Soaking Solutions for Macromolecular Crystals Using Compatible Solutes
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Solution Overview
Problem
Traditional methods for identifying new drug motifs in drug discovery, such as high throughput screenings, result in vast chemical libraries without a proportional increase in lead structures, and existing soaking solutions for biological macromolecular crystals are often detrimental to crystal stability due to the use of organic solvents and cryoprotectants, requiring extensive trial and error for optimization.
Innovation Solution
A systematic and rule-based method for selecting soaking solution compositions that balance organic solvents, compatible solutes, and crystallization solutions to maintain crystal stability, allowing for higher concentrations of organic solvents and varying soaking times, and eliminating the need for distinct soaking and cryo-preservation steps.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If organic solvents and cryoprotectants are used in soaking solutions, then small molecule screening can be performed, but crystal stability deteriorates
Solution Approach 1:
The patent introduces compatible solutes as intermediary substances that mediate between the harmful organic solvents and the crystal structure. These compatible solutes act as protective intermediaries that allow organic solvents to be present in the soaking solution while simultaneously protecting the crystal from damage, thus enabling small molecule screening without compromising crystal stability
Solution Approach 2:
The patent systematically varies the concentrations of organic solvents, compatible solutes, and crystallization solution components to identify optimal parameter combinations. By changing these parameters within a structured array, the method finds conditions where high organic solvent concentrations can be tolerated without damaging the crystal, thereby improving screening effectiveness while maintaining stability
2Reliability
If extensive optimization of soaking solutions is performed, then crystal stability is maintained, but time consumption increases
Solution Approach 1:
The patent performs preliminary optimization by pre-establishing a structured array of soaking solution compositions with varying concentrations of organic solvents, compatible solutes, and crystallization solution components. This preliminary structured optimization creates a ready-to-use set of soaking conditions that can be directly applied to multiple crystallization conditions without requiring extensive trial-and-error optimization for each case
Solution Approach 2:
The patent develops universal soaking solution formulations that can be applied across multiple different biological macromolecule crystal types and crystallization conditions. By creating a standardized array of soaking solutions with compatible solutes that work across different systems, the method eliminates the need for extensive individual optimization for each crystal type, significantly reducing time consumption while maintaining crystal stability
3Quantity of substance
If higher concentrations of organic solvents are used, then small molecule solubility improves, but crystal quality deteriorates
Solution Approach 1:
Compatible solutes serve as protective intermediaries that enable the presence of high concentrations of organic solvents in the soaking solution. These intermediaries shield the crystal structure from the harmful effects of high organic solvent concentrations, allowing small molecules to remain highly soluble while the crystal maintains its quality and integrity throughout the screening process
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
This approach improves crystal quality, increases hit rates in small molecule screenings, and allows for the use of soaking solutions across multiple biological macromolecule types, reducing disorder in disordered regions and enhancing the effectiveness of small molecule screening processes.
Implementation Method 1
During the soaking, the small molecules, which include molecular probes, fragments and drug-size molecules, will diffuse into the biological macromolecular crystal and will bind to the binding sites of the biological macromolecule
Implementation Method 2
Typically, such soaking solutions comprise organic solvents such as DMSO or methanol. Normally, such organic solvents as well as small molecules and compatible solutes (osmolytes having cryoprotective properties) have a disadvantageous effect on the crystals
Data Source
AI summary
Subject-matter of the present invention is an array comprising soaking solutions for soaking a biological macromolecular crystal. Further, the subject of the invention is a rule-based method of selecting specific soaking solution compositions having a specific composition comprising composite solute(s), water (w), crystallization solution (crs) and/or organic solvent(s). Additionally, the subjects matter of the invention the soaking solutions obtained by the method of the invention and a screening method for small molecules comprising molecular probes, fragments and drug-size molecules using the soaking solutions and the use of the soaking solutions in a screening method for small molecules on a macromolecular crystal.