CHK1 kinase inhibition: identification of allosteric hits using MD simulations, pharmacophore modeling, docking and MM-PBSA calculations.

The CHK1 kinase plays a pivotal role in the DNA damage response pathway. Hence, inhibition of CHK1 appeared as a promising strategy to overcome the resistance problem of chemotherapeutic agents resulting from the overexpression of CHK1 that enables cancerous cells to repair their chemotherapy-induced DNA damage. In this study, different computational drug design techniques were employed to identify new CHK1 inhibitors targeting its allosteric pocket. A 1 μs MD simulation of the apo form of the enzyme was run to study its native dynamics. The resulting trajectory was analyzed to select a frame where the ATP binding pocket is most occluded while its allosteric counterpart is most exposed to be used in the design of potential allosteric inhibitors that could trap the enzyme in such nearly inactive state. Besides the selected frame, another three crystal structures of CHK1 complexed with allosteric inhibitors were utilized to generate structure-based pharmacophore models. Seven pharmacophores were generated and utilized in virtual screening of different databases. The retrieved hits were filtered and then docked into the allosteric pocket. Finally, the binding energies of the top-ranked docked hits were calculated. Twenty compounds were selected as candidates for biological evaluation against CHK1 enzyme. The biological screening results showed moderate activities where the percentage of CHK1 inhibition ranged from zero to 28.26%. Four of the tested compounds showed percentage of CHK1 inhibition greater than 20%, of which, two compounds were identified as allosteric hits that upon further optimization could be converted into lead-like compounds.