Design and synthesis of potent, orally bioavailable dihydroquinazolinone inhibitors of p38 MAP kinase

Protein Flexibility in Ligand Docking and Virtual Screening to Protein Kinases

“…The following groups were regarded as charged: staurosporine amino group, 44 nitrogen atoms of terminal amino substituents in isoquinolinesulfonamide derivative inhibitors H7, H8 and H89, 45 the guanidine ring of hymenialdisine, 46 the adenine-derived compound H717 amino group at its diaminocyclohexane substituent at C2, 47 nitrogen in the cyclohexyl amine group of compound SB220025, piperidine nitrogen in dyhydroquinazoline derivative (PDB code dqo). 48 Each ligand was then assigned the MMFF atom types and charges, 49 and subjected to a global energy optimization using the ICM stochastic optimization algorithm. 50 A random database of compounds was generated using every 272nd molecule of the Diverse Set database of ChemBridge (ChemBridge, Inc., San Diego, CA) consisting of 272,938 compounds.…”

Computational Sampling of a Cryptic Drug Binding Site in a Protein Receptor: Explicit Solvent Molecular Dynamics and Inhibitor Docking to p38 MAP Kinase

“…Two of the selected inhibitors, a simple diaryl urea inhibitor and BIRB796, bind crystallographically to the DFG-out conformation. 3,8 The remaining three ligands, a pyridinylimidazole inhibitor, 12 a dihydroquinazolinone inhibitor, 13 and a 4-azaindole inhibitor, 14 all bind crystallographically to the ATP binding pocket, with the DFG motif in its more usual DFG-in conformation.…”

“…Five inhibitors that have been solved crystallographically in complex with p38 were selected for study: a simple diaryl urea inhibitor (PDB code 1KV1), 3 BIRB796 (1KV2), 3 a pyridinylimidazole inhibitor (1A9U), 12 a dihydroquinazolinone inhibitor (1M7Q), 13 and a 4-azaindole inhibitor (1OZ1). 14 In order to test whether structures sampled during the MD simulations were competent to bind any of these inhibitors, docking calculations were performed for each inhibitor with 5000 structural snapshots sampled at 10 ps intervals from the first 50 ns of one production MD trajectory (simulation A; see Results).…”

Outliers in SAR and QSAR: 2. Is a flexible binding site a possible source of outliers?

“…Example 2: Pyrimidinone, dihydroquinazolinone, dihydroquinolinone, and phenylpyrazolylphenylmethanone analogs as p38a MAP kinase inhibitors Sullivan et al [18], Stelmach et al [19] and Fitzgerald et al [20] reported the X-ray crystal structures of pyrimidinone, dihydroquinazolinone, and dihydroquinolinone Table 3. The quality of these X-ray structures is reasonable and similar to one another.…”