Abstract
Natural products space includes at least 200,000 compounds and the structures of most of these compounds are available in digital format. Previous analyses showed (i) that although they were capable of taking up synthetic pharmaceutical drugs, such exogenous molecules were likely the chief ‘natural’ substrates in the evolution of the transporters used to gain cellular entry by pharmaceutical drugs, and (ii) that a relatively simple but rapid clustering algorithm could produce clusters from which individual elements might serve to form a representative library covering natural products space. This exploited the fact that the larger clusters were likely to be formed early in evolution (and hence to have been accompanied by suitable transporters), so that very small clusters, including singletons, could be ignored. In the latter work, we assumed that the molecule chosen might be that in the middle of the cluster. However, this ignored two other criteria, namely the commercial availability and the financial cost of the individual elements of these clusters. We here develop a small representative library in which we to seek to satisfy the somewhat competing criteria of coverage (‘representativeness’), availability and cost. It is intended that the library chosen might serve as a testbed of molecules that may or may not be substrates for known or orphan drug transporters. A supplementary spreadsheet provides details, and their availability via a particular supplier.
Highlights
The possibly surprising quantitative consequence of these and other studies is that diffusion of such drugs through the phospholipid bilayer portions of undamaged biological membranes is negligible [1,3,5,6,7,10,11,13,30]
We [2,16,32,33,34,35,36,37] and others (e.g., [38,39,40,41,42,43]) have sought to assess the extent to which marketed drugs are similar in structural terms to endogenous human metabolites
As in our related projects (e.g., [15,32,33,34,35]), we developed and ran our cheminformatics routines in the KNIME environment [57,58], including on occasion two nodes available from the Molport website at https://www.molport.com/shop/knime-nodes
Summary
It is evident (e.g., [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29]) that pharmaceutical drugs exploit endogenous transporters that normally transport biological metabolites (whether they are endogenous, or are represented by exogenous natural products). The criterion of being marketed was used because this implied that the drugs were efficacious and (since almost all were to be taken orally and/or required to interact with intracellular targets) capable of being transported across at least one biological membrane. It turned out [36] that when standard encodings were employed, and a Tanimoto similarity exceeding ~0.8 was used as a criterion of “similarity”, all drugs could be seen to be similar to either endogenites (~15%) or (more frequently) to natural products (commonly of plant and microbial origin), but that for similarities below this the various encodings often gave completely different rank orders
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