Pharmacophore modeling and docking studies on some nonpeptide-based caspase-3 inhibitors

Abstract

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.

Figure 1

Common pharmacophore hypothesis and distances between pharmacophoric sites. Pink spheres with arrows show hydrogen-bond acceptor with lone pairs of electron. Green sphere shows hydrophobe, and yellow rings show ring aromatics.

Figure 2

Plot between observed and predicted biological activities of the training set of compounds.

Figure 3

Plot between observed and predicted biological activities of the test set of compounds.

Figure 4

Pictorial representation of cubes for the most active (compound 58) and the least active (compound 6b) compounds where blue and red cubes show favorable and unfavorable regions for activity.

Figure 5

Binding interactions of compound 49 at the active site where the docked ligand is green in color. Hydrogen bonds are expressed as dotted lines in purple color, and active site residues are demonstrated in orange color.

Figure 6

Binding interactions of compound 58 at the active site where the docked ligand is green in color. Hydrogen bonds are expressed as dotted lines in purple color, and active site residues are demonstrated in orange color.

Figure 7

Superposition of compounds 49 and 58 on common pharmacophore hypothesis.

Figure 8

Superposition of pharmacophore hypothesis on docked ligand [compound 58 (X₁)] at the binding site where the docked ligand is in red color. Hydrogen bonds are expressed in yellow color, and amino acids are expressed in their standard form (H = histidine, C = cysteine, S = serine, R = arginine, W = tryptophan, Y = tyrosine, D = aspartic acid, F = phenylalanine, and E = glutamic acid).