We detail the use of mRNA display technologies and a unique selection and protein engineering strategy to discover potent macrocycle-based inhibitors of MsbA, an essential bacterial ABC transporter for LPS.  A high-resolution cryo-electron microscopy structure reveals the molecular basis for state-dependent inhibition of MsbA. Unexpectedly, peripherally-bound LPS molecules are also observed, expanding our understanding of the mechanisms of substrate transport.

Collaborative Drug Discovery (CDD) provides a whole solution for today’s biological and chemical data needs, differentiated by ease-of-use and superior collaborative capabilities.  CDD Vault^® software includes Activity & Registration, Visualization, Inventory, and ELN capabilities. Researchers can archive, mine, and securely collaborate within CDD Vault.  Collaborative hypothesis generation and evaluation allow multiple perspectives for multi-parameter optimization.

DNA-Encoded library (DEL) technology is a screening platform used throughout the pharmaceutical industry to discover novel chemical matter that modulates the activity of protein targets. However, DEL has some limitations, perhaps the largest of which is an inability to conduct biochemical and cellular screens.  To help overcome this limitation we will present some data on the production of one-bead-one-compound DELs, with a focus on quality control standards.

This talk will describe methodologies developed by our group for directing the synthesis and screening of genetically encoded libraries of ‘natural product-like’ macrocyclic peptides in living cells. The seminar will also discuss the integration of these methodologies with high-throughput screening platforms and phage display for driving the discovery and evolution of macrocyclic peptides capable of targeting protein-mediated interactions with high potency and selectivity.

This presentation highlights the discovery of macrocyclic PCSK9 ligands with encoded library mRNA display technology enabling incorporation of non-natural aminoacids into peptides. We employed an affinity-based screen of 1013 in vitro-translated macrocyclic peptides to identify high-affinity PCSK9 ligands utilizing a unique, induced-fit pocket partially disrupting the PCSK9-LDLR interaction. The ligands are nonbiologic agents with an allosteric mechanism and the smallest molecules to date capable of disrupting the PCSK9-LDLR interaction in vivo.

We present novel approaches for the direct selection of molecules from DNA-encoded libraries that activate GPCRs via either the G-protein or arrestin signaling pathways. We present results of discovery of biased agonists from DELs with live cell selections against the opioid receptor family.

DNA-Encoded Library (DEL) screening continues to establish itself as a powerful approach to hit generation. In this presentation, we will discuss X-Chem's approach to library design and selection, and how advancements in these areas power artificial intelligence (AI) applied to drug discovery. We will also discuss how X-Chem is enabling the biopharma industry to get the most out of this powerful platform, through AI tools, screening, reagent provision, and technology enablement.

A successful hit discovery campaign relies on the ability to rapidly identify true, target-specific structure-activity relationships (SARs) at an early stage of the hit-to-lead workflow. This is vital to effectively prioritizing hits and reserving downstream resources for off-DNA evaluation. Here we describe our continued efforts in the area, geared toward improving the value and applicability of our existing hit confirmation platform, Bead-Assisted Ligand Isolation Mass Spectrometry (BALI-MS).

Whereas most DNA-encoded libraries (DELs) are analyzed via affinity selection, my laboratory has developed technology to enable activity-based screening. The approach uses a combination of solid-phase DELs and microfluidic screening. I will present recent efforts to use in vitro translation as a generalized “plug-and-play” assay development approach to discover selective translation inhibitors, a new modality that circumvents the rules of druggability.

This talk describes the development and use of a Spotfire-based DEL screen analysis tool to triage and deliver hits with the best balance of screen signal, SAR, physicochemical properties, and coverage of biological profiles. Pfizer’s post-screen DEL process, key learnings that have improved success rates, and our onDNA/offDNA metrics will be described.

DNA binding proteins have been considered intractable for DNA Encoded Libraries (DEL). At Anagenex we are developing methods combining massively parallel biochemistry (customized DNA-Encoded Libraries and AS/MS), machine learning and in-lab experimental design to successfully find small molecule binders for difficult proteins.

When I describe DNA-encoded library technology, I'm almost always asked about limitations on "diversity" within the library pool imposed by the procedural preference for carrying out library synthesis in predominantly aqueous media. After some 20 years of responding to this concern, I'll review how my perception of this topic has evolved.

The University of California Drug Discovery Consortium (UCDDC) strives to leverage the biomedical research and commercialization strengths of the University of California (UC) system to accelerate the development of life-saving therapies and to translate discoveries into knowledge driven commercial enterprises that stimulate California’s economy. The UCDDC Executive Committee works with each UC-campus to advance drug development by providing expertise in drug discovery and by building relationships between industry and academics.

DNA-encoded libraries (DELs) provide a powerful technology for generating large libraries of macrocyclic peptides. However, obtaining membrane-permeable macrocycles from DELs remains challenging. I will present an approach for generating permeable macrocycles appended to DNA, with a particular focus on incorporation of N-methyl and peptoid residues. I will also present a chromatographic selection strategy that allows for separation of DNA-encoded libraries based on the passive permeability potential of the pendant macrocycles.

Many strategies have been developed for the synthesis and selection methods of DNA-encoded libraries (DEL). Here we describe our recent efforts on the development and application of DNA-encoded dynamic libraries (DEDLs), which combines the concept of dynamic combinatorial library (DCL) with DEL.

In an effort to expand the chemical space within the GlaxoSmithKline encoded libraries, we have partnered with the Molander Lab of The University of Pennsylvania to establish photoredox reactions for DNA-encoded libraries. Blue light irradiation of oxidative and reductive photocatalysts have been used to generate carbon-centered radicals, (both on- and off-DNA), resulting in a variety of useful transformations.

The hydrophilic, unprotected nature of the DNA severely limits the repertoire of DEL compatible chemical reactions. A general strategy for transferring DNA-substrates into organic solvents could open the DEL chemical reaction space. Reversible absorption of DNA to a solid support (RASS) facilitates the use of anhydrous solvents and multistep synthetic procedures. This expanded scope of reaction conditions has the potential to generate more conformationally diverse scaffolds with drug-like properties.