Molecular Energetics of Drug-Protein Interaction

Matrix Metalloproteinases

Matrix Metalloproteinases are a class of extracellular enzymes that play an essential role in local proteolysis of the extracellular matrix and in cell migration. In particular, they degrade the basement membrane and facilitate the migration of endothelial cells needed to form new blood vessels. The natural substrates of MMPs are polypeptides. MMP catalyses their hydrolysis in the presence of a catalytic zinc ion (thus the name).

Marimastat is a hydroxamic acid, matrix metalloprotease inhibitor. It mimics the peptide structure of natural MMP substrates. Inhibition of MMPs slows down cancer angiogenesis and metastasis.

Overall structure and binding pocket

Compare MMP (from marimastat complex) with MMP (unbound, apo-structure).

Molecular Determinants of binding

Van der Waals interactions. In the marimastat-bound state, the binding site closes onto the ligand. This reduces solvent accessibility and provides better steric fit between the protein and the drug. In the apo-state, the binding site is more open, water molecules occupy the place of the ligand, providing all types of energetically favorable interactions.

Electrostatics. A zinc ion is permanently present in the catalytic site, providing a net positive charge. The ligand bears a complementary negative charge. (The ligand surface mesh is displayed and colored it by electrostatic potential: (+) - blue, (-) - red. The pocket mesh is displayed, residues bearing net charge at neutral pH are identified: Arg, Lys (and sometimes His) are positively charged, Asp, Glu (and occasionally Cys) are negatively charged.)

Hydrogen bonding. Marimastat makes six hydrogen bonds within the binding pocket. The hydrogen bonds are displayed as colored dotty lines. The strength of a HB depends on relative orientation of the donor-hydrogen-acceptor triple; when they form a straight line, the bond is the strongest. Note that in the absence of ligand, water can also form these bonds with the pocket residues.

Metal coordination. The catalytic zinc ion is coordinated by 3 histidine residues and the marimastat molecule.

Pi-interactions and covalent drug-receptor bonds are not found in this complex.