Application of shape-based and pharmacophore-based in silico screens for identification of Type II protein kinase inhibitors

Abstract

The identification of new, potent and selective inhibitors of important protein kinase targets is a major goal of drug discovery. Here we analyze the crystal structures of 55 protein kinase complexes with Type II inhibitors and find they adopt a conserved twisted V-shape, with an angle of 121 ± 8° and twist of 78 ± 8°. The tightly conserved twist appears important in ensuring ligands curve around the protein backbone and towards the deep pocket. From this, we develop predictive pharmacophore- and shape-based screens to identify Type II inhibitors from a database which also contains Type I inhibitors as decoys. Both approaches exhibit a good level of discrimination for Type II molecules. The most effective pharmacophore model requires six features and three excluded volume regions. Shape-based screening using ROCS generally performs at least as well as pharmacophore approaches. There is only a moderate dependence of shape-based or pharmacophore-based screens on the underlying conformer generator (MOE, Macromodel, Omega and SPE), as well as on ligand linkage chemistry (amide and urea). Finally, we apply our approach to retrieval of Type II inhibitors from a modified version of the DUD database, containing over 104,000 compounds. We observe good enrichment, providing further evidence that the in silico screens developed here will constitute useful guides for identification of small molecule inhibitors targetting protein kinases in their inactive conformational state.

Conformational landscape and low lying excited states of imatinib

“…a As defined in [19] most stable conformers thus obtained, whose relative energies are less than the room temperature energy (0.592 kcal mol…”

“…The conformers with the sixth doublet as C− and C+ have a V-shape, [19], while the conformers having Table 2 Relative free energies and Boltzmann populations of the 20 most stable conformers of imatinib in gas-phase [B3LYP/6-31G(d) level of theory] and in water [PCM-B3LYP/6-31G(d) and PCM-B3LYP/6-31+G(d,p) levels of theory] at room temperature the sixth doublet T− and T+ are U-shaped (see Fig. 2 and Tables 1 and S1).…”

“…Based on quantum chemical methods, recent works have addressed the interaction of IMT with Abl TK or calixarenes aiming at clarifying its mechanism of action [17][18][19][20][21] or at designing suitable drug carriers for TKIs [15,22]. For such purposes, the accurate description of the three-dimensional (3D) arrangement and molecular properties of thermally accessible conformational states is crucial [9,10,18,19,21,[23][24][25].…”

“…For such purposes, the accurate description of the three-dimensional (3D) arrangement and molecular properties of thermally accessible conformational states is crucial [9,10,18,19,21,[23][24][25]. Furthermore, analysis of the possible conformers of a particular drug molecule is mandatory for describing its spectroscopical properties reliably [26][27][28][29][30][31].…”

“…From a spectroscopic point of view, IMT was studied previously by FT-IR and FT-Raman [33], NMR [34], mass spectrometry [35][36][37], HPLC [38][39][40][41][42][43], capillary electrophoresis [44,45] as well as by UV-vis in different solvents [17,32,33,[46][47][48]. Surprisingly, in spite of the importance of conformational space, to the best of our knowledge, only scarce data related to the conformers of IMT have been reported in the literature [19,23]. Due to its high flexibility, IMT is expected to adapt easily to different environments.…”