Smart Design of Small‐Molecule Libraries: When Organic Synthesis Meets Cheminformatics

Abstract

Synthetic chemists are always looking for new methods to maximize the diversity and complexity of small‐molecule libraries. Diversity‐oriented synthesis can give access to new chemotypes with high chemical diversity, exploiting complexity‐generating reactions and divergent approaches. However, there is a need for new tools to drive synthetic efforts towards unexplored and biologically relevant regions of chemical space. Because the number of publicly accessible biological data will increase in the years to come, cheminformatics can represent a real opportunity to develop better chemical libraries. This minireview focuses on novel cheminformatics approaches used to design molecular scaffolds, as well as to analyze their quality, giving a perspective of them in the field of chemical biology and drug discovery through some selected case studies.

Actinomycete-Derived Polyketides as a Source of Antibiotics and Lead Structures for the Development of New Antimicrobial Drugs

“…In the past, the producers of valuable bioactive compounds were mainly isolated from soil samples and either directly or indirectly, using culture filtrates or extracts, subjected to susceptibility testing (diffusion method) ( Figure 1). Recent advances in different disciplines of science, such as robotics [3], biology [4], chemistry [5][6][7], genetics [8], and/or bioinformatics [9] has extended the spectrum of methodology applied to the isolation and identification of actinomycetes and the produced metabolites. In addition to technical innovations which, for example, enable sampling of unexplored and difficult to access environments, Next Generation Sequencing Technologies (NGST) and genome mining facilitate accurate and cost-effective sequencing of actinomycetes genomes and a fast identification of genes encoding the proteins of the secondary metabolite biosynthetic machineries (biosynthetic gene clusters, BGCs).…”

Building Natural Product Libraries Using Quantitative Clade-Based and Chemical Clustering Strategies

“…Despite the vast amounts of time, money, and energy poured into building small-molecule screening collections, the answers to many basic questions about their design and development, such as optimal collection sizes, are largely driven by adherence to dogma or convenience rather than evidence-based reasoning. Such questions grow increasingly relevant, as opinions influencing the last 4 decades of library design have shifted tremendously, with the large collections of the 1980s and 1990s (e.g., combinatorial chemistry [ 7 ]) being replaced by smaller tailored collections in the early 2000s (e.g., “focused” collections [ 8 , 9 ]) and moving toward megascale libraries in recent years (e.g., DNA encoded libraries [ 10 – 15 ]).…”

Readily accessible sp3-rich cyclic hydrazine frameworks exploiting nitrogen fluxionality

“…5). 17 This tool randomly selects a number of 3D-conformers for each molecule, minimizes their energy and selects the lowest-energy one. The selected minimum energy conformers of 10a-q are provided in the ESI.…”