Molecular shape technologies in drug discovery: methods and applications

Shape complementarity is a critically important factor in molecular recognition among drugs and their biological receptors. The notion that molecules with similar 3D shapes tend to have similar biological activity has been recognized and implemented in computational drug discovery tools for decades. But the low computational efficiency and the lack of widely accessible software tools limited the use of early shape-matching algorithms. However, recent development of fast and accurate shape comparison tools has changed the landscape, and facilitated the wide spread use of both the ligand-based and receptor-based shape-matching technologies in drug discovery. In this article, we summarize some of the well-known shape algorithms. We first describe the computational principles for both the superposition-based and the superposition-free shape-matching methods. These include ROCS (Rapid Overlay of Compound Structures), SQ, and the CatShape method in the former category; and the shape signatures algorithm and USR (Ultrafast Shape Recognition) that belong to the latter category. We then highlight some recent validation studies and practical applications of various shape technologies. Because of the rapid development of modern shape-matching algorithms, and the increasingly affordable computational resources and software tools, we anticipate much broader use of the molecular shape technologies in future drug discovery. They will be especially useful in chemogenomics research, where large scale associations between small molecules and protein targets are studied. Thus, molecular shape technologies, together with well-defined pharmacophore constraints, can afford both efficient and effective means for drug discovery and chemical genomics research.