Pharmacophore Modeling and Docking Studies on Some Nonpeptide-Based Caspase-3 Inhibitors

Abstract EN

Neurodegenerative disorders are major consequences of excessive apoptosis caused by a proteolytic enzyme known as caspase-3.

Therefore, caspase-3 inhibition has become a validated therapeutic approach for neurodegenerative disorders.

We performed pharmacophore modeling on some synthetic derivatives of caspase-3 inhibitors (pyrrolo[3,4-c]quinoline-1,3-diones) using PHASE 3.0.

This resulted in the common pharmacophore hypothesis AAHRR.6 which might be responsible for the biological activity: two aromatic rings (R) mainly in the quinoline nucleus, one hydrophobic (H) group (CH3), and two acceptor (A) groups (–C=O).

After identifying a valid hypothesis, we also developed an atom-based 3D-QSAR model applying the PLS algorithm.

The developed model was statistically robust (q2=0.53; pred_r2=0.80).

Additionally, we have performed molecular docking studies, cross-validated our results, and gained a deeper insight into its molecular recognition process.

Our developed model may serve as a query tool for future virtual screening and drug designing for this particular target.