Acceleration of the Drug Discovery Process: A Combinatorial Approach Using NMR Spectroscopy and Virtual Screening

The continued implementation of NMR-based approaches in hit-through-lead drug discovery in academic and corporate settings is founded upon NMR applications that assess structure activity relationships. A very recent application of NMR spectroscopy to these discovery initiatives involves fraganomics, in which NMR is used to iteratively “guide” the assembly of several weakly interacting fragments or small molecules through chemical links. Moreover, several groups have recently reported the potential of integrating NMR spectroscopy with in silico, virtual screens of large chemical repositories possessing diverse collections of small molecules. Importantly an improved understanding of the intermolecular forces that mediate protein-protein/ protein-ligand interactions has been integral to improving these virtual screening approaches, resulting in the identification of novel ligands for several therapeutic targets. Recent success of these structure-based discovery initiatives in targeting protein-protein interactions that are responsible for the non-covalent assembly and/or regulation of macromolecular complexes and are a critical paradigm in many disease pathologies will be discussed. The atomic details of these requisite interactions are the cornerstone of NMR and crystallographic “structure-guided”, drug discovery initiatives aimed at disrupting complex formation. This review will predominantly focus on the recent advances in structure based computational screening approaches, highlighting the successful integration of in silico virtual screens with NMR-based techniques. The application of this powerful, combinatorial approach for the evaluation of well-characterized target space as well as its application to unique chemical space such as the protein-protein interaction inhibition (2P2I) that has recently been shown to be tractable to small molecule intervention will be discussed.