Conformational Analysis

Drug-like molecules have multiple rotatable bonds. Rotations around individual bonds drive the molecules into different conformations. These conformations correspond to local minima on the energy surface. The starting point for any drug design consideration is the knowledge of the receptor-bound conformation of a drug-like molecule. Therefore, many methods have been developed to perform conformational analysis. Systematic searches by incremental rotations around each individual bond torsion angle generate a huge number of geometries. These geometries must be optimized to the local minima on the energy surface. The conformation of a drug-like molecule often changes with the environment. Typically, the conformation in the protein-bound state differs from that in solution, in the gas phase, or in the small molecule crystal structure. Considering torsion angle fragments in small molecules and statistically analyzing them in databases of crystal structures reveals clear torsional preferences. Conformational searches can be made more efficient using this knowledge. Not all values around a rotatable bond have to be tested, and the search can be limited to the regions that have been found to be of preference. Another obstacle to finding the protein-bound conformation of a drug-like molecule is that the molecule interacts with its environment. This environment, the binding pocket of the protein, is often polar. It will involve the bound ligand in multiple hydrogen bonds. Using a knowledge base of the torsional preferences of small organic molecules can greatly enhance conformational searching, especially when docking, comparing molecules, or searching databases based on predefined pharmacophores. https://sn.pub/mkznv9