CP-MLR/PLS directed structure-activity study in modeling of the aggrecanase-1 inhibitory activity of biphenylsulfonamides

Abstract

The inhibition activity of biphenylsulfonamide derivatives on aggrecanase-1 was determined through quantitative analysis of molecular descriptors. The resulting models accounted for more than 83% of the variance in observed inhibition activity and were satisfactorily validated by test-set statistics. Molecular features such as mean square distance (MSD), polarizability weighted lag-1 (GATS1p), and electronegativity weighted lag-5 (GATS5e) were found to be crucial for receptor site interaction, along with the presence of an H attached to C0(sp3) with no heteroatom X attached at next C (H-046). Higher values of MSD, GATS5e, and H-046, coupled with lower values of GATS1p, improved a compound's activity profile. The partial least-squares (PLS) study revealed a "single window" structure-activity model using the most significant descriptors, with two optimum components explaining 84% of the variance in observed activity values. The applicability domain (AD) study confirmed the models' predictability, with all compounds except one outlier within the proposed model's AD. The AD analysis also identified one structurally influential compound.