(411h) Using Molecular Subgraph Libraries for High-Throughput Screening and the Inverse Design Problem

An important set of molecular descriptors in cheminformatics and chemical engineering is the set of molecular subgraphs, sometimes referred to as signature descriptors¹ and used to construct Morgan/circular fingerprints². These molecular subgraphs are of an arbitrary height, K, meaning they contain atomic information about a central atom as well as all atoms within a distance of K bonds from the central atom. In this work, we detail a number of applications of subgraph representations of molecular structures in our computational chemistry software, AMS2019, as well as in the general context of high-throughput screening/inverse design.

First, we discuss the “representability” of large datasets using subgraphs. Specifically, we parse the PubChem database³ (~100 million compounds) into all possible subgraphs and then calculate the number of subgraphs required to fully represent 100%, 90%, 80%, etc. of the database using subgraphs of different (and mixed) heights. Next, we perform DFT calculations with ADF⁴ on the most common 100,000 subgraphs from PubChem and use this library of molecular fragments to generate sigma-profiles for use in high-throughput screening with COSMO-RS⁵ as well as in geometry initialization for accelerating DFT calculations. Finally, we discuss the “inverse design” problem: the problem of finding an optimal molecular structure(s) given molecular structure/property constraints and a design objective. We address the inverse design problem using state-of-the-art Mixed-Integer (Non)Linear Programming (MILP/MINLP) techniques⁶, exploiting problem structures inherent in subgraph representations of molecules. Specific applications to solvent, drug, and electronic materials design are discussed.

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[3] PubChem Database. National Institute of Health. https://pubchem.ncbi.nlm.nih.gov/

[4] ADF2018, SCM, Theoretical Chemistry, Vrije Universiteit, Amsterdam, The Netherlands, http://www.scm.com.

[5] Klamt, Andreas, Volker Jonas, Thorsten Bürger, and John CW Lohrenz. "Refinement and parametrization of COSMO-RS." The Journal of Physical Chemistry A 102.26 (1998): 5074-5085.

[6] Austin, Nick D., Nikolaos V. Sahinidis, and Daniel W. Trahan. "Computer-aided molecular design: An introduction and review of tools, applications, and solution techniques." Chemical Engineering Research and Design 116 (2016): 2-26.