115 research outputs found
Thalidomide increases both intra-tumoural tumour necrosis factor-α production and anti-tumour activity in response to 5,6-dimethylxanthenone-4-acetic acid
Quinazoline-based α1-adrenoceptor antagonists induce prostate cancer cell apoptosis via TGF-β signalling and IκBα induction
Clinical aspects of a phase I trial of 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a novel antivascular agent
Energetics of Displacing Water Molecules from Protein Binding Sites: Consequences for Ligand Optimization
A strategy in drug design is to consider enhancing the affinity of lead molecules with structural modifications that displace water molecules from a protein binding site. Because success of the approach is uncertain, clarification of the associated energetics was sought in cases where similar structural modifications yield qualitatively different outcomes. Specifically, free energy perturbation calculations were carried out in the context of Monte Carlo statistical mechanics simulations to investigate ligand series that feature displacement of ordered water molecules in the binding sites of scytalone dehydratase, p38-αMAP kinase, and EGFR kinase. The change in affinity for a ligand modification is found to correlate with the ease of displacement of the ordered water molecule. However, as in the EGFR example, the binding affinity may diminish if the free energy increase due to the removal of the bound water molecule is not more than compensated by the additional interactions of the water-displacing moiety. For accurate computation of the effects of ligand modifications, a complete thermodynamic analysis is shown to be needed. It requires identification of the location of water molecules in the protein-ligand interface and evaluation of the free energy changes associated with their removal and with the introduction of the ligand modification. Direct modification of the ligand in free-energy calculations is likely to trap the ordered molecule and provide misleading guidance for lead optimization
Mapping the Binding Site of a Large Set of Quinazoline Type EGF-R Inhibitors Using Molecular Field Analyses and Molecular Docking Studies
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Effects of acutely inhibiting PI3K isoforms and mTOR on regulation of glucose metabolism in vivo
3D-QSAR and Receptor Modeling of Tyrosine Kinase Inhibitors with Flexible Atom Receptor Model (FLARM)
Structure−Activity Relationships for Acridine-Substituted Analogues of the Mixed Topoisomerase I/II Inhibitor N
Tyrosine Kinase Inhibitors. 12. Synthesis and Structure−Activity Relationships for 6-Substituted 4-(Phenylamino)pyrimido[5,4- d
Use of a Pharmacophore Model for the Design of EGFR Tyrosine Kinase Inhibitors: Isoflavones and 3-Phenyl-4(1 H
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