What is the \u201cbiological space\u201d and why is this space so important for all researchers interested in developing novel drugs? In the following, I will first establish a definition of the biological space and then highlight its use in computationally developing novel drug compounds and as a starting point in the experimental exploration of biological systems.<\/p>\n
While chemical space has been defined as the entirety of all possible chemical compounds which could ever exist, the definition of biological space is less clear. In the following, I define biological space as the area(s) of chemical space that possess biologically active (\u201dbioactive\u201d) compounds for a specific target or target class1<\/sup><\/strong>. As such, they can modulate a given biological system and subsequently influence disease development and progression. In literature, this space has also been called \u201cbiologically relevant chemical space\u201d2<\/sup><\/strong>.<\/p>\n Only a small percentage of the vast chemical space has been estimated to be biologically active and is thus relevant for drug development, as randomly searching bioactive compounds in chemical space with no prior information resembles the search for \u201cthe needle in a haystack\u201d. Hence, it should come as no surprise that bioactive molecules are often used as a starting point in in-silico explorations of biological space. The biological space is comprised of small molecules which are active on specific targets. If researchers want to explore the role the role of targets in a given biological system experimentally, they can use small molecules which are potent and selective towards a specific target (thus confided to a particular area in chemical space)11-12<\/sup><\/strong>.
\nThe plethora of in-silico methods for this task includes similarity and pharmacophore searching methods3-6<\/sup> <\/strong>for novel compounds, scaffold-hopping approaches to derive novel chemotypes7-8<\/sup><\/strong> or the development of quantitative structure-activity relationships (QSAR)9-10<\/sup><\/strong> to explore the interplay between the 3D chemical structure and its biological activity towards a specific target.<\/p>\n
\nDue to their high selectivity ( f.e. a greater than 30-fold selectivity towards proteins of the same family12<\/sup><\/strong>), these so-called \u201ctool compounds\u201d can help establish the biological tractability – the relationship between the target and a given phenotype – and its clinical tractability – the availability of biomarkers – of a target11<\/sup><\/strong>. They are thus highly complementary to methods such as RNAi, CRISPR12<\/sup> and knock-out animals11<\/sup><\/strong>. Consequently, tool compounds are used in drug target validation and the information they provide on the biological system can increase the probability of a successful drug 11<\/sup><\/strong>. Most importantly, tool compounds are particularly important to annotate targets in currently unexplored biological systems and thus important for novel drug development13<\/sup><\/strong>.<\/p>\n