QSAR Rationale of Matrix Metalloproteinase Inhibition Activity in a Class of Carboxylic Acid Based Compounds.
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2013-10
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Abstract
The matrix metalloproteinase-13 (MMP-13) inhibitory activities of carboxylic acid based
compounds, in presence and absence of bovine serum albumin (BSA), have been
analyzed quantitatively in terms of chemometric descriptors. The statistically validated
quantitative structure-activity relationship (QSAR) models obtained through combinatorial
protocol in multiple linear regression (CP-MLR) analysis and the participated descriptors
in these models provided rationales to explain the inhibitory activities of these congeners.
For MMP-13 inhibition activity, the identified descriptors (BEHm1, BELm1 and BEHm8)
have highlighted the role of the atomic mass in terms of the highest and lowest
eigenvalues derived from Burden matrix. The positive correlation with activity suggested
that their higher values are desirable in improving the activity of a compound. Additionally,
the descriptor C-027 representing R-CH-X type fragment in a molecular structure
advocates the absence of such type of fragment for the improved activity. On the other
hand presence of RCO-N< or >N-X=X type fragment (descriptor N-072) would be
beneficiary to the MMP-13 inhibitory activity.
The structural features, rationalized by the descriptors MSD (Balaban’s mean square distance index), nCrHR (number of ring tertiary C (sp3), H-047 (H attached to
C1(sp3)/C0(sp2)) and H-050 (H attached to heteroatom) have imparted positive impact on
the MMP-13 w/BSA inhibition activity. The atomic properties such as atomic polarizability
and atomic Sanderson’s electronegativity have shown their positive impact on the activity
via descriptors BELp4 and GATS3e in respective eigenvalues or lag. The other
descriptors, MATS1m and MATS3e, have revealed the negative influence of atomic mass
and electronegativity on the of MMP-13 w/BSA inhibition activity. The results obtained
from CP-MLR analysis have been supported further through partial least-squares (PLS)
study.
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Keywords
Matrix metalloproteinase inhibitors, carboxylic acid based compounds, chemometric descriptors, combinatorial protocol in multiple linear regression, (CP-MLR) analysis, QSAR
Citation
Sharma B K, Singh P, Prabhakar Y S. QSAR Rationale of Matrix Metalloproteinase Inhibition Activity in a Class of Carboxylic Acid Based Compounds. British Journal of Pharmaceutical Research. 2013 Oct; 3(4): 697-721.