Abstract

Background: Mcl-1 is a kind of antiapoptotic protein and its overexpression is closely related to the occurrence of cancer. Aryl sulfonamide derivatives are expected to become new anticancer agents due to their high inhibitory activity on the Mcl-1 protein.

Objective: The study aimed to establish the QSAR model with good prediction ability and elaborate the influence of structure and chirality on the inhibitory activity.

Methods: Multiple QSAR models were built with different types of descriptors and modeling methods. The molecular docking was performed on compounds 45, 25, 26, 24R, and 24S. The MCCV method was used to perform rigorous validations with up to 216 = 65,536 samplings for MLR, SVM, LSSVM, RF, and GP methods based on the model of 2D and 3D combined descriptors.

Results: The comprehensive models including 2D and 3D descriptors demonstrated that nonlinear LSSVM and GP methods gave better results (R2>0.94, RCV2>0.86). The training set had a good predictive power on the test set. The predictive performances of MCCV tests are basically coincident with the results of the single test set. The results of molecular docking showed that the hydrogen bond acceptor at the appropriate position of the substituent on the chiral center can form the hydrogen bond interaction with residue ASN260, which results in the stronger interaction between ligand and protein and higher inhibitory activity. The interaction differences between R and S configuration with Mcl-1 protein are mainly attributed to two residues, HIS224 and ASN260. Two opposite effects lead to the activity of R enantiomer slightly higher than that of S one. The results on chiral compound 24 with ambiguous absolute configuration demonstrated that the steric effect of the substituents on chiral carbon atom is crucial. When there are two substituents with big volume at the same time, high steric effect will prevent the binding of the substituent and the protein, which results in the low inhibitory activity.

Conclusion: The study may provide theoretical guidance on the design and synthesis of novel aryl sulfonamide derivatives with high inhibitory activity.