Chemoinformatics-based enumeration of chemical libraries: a tutorial
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nal of Cheminformatics Open Access
EDUCATIONAL
Chemoinformatics‑based enumeration of chemical libraries: a tutorial Fernanda I. Saldívar‑González1* , C. Sebastian Huerta‑García2 and José L. Medina‑Franco1
Abstract Virtual compound libraries are increasingly being used in computer-assisted drug discovery applications and have led to numerous successful cases. This paper aims to examine the fundamental concepts of library design and describe how to enumerate virtual libraries using open source tools. To exemplify the enumeration of chemical libraries, we emphasize the use of pre-validated or reported reactions and accessible chemical reagents. This tutorial shows a step-by-step procedure for anyone interested in designing and building chemical libraries with or without chemo‑ informatics experience. The aim is to explore various methodologies proposed by synthetic organic chemists and explore affordable chemical space using open-access chemoinformatics tools. As part of the tutorial, we discuss three examples of design: a Diversity-Oriented-Synthesis library based on lactams, a bis-heterocyclic combinatorial library, and a set of target-oriented molecules: isoindolinone based compounds as potential acetylcholinesterase inhibitors. This manuscript also seeks to contribute to the critical task of teaching and learning chemoinformatics. Keywords: Chemical enumeration, Chemoinformatics, Combinatorial libraries, DOS synthesis, Drug design, Education, KNIME, Python Introduction Hit identification is the starting point and one of the most crucial stages of small-molecule drug discovery [1]. One approach to increase the likelihood of finding new hit compounds is presented by the computational generation of virtual chemical libraries to be used in various virtual screening methods. Thus, many researchers are developing new de novo chemical libraries and libraries “make-on-demand” by different in silico approaches [2]. For example, GDB‐17 generated by Reymond et al. is a chemical library that explores the chemical space broadly by enumerating more than 160 billion organic small molecules with up to 17 atoms [3]. Another example is the 95 million compounds in the virtual library CHIPMUNK (CHemically feasible In silico Public Molecular UNiverse *Correspondence: [email protected] 1 DIFACQUIM Research Group, School of Chemistry, Department of Pharmacy, Universidad Nacional Autónoma de México, Avenida Universidad 3000, 04510 Mexico, Mexico Full list of author information is available at the end of the article
Knowledge base) that were enumerated by performing a selected set of reactions widely used in traditional combinatorial chemistry [4]. Other examples of virtual libraries based on prevalidated or reported reactions, as well as accessible chemical reagents developed by pharmaceutical companies are BI-Claim developed by Boehringer Ingelheim [5], Eli Lilly’s Proximal Collection [6], Pfizer global virtual library (PGVL) [7], and Merck’s Accessible inventory (MASSIV) [8]. This approach was also used by chemical vendor
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