NMR Crystallography Structure Determination
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Solution Overview
Problem
Current methods for determining the three-dimensional structure of pharmaceutical solids using NMR crystallography are time-consuming, costly, and limited by the need for exhaustive conformational searches, which are impractical for larger or more flexible molecules, leading to inaccuracies and high experimental costs.
Innovation Solution
A method utilizing NMR values and atomic coordinates from reference compounds to rapidly determine the three-dimensional structure of a target compound by identifying similar substructures, calculating relevant statistical matches, and compiling atomic coordinate data to generate a three-dimensional structure, which can also screen for test compounds with similar structures.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If exhaustive conformational search methods are used to determine three-dimensional structure, then measurement precision is improved, but loss of time and productivity deteriorate
Solution Approach 1:
The patent segments the conformational search problem by dividing conformational space into discrete nonoverlapping volumes and assigning each volume as allowed or disallowed based on NMR constraints. This segmentation transforms an exhaustive continuous search into a manageable discrete evaluation of specific conformational regions.
Solution Approach 2:
The patent performs preliminary action by using simulated annealing to stochastically sample and identify allowed conformational volumes before final structure determination. This preliminary sampling establishes constraints that guide the subsequent structure solution process, avoiding the need for exhaustive searches.
2Measurement precision
If exhaustive conformational search methods are used to determine three-dimensional structure, then measurement precision is improved, but productivity deteriorates
Solution Approach 1:
The patent segments the conformational search problem by dividing conformational space into discrete nonoverlapping volumes and assigning each volume as allowed or disallowed based on NMR constraints. This segmentation transforms an exhaustive continuous search into a manageable discrete evaluation of specific conformational regions.
Solution Approach 2:
The patent applies partial action by using simulated annealing to stochastically sample conformational space rather than performing exhaustive searches. This partial sampling approach identifies allowed conformational volumes sufficiently for structure determination without the computational burden of complete enumeration.
3Adaptability or versatility
If NMR crystallography is applied to larger or more flexible molecules, then adaptability is improved, but reliability deteriorates due to impracticality of exhaustive searches
Solution Approach 1:
The patent segments the conformational search problem by dividing conformational space into discrete nonoverlapping volumes and assigning each volume as allowed or disallowed based on NMR constraints. This segmentation transforms an exhaustive continuous search into a manageable discrete evaluation of specific conformational regions.
Solution Approach 2:
The patent changes the search strategy parameter from exhaustive enumeration to stochastic sampling with simulated annealing. This parameter change makes the method scalable to larger and more flexible molecules by reducing computational complexity while maintaining structural accuracy through NMR constraint validation.
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 significantly reduces the time and cost of determining molecular structures, enabling fast and accurate characterization of biologically relevant molecules, and facilitates the identification of test compounds with similar structures, thereby accelerating drug development and design processes.
Implementation Method 1
nuclear magnetic resonance (NMR) crystallography
Data Source
AI summary
The invention relates to new uses of nuclear magnetic resonance (NMR) crystallography methods to determine and/or characterize the three-dimensional structure of compounds of interest.