Many publicly available databases, such as ChEMBL, [14] BindingDB, [15] DrugBank, [16] PubChem, [17] KiBank, [18] the PDSP Ki Database, [19] ChemProt-2.0 [20] and PDBbind [21] and commercial products including WOMBAT [22] and MDDR, [23] contain either specific assay data for the binding of compounds with targets, or associations of molecules with pharmacological properties.
These efforts resulted in a hybrid compound with target potency increased by a 1000-fold, while maintaining selectivity against selected protein kinases and an improved level of solubility and protein binding.
Furthermore, molecular docking studies have been carried out for the compounds 1 5 with target protein CHK1.
A total of 223 targets were retained for 35 compounds, with 99 targets belonging to Salvia miltiorrhizae, 143 targets to Panax notoginseng and 17 targets to Borneolum.
Subsequent exclusion of compounds with off target effects such as outer- or inner membrane permeabilization identified compounds 7c, 7g, 12c, 12i and 13g as efflux pump inhibitors (EPIs).
The in silico molecular docking study demonstrated strong binding affinity of the compounds with the target enzymes (InhA, CYP121 and TMPK) of M. tuberculosis.
The molecular docking studies were conducted in order to get insight the binding pattern and extent of binding of compounds with the target enzymes.
In this work, a matrix-based method [1] is used to transform the original data space of chemical compounds into an alternative space where compounds with different target properties can be better separated.
Our results show the utility of combining focused small molecule derivation, applied to a biological screen using the zebrafish model, to identify new compounds with desired target activity and specificity.
