Calculated conformer energies for organic molecules with multiple polar functionalities are method dependent: Taxol (case study)

In the present work, the relative energies of seven conformations of Taxol derived from NMR and X-ray analyses were compared with a set of widely used force fields and semiempirical MO methods coupled to a continuum solvent treatment. The procedures not only diverge significantly in their assessment of relative conformational energies, but none of them provide satisfactory agreement with experiment.For Taxol, molecular mechanics and semiempirical QM methods are unable to provide a consistent energetic ranking of side-chain conformations. For similar highly polar organic structures, "energy-free" conformational search methods are advised.Conformational and structural analysis of complex organic molecules has been significantly advanced by the development of molecular mechanics schemes parameterized for a wide variety of organic functionalities. For small organic molecules, the Allinger family of programs has served the community very well for many years.[1] One widely used package that incorporates a range of force fields and features of the Allinger protocols, solvation continuum models and conformational searching options is MacroModel.[2] Two studies by Liljefors and colleagues devoted to an evaluation of quantitative aspects of conformational analysis using the MacroModel force fields demonstrate them to perform rather well for a wide range of organic structures with few polar substitutents.[3] A more recent investigation by Halgren on similar structures points out that there is still work to be done to accurately and completely map conformational energy profiles for organic molecules. [4] An area in which molecular mechanics and conformational analysis are critical is in the evaluation of drug candidates and in the molecular design of novel analogs. A case in point is the intense activity around Taxol (paclitaxel), one of the more clinically effective chemotherapeutic agents against a range of otherwise intractable cancers. During the past decade, numerous NMR s