Bisindolylmaleimides New Ligands of CaM Protein

Abstract

In the present study, we reported the interactions at the molecular level of a series of compounds called Bisindolylmaleimide, as potential inhibitors of the calmodulin protein. Bisindolylmaleimide compounds are drug prototypes derived from Staurosporine, an alkaloid with activity for cancer treatment. Bisindolylmaleimide compounds II, IV, VII, X, and XI, are proposed and reported as possible inhibitors of calmodulin protein for the first time. For the above, a biotechnological device was used (fluorescent biosensor hCaM M124C-mBBr) to directly determine binding parameters experimentally (Kd and stoichiometry) of these compounds, and molecular modeling tools (Docking, Molecular Dynamics, and Chemoinformatic Analysis) to carry out the theoretical studies and complement the experimental data. The results indicate that this compound binds to calmodulin with a Kd between 193–248 nM, an order of magnitude lower than most classic inhibitors. On the other hand, the theoretical studies support the experimental results, obtaining an acceptable correlation between the ΔGExperimental and ΔGTheoretical (r2 = 0.703) and providing us with complementary molecular details of the interaction between the calmodulin protein and the Bisindolylmaleimide series. Chemoinformatic analyzes bring certainty to Bisindolylmaleimide compounds to address clinical steps in drug development. Thus, these results make these compounds attractive to be considered as possible prototypes of new calmodulin protein inhibitors.

Bisindolyl Maleimides and Indolylmaleimide Derivatives—A Review of Their Synthesis and Bioactivity

“…Another example of new targets is the identification of BIMs as inhibitors of calmodulin protein [ 67 ]. In this study, standard BIM compound targets are summarised as in Table 1 , and it is noted that most bioassays are conducted where the reported effects could arise from interaction with more than one molecular target.…”

“…This has important considerations for the activity of BIMs in drug-resistant cells and should especially be considered for other BIMs in relation to the likelihood of cellular off-target effects [66]. Another example of new targets is the identification of BIMs as inhibitors of calmodulin protein [67]. In this study, standard BIM compound targets are summarised as in Table 1, and it is noted that most bioassays are conducted where the reported effects could arise from interaction with more than one molecular target.…”

“…In testing a series of BIMs binding to calmodulin, BIM II, IV, VII, X and XI were identified with nanomolar affinity and have the potential as the starting point of new calmodulin inhibitors. Another example of new targets is the identification of BIMs as inhibitors of calmodulin protein [67]. In this study, standard BIM compound targets are summarised as in Table 1, and it is noted that most bioassays are conducted where the reported effects could arise from interaction with more than one molecular target.…”

Inhibition of FGFR2 Signaling by Cynaroside Attenuates Liver Fibrosis

“…In the ligand-docking stage, the protein model and CYN structure were utilized to perform extra-precision (XP) docking, and the compound-protein complex with the lowest energy was selected as the most stable conformer. Binding free energy was calculated using specific algorithms [51][52][53]. MMGBSA was used to analyze bond properties with parameters including force field = OPLS4 and solvation model = VSGB.…”