity) properties have been estimated to be promising. The outcomes of this study revealed important
protein–ligand interaction patterns that may lead towards the development of novel, potent HIV-1 PR inhibitors. 相似文献
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