Chemical Space

Systematic enumeration and analysis of chemical space, including combinatorial molecule generation, complexity measures, and synthetic accessibility scoring.

Chemical Space Analysis

Paper	Year	Key Idea
AllChem: Generating and Searching 10^20 Structures	2007	Recursive synthon generation from reactions and building blocks, with topomer similarity search
VEHICLe: Heteroaromatic Rings of the Future	2009	Complete enumeration of 24,847 heteroaromatic ring systems with ML-based tractability prediction
ACSESS: Diverse Optimal Molecules in the SMU	2015	Diversity-biased stochastic search finds diverse optimal molecules without exhaustive enumeration
Surge: Fastest Open-Source Chemical Graph Generator	2022	Three-stage canonical generation path method, 42-161x faster than MOLGEN 5.0
Molecular Complexity from the GDB Chemical Space	2025	Simple graph-based molecular complexity measures (MC1, MC2) derived from GDB enumeration
CHX8: Complete Eight-Carbon Hydrocarbon Space	2026	Exhaustive enumeration of 31,497 stable hydrocarbons up to 8 carbons with RSE strain metric

Dataset	Size	Description
GDB-11	26.4M	Exhaustive enumeration of molecules up to 11 atoms of C, N, O, F
GDB-13	977M	Exhaustive enumeration of molecules up to 13 atoms of C, N, O, S, Cl
GDB-17	166.4B	Exhaustive enumeration of molecules up to 17 atoms of C, N, O, S, halogens

Computational Chemistry

Three panels comparing sampling strategies in a multi-modal fitness landscape: exhaustive enumeration, genetic algorithm clustering around few peaks, and ACSESS covering all peaks with fewer evaluations

ACSESS: Diverse Optimal Molecules in the SMU

Property-optimizing ACSESS combines diversity-biased sampling with iterative fitness thresholding to discover diverse sets of molecules with favorable properties. Tested on GDB-9 (dipole moment optimization) and NKp fitness landscapes, it outperforms standard genetic algorithms in diversity while matching or exceeding their fitness, using only ~30,000 evaluations to navigate a 300,000-molecule space.

Computational Chemistry

Diagram showing AllChem's combinatorial synthon assembly pipeline: 7,000 building blocks transformed by 100 reactions into 5 million synthons, which combine in A-B-C topology to represent 10^20 structures

AllChem: Generating and Searching 10^20 Structures

AllChem generates ~5 million synthons by recursively applying ~100 reactions to ~7,000 building blocks, combinatorially representing up to 10^20 complete structures with an A-B-C topology. Topomer shape similarity enables efficient searching of this space, and every hit comes with a proposed synthetic route.

Computational Chemistry

CHX8 enumeration pipeline from 77,524 structures to 31,497 stable molecules, example strained scaffolds with RSE values, and box plots of relative strain energy distribution by heavy atom count

CHX8: Complete Eight-Carbon Hydrocarbon Space

CHX8 exhaustively enumerates all mathematically feasible hydrocarbons with up to eight carbon atoms (77,524 structures), then DFT-optimizes them to identify 31,497 stable molecules. A universal relative strain energy (RSE) metric referenced to cyclohexane serves as a synthesizability proxy. CHX8 covers 16x more C8 hydrocarbons than GDB-13 and reveals that over 90% of novel structures should be synthetically accessible.

Computational Chemistry

Six molecules with atoms colored by divalent (blue, simple) vs non-divalent (red, complex) nodes, showing increasing MC1 complexity from hexane to pivaloyl methylamine

Molecular Complexity from the GDB Chemical Space

Buehler and Reymond introduce two molecular complexity measures, MC1 (fraction of non-divalent nodes) and MC2 (count of non-divalent nodes excluding carboxyl groups), derived from analyzing synthesizability patterns in GDB-enumerated molecules. They compare these measures against existing complexity scores across GDB-13s, ZINC, ChEMBL, and COCONUT.

Computational Chemistry

Three-stage canonical generation pipeline (geng, vcolg, multig) alongside a log-scale speed comparison showing Surge outperforming MOLGEN 5.0 by 42-161x across natural product molecular formulas

Surge: Fastest Open-Source Chemical Graph Generator

Surge is a constitutional isomer generator based on the canonical generation path method, using nauty for graph automorphism computation. Its three-stage pipeline (simple graph generation, vertex coloring for atom assignment, edge multiplicity for bond orders) generates 7-22 million molecules per second, outperforming MOLGEN 5.0 by 42-161x on natural product molecular formulas.

Computational Chemistry

Grid of heteroaromatic ring systems rendered with RDKit, showing known ring systems in blue-tinted panels and predicted tractable rings in amber-tinted panels

VEHICLe: Heteroaromatic Rings of the Future

VEHICLe (Virtual Exploratory Heterocyclic Library) is a complete enumeration of 24,867 mono- and bicyclic heteroaromatic ring systems built from C, N, O, S, and H. Of these, only 1,701 have ever appeared in published compounds. A random forest classifier trained on known vs. unknown ring systems predicts that over 3,000 additional ring systems are synthetically tractable.

Chemical Space Analysis#

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