To know conformation energy profile of compounds is important for drug design or understanding structure activity and physical property relationships such as water solubility or cell membrane permeability of the drug candidate molecules. But the time for searching stable conformations(local energy minima) in large conformation space becomes longer than several hundred years by conventional systematic search method assuming even one second energy minimization time per one initial conformation for the peptide size of 10 residues or more. By the method developed here the time reduced to several 10 days on single processer computer and the time can be reduced more and more in case of parallel calculations. In the method energetically stable conformers of a smaller size ring structure than the target structure is used as seed structures and an atom or atoms are inserted to the ring conformers to build initial structures then the energy is minimized and energetically stable ring expanded structure conformers are obtained. This process is repeated starting from smaller size ring structure for which the conventional search method is applicable until to reach the target ring structure. Detail of the method will be explained and the example results of applying the method to compounds of more than 20 rotatable bonds will be presented including cyclosporin A. In cyclosporin A case observed conformations as the complex with cyclophilin A or with the antibody in crystal state by X ray analysis or in aqueous environment by NMR analysis were found among the searching result conformations. The example of comparison of the observed and searched structures and the energy distribution of searched conformers is shown in Fig. 1. We concluded that the all conformations of energy range within about 10 Kcal/mol from the lowest are completely searched by the developed method since observed conformations under different conditions were found and that the method is useful as conformation sampling tool.

New extremely efficient conformation search method based on energy evaluation for macrocyclic compounds including peptides size of greater than 10 residues

254th National Meeting (2017)

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