Recent Changes in the Scaffold Diversity of Organic Chemistry As Seen in the CAS Registry

Abstract

A large set of organic compounds extracted from the CAS Registry is analyzed to study recent changes in structural diversity. The diversity is characterized using the framework content of the compounds; the framework of a molecule is the scaffold consisting of all its ring systems and all the chain fragments connecting them. The compounds are partitioned based on their year of first report in the literature, which allows framework occurrence frequencies to be compared across a 10-year interval. The results are consistent with a process in which frameworks with the greatest frequency of use in the past are the most likely to be used again, but it is also found that the frequency ordering changes over time. These fluctuations in ordering are attributed to stochastic factors, scientific and economic, that can affect how chemical space is explored. Framework diversity is found to have increased over time despite the extensive reuse of a relatively small number of frameworks; this increase is due to the large number of new frameworks. The long tail of the framework distribution, composed of frameworks that occur in few compounds or only one compound, is found to be a large and growing part of framework space.

Evaluation of 3-Dimensionality in Approved and Experimental Drug Space

“…To address the lack of 3-dimensionality in pharmaceuticals, there have been efforts in academic and industry laboratories to design and synthesize libraries of 3D molecules to be used in drug discovery campaigns. ,,,,, These structures include compounds prepared through diversity-oriented syntheses with a higher than typical number of sp 3 carbons, as well as chiral and spiro centers. Such strategies are often regarded as possible solutions to the over-representation of flat molecules in fragment libraries and drug discovery feedstocks. ,,,,,, To evaluate the success of such approaches, a PMI analysis (Figure ) was carried out on 15 unique fragments from three different reports (Figure S4). ,, These studies each sought to generate organic fragments with high degrees of 3-dimensionality.…”

Statistics of the Popularity of Chemical Compounds in Relation to the Non-Target Analysis

“…The power functions in logarithmic coordinates are transformed into linear graphs (the example in Figure 1b). These graphs are common for compounds distribution over the frequency of their participation in organic synthesis [8,9] and for the types of molecular fragments distribution over the frequency of their presence in known compounds [10,11]. There are general regularities in such "chemical" frequency distributions, conditionally dividing chemical space into subspaces of more and less popular compounds.…”

“…The distribution of ChemSpider database entries over molecular weight was also derived [2]. The statistics of the most common fragments of known chemical compounds have been published, including the distribution of compounds over the number of different fragments [10,11]. Some other statistical data on common compounds can be found in chemical databases (see reviews [12,13]).…”

Structural Approach to Assessing the Innovativeness of New Drugs Finds Accelerating Rate of Innovation

“…The CAS REGISTRY was used to obtain information about the frameworks of each NME in the final data set. This information was extracted from the framework data that CAS algorithmically extracts and systematically stores for every registered substance that meets certain criteria …”