Chemoinformatics-based enumeration of chemical libraries: a tutorial

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 chemoinformatics 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.

VLVS: A Knime Based Virtual Library Generation and Screening Workflow

“…Gonzalez and colleagues have described a workflow to obtain a series of lactam derivative molecules using KNIME software and plugins. [46] As in our study, possible building block molecules were loaded into the workflow, filtered according to the Ro3 rule, and then possible molecules were obtained. Then, possible intermolecular cyclization schemes were defined and applied to the obtained molecules.…”

Applications of Virtual Screening in Bioprospecting: Facts, Shifts, and Perspectives to Explore the Chemo-Structural Diversity of Natural Products

“…These methods apply sequential and hierarchical steps that aim at filtering and selecting compounds with desirable physicochemical, pharmacokinetic, and pharmacodynamic properties while discarding those that do not fit the desirable characteristics. A virtual screening workflow comprises two main computational tasks ( Figure 1A ): (1) the first one is the library preparation, which includes, among other computational tasks, obtaining the structures of the compounds, file conversion to readable formats, such as SMILES (simplified molecular-input line entry system), SDF (structure data file), and MOL2 (MDL Molfile) (Saldívar-González et al, 2020 ), conformer generation, and the correction of stereochemical and valence errors (Ropp et al, 2019 ); (2) the second one corresponds to the application of computational techniques to filter the desirable compounds (Gimeno et al, 2019 ). The final step corresponds to experimental validation using in vitro and in vivo assays, which include enzymatic inhibition assays and/or cell line inhibition (Spyrakis et al, 2019 ; Ye et al, 2019 ).…”

Progress on open chemoinformatic tools for expanding and exploring the chemical space

“…In order to support teaching in chemoinformatics, a tutorial that describes how to enumerate virtual libraries was published recently [ 50 ]. The tutorial describes a step-by-step procedure for anyone interested in designing and building chemical libraries with or without experience in using computational tools.…”