Putative bioactive conformers of small molecules: A concerted approach using NMR spectroscopy and computational chemistry (original) (raw)

The knowledge of a bioactive conformation of a known lead or potential lead compounds undoubtedly will offer a save of money and time consuming to pharmaceutical companies aiming towards the development of new drugs. This review article deals with the use of different approaches to explore conformers of biologically active molecules at various environments which may simulate the biological ones. The molecules under study are mostly synthetic organic, with low molecular weight or small peptides. Two of the major structural characteristics of these molecules are: (i) T. Mavromoustakos, S. Golic Grdadolnik, M. Zervou et al. 2 amphiphilicity; and (ii) existence of flexible and rigid pharmacophoric segments. The rigid part of the molecule does not possess much of interest in terms of conformational analysis. However, the flexible segment constitutes a challenging field for conformational analysis exploring of putative bioactive conformations. NMR spectroscopy is a powerful tool to derive putative bioactive conformers of biologically active molecules. Application of 2D NOESY or ROESY spectroscopy could provide enough information for this purpose. Thus, quantitative analysis of the cross peaks reveals interatomic distances between the nuclei interacting through space. When a molecule contains bonds that restraint the molecular motion resulting in different distinct conformations detected by NMR spectroscopy, the use of 2D EXSY spectroscopy can differentiate between conformational exchange processes and spatial interactions. Molecular Modeling (Computational Chemistry) is a supplementary tool for providing the visual means to medicinal chemists, who are interested in the design and synthesis of novel bioactive molecules. Thus, energy minimization algorithms, conformational analysis tools like grid scan, Monte Carlo and molecular dynamics simulations in combination with the experimentally derived distance restraints will determine the putative bioactive conformers. Conformational analysis in a simulated environment is not always sufficient. The derived low energy conformers within a range of energy should be docked in the active site of the receptor. In many cases, drug molecules containing flexible segments can easily adopt conformations with higher energies in the biological matrices or at the active site of the receptor. The increase of energy is then compensated by the many different favorable interactions In some cases, Quantum Mechanics calculations are useful and can be more informative in terms of conformational analysis. For example, chemical shift simulation of NMR spectra may screen low energy conformers derived from the coupling of conformational analysis techniques and NMR spectroscopy. Moreover, 3D QSAR studies provide valuable structural information concerning the optimum bioactive conformation.