Computational inhibition of Matrix metalloproteinase 9 (MMP-9) as potential cancer therapeutics

Haleluya T. Merga
Dr. Anne E. Moody, Faculty Mentor

Matrix metalloproteinase-9 (MMP-9) is a zinc-dependent endopeptidase involved in tissue remodeling, wound healing, and neuroplasticity. Although important in normal physiology, overexpression of MMP-9 promotes extracellular matrix degradation and contributes to cancer invasion and metastasis. Developing selective inhibitors has been difficult because of high structural similarity between MMP-9 and MMP-2, which has led to off-target inhibition.

 

Generic de novo design method was used to generate 397 candidate inhibitors. All candidates were docked into the catalytic domain of MMP-9 using DOCK6, with the catalytic Zn2+ ion included in the docking model. Top-ranked ligands, along with the control inhibitor batimastat (BB-94), were further evaluated by molecular dynamics simulations using AMBER, followed by binding free energy analysis. 

 

Several candidates maintained stable interactions with the catalytic zinc ion and showed favorable binding throughout the simulations. Comparative analysis with MMP-2 also suggested greater binding preference for MMP-9, supporting their potential as lead compounds for cancer therapeutics.

 

Keywords: Matrix metalloproteinase, Cancer metastasis, catalytic Zn2+, Selective inhibitors, generic de novo , Dock 6, Molecular dynamics, Binding free energy

Topic(s):Biochemistry and Molecular Biology
Chemistry
Biology

Presentation Type: Oral Presentation

Session: TBA
Location: TBA
Time: TBA