Backgound: Exploring potent compounds is critical to generating multi-target drug discovery.
Hematin crystallization is an important mechanism of malaria.
Methods: A series of chloroquine analogues were designed using a repositioning approach to develop
new anticancer compounds. Protein-ligand interaction fingerprints and ADMET descriptors were used to
assess docking performance in virtual screenings to design chloroquine hybrid β-hematin inhibitors. A
PLS algorithm was applied to correlate the molecular descriptors to IC50 values. The modeling presented
excellent predictive power with correlation coefficients for calibration and cross-validation of r2 = 0.93
and q2 = 0.72. Using the model, a series of 4-aminoquinlin hybrids were synthesized and evaluated for
their biological activity as an external test series. These compounds were evaluated for cytotoxic cell
lines and β-hematin inhibition.
Results: The target compounds exhibited high β-hematin inhibition activity and were 3-9 times more
active than the positive control. Furthermore, all the compounds exhibited moderate to high cytotoxic
activity. The most potent compound in the dataset was docked with hemoglobin and its pharmacophore
features were generated. These features were used as input to the Pharmit server for screening of six databases.
Conclusion: The compound with the best score from ChEMBL was 2016904, previously reported as a
VEGFR-2 inhibitor. The 11 compounds selected presented the best Gold scores with drug-like properties
and can be used for drug development.