ROCK I Kinase Binding Pocket Structures for Inhibitor Design
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Solution Overview
Problem
Current methods lack structural information on the unique features of the active site of Rho-kinase I (ROCK I), hindering the discovery of drugs for diseases related to ROCK's regulatory processes.
Innovation Solution
The development of crystal structures of ROCK I-inhibitor complexes and the use of computer-readable storage media to display three-dimensional graphical representations of ROCK I binding pockets, enabling the design, selection, and optimization of compounds that bind to ROCK I molecules or complexes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Loss of information
If crystal structures of ROCK I are determined, then structural information on unique features of the active site is obtained, but the complexity of the determination process increases
Solution Approach 1:
The patent uses crystallization buffers and specific pH conditions as intermediaries to facilitate the formation of high-quality ROCK I crystals. These intermediaries enable the determination process by creating optimal conditions for crystal growth without requiring complex alternative approaches
Solution Approach 2:
The patent systematically varies crystallization parameters including pH (testing buffers at pH 5.0, 5.5, 6.0), temperature, and buffer composition to optimize crystal formation. This parameter optimization approach enables structural determination while managing the complexity of the crystallization process
2Measurement precision
If crystal structures with inhibitors are determined, then detailed binding pocket information is obtained, but the complexity of obtaining and analyzing complex structures increases
Solution Approach 1:
The patent performs preliminary crystallization of ROCK I with inhibitors already bound, rather than attempting to solve the structure first and then analyze binding pockets. This preliminary action of co-crystallization simplifies the overall process by obtaining binding pocket information directly from the crystal structure determination
Solution Approach 2:
The patent uses X-ray crystallography to directly visualize binding pockets, replacing the need for separate biochemical assays or computational modeling approaches. This substitution provides precise structural information while streamlining the overall analytical process
3Reliability
If multiple crystallization conditions are tested, then optimal crystal growth is achieved, but the time and resources required increase
Solution Approach 1:
The patent tests a focused set of crystallization conditions (pH 5.0, 5.5, 6.0 with specific buffers) rather than exhaustively screening all possible conditions. This partial action approach achieves reliable crystal growth for ROCK I while limiting the time and resources invested in optimization
Solution Approach 2:
The patent uses established crystallization protocols and buffer systems as starting points, copying successful approaches from related kinases. This allows rapid optimization of ROCK I crystallization conditions without requiring de novo development of crystallization methods
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
Facilitates the identification of inhibitors for ROCK I, allowing for targeted drug design to address diseases involving ROCK I, by providing detailed structural information and enabling the visualization and optimization of compound interactions with ROCK I binding sites.
Implementation Method 1
The crystal structures were determined by X-ray diffraction
Implementation Method 2
The crystal structures were determined by X-ray diffraction
Data Source
AI summary
The present invention relates to human Rho-kinase I (ROCK I), ROCK I binding pockets, ROCK I-like binding pockets. More particularly, the present invention provides a computer comprising a data storage medium encoded with the structure coordinates of such binding pockets. This invention also relates to methods of using the structure coordinates to solve the structure of homologous proteins or protein complexes. In addition, this invention relates to methods of using the structure coordinates to screen for and design compounds, including inhibitory compounds, that bind to ROCK I protein or ROCK I protein homologues, or complexes thereof. The invention also relates to crystallizable compositions and crystals comprising ROCK I kinase domain and ROCK I kinase domain complexed with an inhibitor of that domain. The invention also relates to methods of identifying inhibitors of the ROCK I kinase domain.