Abstract
BackgroundThere is a growing body of literature describing the properties of marketed drugs, the concept of drug-likeness and the vastness of chemical space. In that context, enumerative combinatorics with simple atomic components may be useful in the conception and design of structurally novel compounds for expanding and enhancing high-throughput screening (HTS) libraries.ResultsA random combination of mono- and diatomic carbon, hydrogen, nitrogen, and oxygen containing components in the absence of molecular weight constraints but with the ability to form rings affords virtual compounds that fall in bulk physicochemical space typically associated with drugs, but whose ring assemblies fall in new or under-represented areas of chemical shape space. When compared against compounds in the ChEMBL_14, MDDR, Drug Bank and Dictionary of Natural Products, the percentage of virtual compounds with a Tanimoto index of 1.0 (ECFP_4) was found to be as high as 0.21. Depending on therapeutic target, this value may be in range of what might be expected from an experimental HTS campaign in terms of a true hit rate.ConclusionVirtual compounds derived through enumerative combinatorics of simple atomic components have drug-like properties with ring assemblies that fall in new or under-represented areas of shape space. Structures derived in this manner could provide the starting point or inspiration for the design of structurally novel scaffolds in an unbiased fashion.
Highlights
There is a growing body of literature describing the properties of marketed drugs, the concept of drug-likeness and the vastness of chemical space
Analysis of the known druggable space (KDS), Dictionary of Natural Products (DNP) and enumerated sets indicate that the collection of randomly generated virtual compounds resembles that of the DNP with respect to the ratio of carbon, nitrogen and oxygen atoms present in each molecule, but with a narrower molecular weight range (Figure 1)
Physicochemical property analysis reveals that a majority of the randomly generated virtual compounds falls in the range of generally accepted drug space (Figure 2), despite starting with a single carbon atom as the core and using only ten simple fragments
Summary
There is a growing body of literature describing the properties of marketed drugs, the concept of drug-likeness and the vastness of chemical space. Enumerative combinatorics with simple atomic components may be useful in the conception and design of structurally novel compounds for expanding and enhancing high-throughput screening (HTS) libraries. Contemporary small molecule drug discovery often relies on high-throughput screening (HTS) of either structurally diverse or mechanistically focused compound library sets to identify hits that have the potential for multiparameter optimization against biological targets of interest. For example, diverted total synthesis [3], diversity-oriented synthesis (DOS) [4] and biology-oriented synthetic (BIOS) [5] approaches have provided compounds for biological evaluation that possess increasing levels of structural and stereochemical complexity. Non-traditional lead-like molecules include, for example, macrocyclic derivatives, which have been described in the literature as an underexploited structural class for drug discovery [6]. Since natural products span regions of chemical space not represented by bioactive medicinal chemistry compounds [7], their scaffolds may serve as the inspiration for the design of structurally novel combinatorial libraries [8]
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