Abstract
The MMP-13 inhibition activity of non-zinc-chelating compounds has been quantitatively analyzed in terms of chemometric descriptors. The statistically validated quantitative structure-activity relationship (QSAR) models provided rationales to explain the inhibition activity of these compounds. The descriptors, identified through combinatorial protocol in multiple linear regression (CP-MLR) analysis, have highlighted the role of 3-path Kier alpha-modified shape index (S3K), complementary information content index of 1-order neighborhood symmetry (CIC1), eigenvalue sum from mass weighted distance matrix (SEigm), lowest eigenvalue n. 6 of Burden matrix / weighted by atomic van der Waals volumes (BELv6) and by atomic polarizabilities (BELp6), 3-order topological charge index (GGI3) and the functionality, R--CR--R (C-025). From statistically validated models, it appeared that the descriptors S3K, BELv6, BELp6 and SEigm make positive contribution to activity and their higher values are conducive in improving the MMP- 13 inhibition activity of a compound. On the other hand, the descriptors CIC1, GGI3 and C-025 render detrimental effects to activity. Therefore, the absence of functionality, R--CR--R and lower values of descriptors CIC1 and GGI3 would be advantageous. PLS analysis has further corroborated the dominance of the CP-MLR identified descriptors. Applicability domain analysis revealed that the suggested models have acceptable predictability. All the compounds are within the applicability domain of the proposed models and were evaluated correctly.
Highlights
The matrix metalloproteinases (MMPs), a family of more than 27 zinc- and calcium-containing enzymes, are involved in the degradation of extracellular matrix and tissue remodeling [1,2,3]
The preliminary assessment of complete data-set suggested that the lone compound 25, having a methyl group at R2 remained as an ‘outlier’
The MMP-13 inhibition activity of non-zinc-chelating compounds has been quantitatively analyzed in terms of chemometric descriptors
Summary
The matrix metalloproteinases (MMPs), a family of more than 27 zinc- and calcium-containing enzymes, are involved in the degradation of extracellular matrix and tissue remodeling [1,2,3]. It was suggested that MSS is caused by the inhibition of normal extracellular matrix turnover due to inhibition of other MMPs rather than MMP-13 [16,17,18,19,20,21]. At present, it is unclear which MMP isoforms may be involved [22] and to what extent they contribute to MSS. Selective inhibition of MMP-13, devoid of MSS, may prove to be better therapeutic research area
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