Elucidating the Size of Chemical Space with Assembly Theory

Abstract

Chemical space is unimaginably vast with common heuristic estimates suggesting that there are ca. 10^60 'drug-like' molecules possible below a molecular mass of 500 Da. However, these estimates largely ignore the structural and synthetic complexity of the molecules enumerated. Here we present a first-principles estimate of the size of chemical space using the Assembly Theory, which quantifies the amount of causation required to form a molecule, captured in the assembly Index. This is a measurable molecular complexity measure derived from the minimum number of recursive bond-joining operations required to construct a molecular graph. Assembly Theory partitions chemical space into levels defined by Assembly Index, allowing bounds to be placed on its growth as molecular complexity increases. We show that chemical space (the accumulated Assembly Index level sets) grows at least super-exponentially, and at most, double-exponentially with respect to the Assembly Index. Using the GDB-13 database as a reference for growth-rate estimation, we model how chemical space expands under increasing complexity and contracts under structural constraints, including atom and bond types, number of rings, ring size, and chemical motifs. Under constraints comparable to standard drug-like estimates, including molecular mass below 500 Da, our analysis yields a chemical space of approximately 10117 molecules at Assembly Index 25. Finally, we constrain chemical space by biologically relevant motifs and identify structurally relevant molecules near the accessible boundaries of these assembly-defined spaces.