Enabling rational, accelerated 4D structural drug design using experimental rather than theoretical data

Conformational analysis - measuring drug 3D-shapes

The quantified 3D-shapes (conformations) that a molecule or part of a molecule can adopt is termed its ‘conformetrics’. Measurement of a free drug molecule’s conformetrics is far from trivial because in most cases drugs are flexible molecules and, with typically 5-13 rotatable bonds, display very complex conformational envelopes.

The Conformetrix proprietary technology platform allows a molecule’s conformetrics to be precisely measured directly from experimental data (see upper figure). The method was developed by C4X Discovery founders Charles Blundell and Andrew Almond to address the inability of existing experimental and computational chemistry methods to determine this information (see publication). It uses Nuclear Magnetic Resonance (NMR) data to provide detailed, atomic resolution information for the molecule in its near-natural state (i.e. solution). The NMR data is used in the C4X discovery proprietary software suite which interprets it in a novel, patented algorithm (see press release) to determine the molecule’s dynamic 3D-shape (conformetrics). The output is an accurate description of the complete dynamic behaviour of the molecule in 3D-space, providing medicinal chemists with the vital information and insight they need to make key drug discovery design decisions.

nmr conformetrix analysis to dynamic 3d shape

Typical drug molecule dynamic 3D-structures can be solved in 1-2 weeks, integrating well with the medicinal chemistry design-make-test cycle. Our in-house database contains several hundred dynamic 3D-structures, a few examples of which are shown in the lower figure. All classes and kinds of drug molecules and natural ligands (e.g., cofactors, peptides) can be analysed, meaning that every C4X Discovery programme is structurally enabled, irrespective of the target class and availability of target 3D-information.

molecule 3d shapes

If you would like to know more about how we measure solution state free ligand 3D structures, please read our article 'Quantification of free ligand conformational preferences by NMR and their relationship to the bioactive conformation' in Bioorganic & Medicinal Chemistry.