Understanding the binding of inhibitors of matrix metalloproteinases by molecular docking, quantum mechanical calculations, molecular dynamics simulations, and a MMGBSA/MMBappl study
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https://hdl.handle.net/10037/10215Dato
2015-01-14Type
Journal articleTidsskriftartikkel
Peer reviewed
Sammendrag
Matrix metalloproteinases (MMPs) consist of a class of proteins required for normal tissue function. Their
over expression is associated with many disease states and hence the interest in MMPs as drug targets.
Almost all MMP inhibitors have been reported to fail in clinical trials due to lack of specificity. Zinc in the
binding site of metalloproteinases performs essential biological functions and contributes to the binding
affinity of inhibitors. The multiple possibilities for coordination geometry and the consequent charge on
the zinc atom indicate that parameters developed are not directly transferable across different families
of zinc metalloproteinases with different zinc coordination geometries, active sites and ligand
architectures which makes it difficult to evaluate metal–ligand interactions. In order to assist in drug
design endeavors for MMP targets, a computationally tractable pathway is presented, comprising docking
of small molecule inhibitors against the target MMPs, derivation of quantum mechanical charges on the
zinc ion in the active site and the amino acids coordinating with zinc including the inhibitor molecule,
molecular dynamics simulations on the docked ligand–MMP complexes and evaluation of binding affinities
of the ligand–MMP complexes via an accurate scoring function for zinc containing metalloprotein–ligand
complexes. The above pathway was applied to study the interaction of inhibitor Batimastat with MMPs,
which resulted in a high correlation between the predicted binding free energies and experiment, suggesting
the potential applicability of the pathway. We then proceeded to formulate a few design principles which
identify the key protein residues for generating molecules with high affinity and specificity against
each of the MMPs.
Beskrivelse
This article is licensed under a Creative Commons Attribution 3.0 Unported Licence.
DOI: 10.1039/c5mb00003c
DOI: 10.1039/c5mb00003c