The Chemical Space Project

Abstract

One of the simplest questions that can be asked about molecular diversity is how many organic molecules are possible in total? To answer this question, my research group has computationally enumerated all possible organic molecules up to a certain size to gain an unbiased insight into the entire chemical space. Our latest database, GDB-17, contains 166.4 billion molecules of up to 17 atoms of C, N, O, S, and halogens, by far the largest small molecule database reported to date. Molecules allowed by valency rules but unstable or nonsynthesizable due to strained topologies or reactive functional groups were not considered, which reduced the enumeration by at least 10 orders of magnitude and was essential to arrive at a manageable database size. Despite these restrictions, GDB-17 is highly relevant with respect to known molecules. Beyond enumeration, understanding and exploiting GDBs (generated databases) led us to develop methods for virtual screening and visualization of very large databases in the form of a "periodic system of molecules" comprising six different fingerprint spaces, with web-browsers for nearest neighbor searches, and the MQN- and SMIfp-Mapplet application for exploring color-coded principal component maps of GDB and other large databases. Proof-of-concept applications of GDB for drug discovery were realized by combining virtual screening with chemical synthesis and activity testing for neurotransmitter receptor and transporter ligands. One surprising lesson from using GDB for drug analog searches is the incredible depth of chemical space, that is, the fact that millions of very close analogs of any molecule can be readily identified by nearest-neighbor searches in the MQN-space of the various GDBs. The chemical space project has opened an unprecedented door on chemical diversity. Ongoing and yet unmet challenges concern enumerating molecules beyond 17 atoms and synthesizing GDB molecules with innovative scaffolds and pharmacophores.

Discovery and characterization of a novel non-competitive inhibitor of the divalent metal transporter DMT1/SLC11A2

“…1A. LBVS was performed using pharmacophore and shape similarity scoring functions recently developed in our laboratory [20][21][22][23]. A total 140 compounds were purchased as 1 mg solid sample from Princeton Biomolecular Research (Monmouth Junction, NJ, USA) and conditioned as 10 mM stocks in DMSO.…”

The drug-maker's guide to the galaxy

“…In a proof-of-principle experiment, Reymond started with a known molecule that binds the nicotinic acetylcholine receptor, a useful target for disorders involving the nervous system or muscle function, and compiled a shortlist of 344 related compounds. The team synthesized three, and found that two could activate the receptor potently, and could be useful for treating muscular atrophy in ageing 1 . The approach is like using a geological map to work out where to dig for gold, Reymond says.…”

Extending accessible chemical space for the identification of novel leads

“…Due to the presence of oligonucleotides, DNA-encoded libraries can be screened using immobilized proteins, followed by isolation of bound compounds and sequencing of the associated DNA signatures (Figure 3), which makes testing of such large libraries feasible. Classical chemical diversity has recently also been pushed to unprecedented heights computationally by application of stochastic search algorithms [24] or systematic enumeration of synthetically feasible organic compounds [25]. For example, molecules with up to 17 C, N, O, S, and/or halogen atoms have been systematically generated, yielding a virtually formatted library of more than 166 billion compounds with less than 300 Da [25]; an unimaginably large library from a medicinal chemistry viewpoint -and yet only a small sample of global chemical space.…”

“…Classical chemical diversity has recently also been pushed to unprecedented heights computationally by application of stochastic search algorithms [24] or systematic enumeration of synthetically feasible organic compounds [25]. For example, molecules with up to 17 C, N, O, S, and/or halogen atoms have been systematically generated, yielding a virtually formatted library of more than 166 billion compounds with less than 300 Da [25]; an unimaginably large library from a medicinal chemistry viewpoint -and yet only a small sample of global chemical space. Nonetheless, such in silico libraries map chemical space to a larger extent than ever before and provide a computational resource for compound selection.…”