Hit identification of CK2 inhibitors by virtual screening

Abstract

Aim.To search for new CK2 inhibitors by virtual screening. Methods. Virtual screening of a small organic compounds library was performed by molecular docking using the Autodock 4.2.6 package and pharmacophore screening with the "PharmDeveloper" program. The compound activity was determined by in vitro biochemical tests using γ-P32 ATP. Results. 298 compounds were selected for biochemical testing according to the results of virtual screening. In vitro experiments showed that 18 compounds have inhibitory activity against CK2 with IC 50 in the range of 1.4 to 20 μM. The active compounds belonged to 15 chemical classes. Conclusions. A number of effective CK2 inhibitors were found using molecular modeling and biochemical testing methods. LE values of these compounds were higher than 0.3 that makes these compounds excellent candidates for further drug development. K e y w o r d s:CK2 protein kinase, molecular docking, pharmacophore modeling, virtual screening, in vitro testing.is the most pleiotropic kinase among the protein kinase superfamily [2]. One of the explanations of such a pleiotropy may be that CK2 is present in all compartments of the cell from the nuclear to the plasma membrane, where it can interact with a large number of substrates [3, 4]. Taking into account all these facts, it is not surprisingly that CK2 is involved

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“…The mentioned compounds did not affect the SMP responses to the application of the nicotinic cholinergic receptor agonist nicotine (used concentration 10 -6 M), supporting the hypothesis of the selective action of the tested substances specifically on muscarinic acetylcholine receptors [21]. It was also established that both compounds and the known non-selective inhibitor of muscarinic cholinergic receptors, ipratropium bromide (in all cases used at a concentration of 10 -6 M, with a pre-incubation duration of 10 minutes in the presence of the tested substance), could inhibit the contractions of SMP of the trachea activated by the selective M3 cholinergic receptor agonist cevimeline (fixed concentration of 10 -4 M).…”

“…The second is on the reverse, intracellular part, formed by transmembrane domains. The orthosteric site has better characteristics than the allosteric one (larger volume of 1013.7 Å 3 compared to 461.8 Å 3 for the allosteric site, aromatic factor of 0.15 compared to 0, and drug-like index (DLID) [21] of 1.35 compared to 0.13). After detailed analysis and determination of the parameters of these sites, the orthosteric site was chosen for docking studies.…”

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“…Grid-box has been built around binding pocket 1 (see figure 11) for organic atoms (C, O, N, P, Br, Cl, F, H, I, S) with resolution 0.186 Å. Other settings of the grid were published earlier [31]. Grid and docking parameter files with maps for docking are accessible in SI.…”