Database of Case Studies in Drug Discovery

Abstract

Molecular ConceptorTM (http://www.molecular-conceptor.com) is a drug design e-courseware that has been developed as a reference, a source of inspiration for medicinal chemists and a database of case studies in drug discovery. Synergix has developed Molecular Conceptor, as drug design e-courseware that can be used as a reference by medicinal chemists as a source of inspiration in drug design, and as an expanding compendium of knowledge in drug discovery. Molecular Conceptor includes 40 volumes and chapters that cover a wide range of topics such as structure-based drug design, ligand-based drug design, cheminformatics, molecular similarity, 3D-QSAR (three-dimensional Quantitative Structure-Activity Relationships), peptidomimetics, molecular docking and many others. In this report, we have chosen ‘molecular mimicry’ as a representative example to illustrate how it appears in Molecular Conceptor. This topic appears in many sections of the e-courseware, including: (i) three chapters devoted to pharmacophore-based drug design and (ii) several chapters on molecular similarity, 3D database searching, principles of rational drug design and library design. Two-dimensional (2D) representations are often misleading for understanding SAR, and one of the key features of Molecular Conceptor is its ability to visualize molecules in 3D, which is crucial to grasping the subtle recognition and discrimination processes of molecular machinery. In the example illustrated in Figure 1, moving the nitrogen atom in the pyrimidine heterocycle from A to B turns an inactive molecule into a very potent one. This is extremely difficult to see in the 2D formulas. A cogent explanation is given in Molecular Conceptor that can only be derived by viewing the molecules in 3D. Molecules A and B differ solely in the position of the nitrogen atom in the pyrimidine ring and exhibit very different biological activities (left). A possible explanation for this difference is visualized in three-dimension (right). Molecular mimicry is extremely useful in the early stages of drug discovery. When little knowledge is available, such as for example, one active reference compound, this is enough and the project can start. The aim of many such projects was described by terms such as ‘non-peptides, non-nucleotides, non-steroids, non-tricyclic mimetics’ and so forth. Snapshots of some pages associated with this topic are available in Figure 2 and Supplementary Material to this report. Simple and more complex case studies are presented, decomposed and assessed so that methodological rules can be deduced. The core topic is presented in three successive chapters: the first discusses ways to analyse the project (principles of analyses, control of molecular geometries, misuse of structural information, managing hypotheses); the second addresses the design issue (e.g. the four design methods) and the third discusses success stories from 13 different therapeutic areas. Other chapters such as the ones dealing with 3D-QSAR, molecular similarity, library design and ADME (Absorption, Distribution, Metabolism, Elimination) properties highlight the importance of molecular mimicry in these different areas. When molecular mimicry is applied to peptides, it is referred to as ‘peptidomimetics’. This type of approach is mandatory in drug research when dealing with a peptide molecule that cannot be developed as a drug. This topic is presented in detail in two different chapters: (i) Introduction to Peptidomimetics and (ii) Peptidomimetic Examples. However, many other examples are presented for diverse purposes in other sections of the software. For instance, the successful design of Aliskiren (a renin inhibitor now in late stages of development) is presented in both the chapter on examples of peptidomimicry as well as in the chapter on case histories in drug discovery. Snapshot of a page from Molecular Conceptor. In conclusion, the concept of molecular similarity has nurtured the imagination and creativity of several generations of medicinal chemists. Because of the fuzziness of the concept, medicinal chemists live with the contradiction that similar compounds simultaneously have and do not have similar activities. The key concepts and features of thousands of scientific articles devoted to this topic are summarized in Molecular Conceptor. The essence of millions of hours of scientific work, human creativity, investment in human resources and expenditures in R & D are presented on a friendly and efficient platform. Molecular Conceptor is rapidly becoming a prime reference for medicinal chemists, a source of inspiration in drug design and can also be used to train newly recruited medicinal chemists in the industry (1-4). Figure S1: Snapshots of pages from Molecular Conceptor dealing with molecular mimicry. For clarity, both the navigation tree and the text of the pages have been omitted Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.