molecules Review Encoded Library Technologies as Integrated Lead Finding Platforms for Drug Discovery Johannes Ottl, Lukas Leder, Jonas V. Schaefer and Christoph E. Dumelin * Novartis Institutes for Biomedical Research, 4056 Basel, Switzerland; [email protected] (J.O.); [email protected] (L.L.); [email protected] (J.V.S.) * Correspondence: [email protected] Academic Editors: Raphael Franzini and Christopher Arico-Muendel Received: 27 March 2019; Accepted: 21 April 2019; Published: 25 April 2019 Abstract: The scope of targets investigated in pharmaceutical research is continuously moving into uncharted territory. Consequently, finding suitable chemical matter with current compound collections is proving increasingly difficult. Encoded library technologies enable the rapid exploration of large chemical space for the identification of ligands for such targets. These binders facilitate drug discovery projects both as tools for target validation, structural elucidation and assay development as well as starting points for medicinal chemistry. Novartis internalized two complementing encoded library platforms to accelerate the initiation of its drug discovery programs. For the identification of low-molecular weight ligands, we apply DNA-encoded libraries. In addition, encoded peptide libraries are employed to identify cyclic peptides. This review discusses how we apply these two platforms in our research and why we consider it beneficial to run both pipelines in-house. Keywords: Encoded Library Technologies; DNA-encoded libraries; mRNA display; drug discovery; lead generation; integrated lead finding; high-throughput screening 1. Introduction Advances in disease characterization and target identification [1,2] constantly move the drug discovery portfolio into unchartered territory. More and more emerging targets are attractive from a pathological point, but are at the same time challenging to modulate with established low molecular weight (LMW) compounds or biologic agents. One way to cope with that is to considerably enlarge the chemical space available to current hit finding methods (Figure1). This is underlined by the fact that the size of compound libraries is normally limited to a range of about 106 mostly due to archive and screening logistics. This lowers the chances to identify hits with high affinity and selectivity or for demanding targets. LMW agents originating from traditional compound libraries may in principle be bioavailable, allow for cell penetration and are suited to bind in defined pockets of proteins such as enzymes. Yet they frequently perform worse against protein-protein interactions (PPIs). PPIs tend to have rather large and extended interaction surfaces. On the other side of the spectrum, biologics are better suited for such applications. They are able to address extended PPIs on large surfaces and are usually both very selective and potent. However, their large molecular weight, amongst others, largely excludes addressing intracellular targets in a therapeutic manner as well as oral administration. Encoded libraries can help to overcome these shortcomings. Compounds originating from DNA-encoded libraries (DEL) resemble LMW molecules, but offer the opportunity to screen up to 109 and more possible chemical entities. This size thus is 1’000-fold larger than a usual compound collection of pharmaceutical companies and significantly increases the chances of finding new chemical starting points. As a second pillar, encoded peptide libraries as utilized in the Novartis-internal Peptide Discovery Platform (PDP) can fill the gap between LMW and biologics. Peptides with a typical length of 5–20 amino acids have an intermediate size and are able to interact with target proteins in many Molecules 2019, 24, 1629; doi:10.3390/molecules24081629 www.mdpi.com/journal/molecules Molecules 2019, 24, x 2 of 21 Molecules 2019, 24, 1629 2 of 22 Discovery Platform (PDP) can fill the gap between LMW and biologics. Peptides with a typical length of 5–20 amino acids have an intermediate size and are able to interact with target proteins in many ways,ways, like like covering largelarge surfaces surfaces or or small small binding binding pockets. pockets. Depending Depending on the on set-up, the set-up, peptidic peptidic libraries librariescan encode can encode up to 10 up12 dito ff10erent12 different sequences, sequences, allowing allowing for identification for identification of high of a ffihighnity affinity binders binders against againstalmost almost any target any [target3]. [3]. Figure 1. Model of chemical space available for hit finding and positioning of the encoded library Figure 1. Model of chemical space available for hit finding and positioning of the encoded library technologies DEL and PDP. While those ligands on the left typically have a higher bioavailability and technologies DEL and PDP. While those ligands on the left typically have a higher bioavailability and cell permeability due to their smaller size, this gets less and less pronounced towards larger molecular cell permeability due to their smaller size, this gets less and less pronounced towards larger molecular weights. In contrast, bigger molecules like peptides and biologics most often possess higher affinities weights. In contrast, bigger molecules like peptides and biologics most often possess higher affinities and selectivities towards their targets compared to LMW compounds. The typical numbers of library and selectivities towards their targets compared to LMW compounds. The typical numbers of library sizes are about 106 for archive-based compound collections, about 109 for DELs, 1012 for peptide sizes are about 106 for archive-based compound collections, about 109 for DELs, 1012 for peptide libraries and about 1010 for biological agents. libraries and about 1010 for biological agents. 2. DNA-Encoded Libraries 2. DNA-Encoded Libraries First theoretically proposed by Brenner and Lerner in 1992 [4], the selection of LMW compounds fromFirst DNA-encoded theoretically libraries proposed by by now Brenner is an establishedand Lerner in technology 1992 [4], the employed selection by of numerous LMW compounds academic fromand DNA-encoded industrial laboratories libraries [ 5by–7 ].now Being is an a scalableestablished benchtop technology technology employed for performing by numerous affi academicnity-based andhit industrial finding, DEL laboratories screens facilitate [5–7]. 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DespiteThere their are distincthundreds designs, of different most ofproprietary them employ DELs the used same by common the individual "split-and-pool" labs and institutions. approach for Despitethe generation their distinct of chemical designs, diversity most of on them a massive employ scale the [ 11same,12]. comm This techniqueon "split-and-pool" employs a approach combinatorial for theassembly generation of two of to fourchemical building diversity blocks [13on,14 a] rathermassive than scale the most [11,12]. straightforward This technique way of employs synthesizing a Molecules 2019, 24, x 3 of 21 Molecules 2019, 24, 1629 3 of 22 combinatorial assembly of two to four building blocks [13,14] rather than the most straightforward way of synthesizing DELs