Exhaustive CoMFA and CoMSIA analyses around different chemical entities: a ligand-based study exploring the affinity and selectivity profiles of 5-HT_1A ligands

Figures & data

Figure 1. Chemical structure of the ligands BMY-7378, WAY-100635 and the related α₁-ADR and 5-HT_1A affinity values.

Table 1. Chemical structures of compounds 1–42 (Group A).

Table 2. Chemical structure of compounds 43–91 (Group B).

Figure 2. Schematic representation of the library members.

Figure 3. Distribution of the experimental-based weighted affinity and of the experimental ones of the dataset compounds.

Table 3. Summary of CoMFA and CoMSIA analyses calculated as Models I and II.

	Model I		Model II
	CoMFA	CoMSIA	CoMFA	CoMSIA
No. compounds	68	68	73	73
Optimal number of components (ONC)	7	6	6	6
Leave one out r^2 (r^2loo)	0.60	0.58	0.62	0.55
Cross-validated r^2 (r^2cv)	0.75	0.74	0.73	0.71
Std. error of estimate (SEE)	0.278	0.312	0.294	0.280
Non cross-validated r^2 (r^2ncv)	0.94	0.93	0.92	0.91
F-value	101.014	65.725	87.006	64.876
Steric contribution	0.678	0.173	0.644	0.175
Electrostatic contribution	0.322	0.139	0.356	0.155
H-bond acceptor contribution	–	0.213	–	0.214
H-bond donor contribution	–	0.117	–	0.104
Hydrophobicity contribution	–	0.358	–	0.352
Bootstrap r^2 (r^2boot)	0.97	0.95	0.94	0.93
Standard error of estimate r^2boot (SEE r^2boot)	0.268	0.271	0.250	0.280
Test set r^2 (r^2pred)	0.80	0.79	0.78	0.77

Figure 4. Distribution of the predicted weighted pK_i values (p-w. pK_i) with respect to the experimental-based pK_i (e-w. pK_i) of the training set compounds and of the test set compounds according to Model I CoMFA (a) and CoMSIA (b) analyses.

Figure 5. Distribution of the predicted pK_i values of training set compounds and of the test set compounds with respect to the experimental data according to Model II CoMFA (a) and CoMSIA (b) analyses.

Figure 6. Contour map of Model I CoMFA steric regions are shown around the compounds 12 and 39 (a) and 52, 67 (b) while those of the electrostatic map are shown in (c) and (d).

Figure 7. Model I CoMSIA hydrophobic favoured and disfavoured (white area) regions are shown around 12 and 39 (a) and 52, 67 (b). The compounds are displayed in ball and stick mode.

Chart 1. Contour maps of Model II CoMFA model steric and electrostatic regions are shown for Group A 19, 39 and Group B 53 cis, 67.

Chart 2. Contour maps of Model II CoMSIA model hydrophobic, H-bond acceptor and H-bond donor descriptors are shown. Compounds 19, 39 and 53 cis, 67 are depicted.

Chart 3. Superimpositions of the in-house derivative 63 cis and the external set compounds 93, 95 and 97 are depicted. The chemical structure and the 5-HT_1A affinity values for 92–97 are also shown.