Caseinolytic protease (ClpP) found in the human mitochondria is a major member of mitochondrial protein quality control system. This serine protease removes damaged or misfolded proteins in mitochondrial matrix. It is overexpressed in a wide range of acute myeloid leukemia (AML) cases and not in normal hematopoietic precursors [1].

Inhibition of the ClpP is a therapeutic strategy for human acute myeloid leukemia. We have developed ClpP Targeted Library (676 compounds in total). It is a special screening collection containing drug-like compounds with predicted inhibiting activity against ATP-dependent Clp protease proteolytic subunit. The library has been carefully designed with combined of two receptor-based approaches – pharmacophore screening and molecular docking. The four-point pharmacophore model with excluded volumes (on hydrogen atoms of the amino acid residues of the active center) was based on crystal of ClpP with N-formyl methionine (PDB ID: 1TG6) [2]. Top-scored compounds resulted from pharmacophore screening further were docked in the same crystal. Final selection of compounds has been made with docking score cut-off filtering, inspection of intermolecular hydrogen bonds and hydrophobic contacts with key active sites residues, the catalytic triad Ser97, His122 and Asp171 in particular.

This library provides an excellent basis for acute myeloid leukemia drug discovery projects.

The summary of the ClpP Targeted Library characteristics:

References:

1. Alicia Cole at al. Inhibition of the Mitochondrial Protease ClpP as a Therapeutic Strategy for Human Acute Myeloid Leukemia. Cancer Cell. Vol. 27, 2015, pp. 864–876.
2. Sung Gyun Kang at al. Crystallography and mutagenesis point to an essential role for the N-terminus of human mitochondrial ClpP. Journal of Structural Biology. Vol. 148, 2004, pp. 338–352.

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