Hou et al. at Soochow and Zhejiang Universities in China have used various computational methods to find new inhibitors for LIM kinase 2. They have also used the same methods to evaluate the effectiveness of many existing inhibitors which have been studied experimentally, to understand why certain inhibitors might be more potent than others. Hou’s recent paper1 featured on the cover of Molecular Biosystems, Issue 10.
LIM kinases (LIMKs) have been found to be highly expressed in many types of tumors, and regulate several proteins crucial for cell division. Inhibitors of these kinases would therefore make possible avenues for cancer therapies. Most current inhibitors target LIMK1, one of the two isoforms that make up the LIMK family, but there is a need for improved inhibitors for LIMK2, the other isoform, and the focus of the current study.
Little research has been done on LIMK2 previously, as there is no crystal structure available in the Protein Data Bank (PDB), a requirement for theoretical models. In order to overcome this obstacle, Hour et al used homology modeling with LIMK1 to obtain a structure for LIMK2. This process used the sequence of LIMK2, and the known crystal structure of LIMK1 to produce a LIMK2 structure by established modeling programs. Due to the high level of sequence similarity (~60%), the structures for LIMK1 and LIMK2 are likely to be very similar as well. After a structure was obtained, small inhibitor molecules from an experimental study could be docked to LIMK2 and analysed computationally.
The researchers found that the flexibility of the binding site itself is extremely important for inhibitor recognition, as determined by analyzing the conformations of amino acids at the binding site before and after binding occurred. This flexibility would allow LIMK2 to bind many types and sizes of inhibitors, as observed experimentally. Additionally, the nonpolar interactions (van der Waals forces) at the binding site account for the majority of the binding energy, and can be correlated with the binding affinity of an inhibitor.
Most significantly, the researchers were able to design and test four new inhibitors based on the criteria for ideal binding affinity. These designed inhibitors have two sides connected by a linker (type II inhibitors). One side will bind to the substrate or allosteric site, while the other will bind to a nucleotide pocket, which are spatially close to each other on the surface of LIMK2. The inhibitors proposed by the researchers could later be tested experimentally, but the simulation results suggest that they will be as effective as those currently available, if not more effective.
- Theoretical study on the interaction of pyrrolopyrimidine derivatives as LIMK2 inhibitors: insight into structure-based inhibitor design, Mingyun Shen, Shunye Zhou, Youyong Li, Dan Li and Tinguin Hou, Mol. BioSyst., 2013, 9, 2435-2446. DOI: 10.1039/C3MB70168A
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