Binding affinities for sulfonamide inhibitors with matrix metalloproteinase-2 using a linear response method

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Structural Biology

Background:

• Matrix metalloproteinases (MMPs) are implicated in various pathological conditions, making them attractive therapeutic targets.
• MMP-2, specifically, plays a crucial role in tumor progression and metastasis.
• Previous work by Feng et al. provided the solution structure of the MMP-2 catalytic domain with a hydroxamic acid inhibitor (SC-74020).

Purpose of the Study:

• To develop a binding affinity model for MMP-2 inhibitors.
• To investigate the binding modes of alpha-N-sulfonylamino hydroxamic acid derivatives targeting the S(2)' and S(1) pockets of MMP-2.
• To assess the predictive accuracy of computational models for MMP-2 inhibitor binding.

Main Methods:

• Utilized published binding affinity data and structural information of MMP-2.
• Constructed a binding affinity model focusing on the S(2)' pocket using nine alpha-N-sulfonylamino hydroxamic acid derivatives.
• Generated two binding geometries (Mode A: S(2)' pocket, Mode B: S(1) pocket) for each ligand.

Main Results:

• The binding affinity model for Mode A (S(2)' pocket) achieved a root-mean-square deviation (rmsd) of 0.583 kcal/mol and a correlation coefficient (r²) of 0.779 against experimental data.
• Mode B (S(1) pocket) showed a higher rmsd of 0.834 kcal/mol and a lower correlation coefficient (r²) of 0.500.
• Computed activities demonstrated a strong correlation with experimental data for the S(2)' pocket targeting mode.

Conclusions:

• The S(2)' pocket, gated by Phe(76), is more likely to accommodate the alpha-substituent compared to the solvent-exposed S(1) subsite.
• This binding preference may have been overlooked in previous studies using crystallographic structures that do not fully represent the open S(2)' pocket.
• The developed model provides valuable insights for designing more effective MMP-2 inhibitors.