Insights in Medicinal Chemistry and GPCR
Posted 23rd February 2018 by Jane Williams
1. The future of encoded library technology (ELT)
DNA encoded libraries build upon work done in the late 20th century in dynamic combinatorial chemistry. Large numbers of chemical building blocks, tagged with DNA ‘bar codes’ are held in a dynamic equilibrium with one another, reversibly forming compound structures. By adding a receptor to the mixture, the best binding structure is removed from equilibrium, driving its amplification and allowing it to be identified.
A number of authors, including Stevan Djuric (Abbvie, IL, USA) and Xiaopeng Bai (GSK, MA, USA), discussed recent developments in ELT, such as using chemoresistant DNA to extend the combinatorial toolkit and its incorporation into the drug development cycle for efficient affinity assessment.
2. Protein degradation as a new avenue for drug design
Classical drug design often focuses on building compounds to disrupt natural pathways. Rather than inhibiting proteins, researchers have recently been attempting a different tactic – inducing the irreversible breakdown of their structure. This is being done through the cells existing ubiquitin proteasome pathway (UPP), which marks proteins for degradation. Proteolysis targeting chimeras (PROTACs) are small linker compounds, with one end binding to E3 ubiquitin ligase, and the other to the protein of interest (POI).
By using PROTACs to bind both the E3 ubiquitin ligase and the POI, the UPP can be used to selectively degrade the POI. In essence, the PROTAC recruits the POI to the E3 ligase for ubiquitylation, marking the protein for degradation by the 26S proteasome. Ian Churcher (BenevolentBio, London, UK), George Burslem (Yale University, CT, USA) and Alessio Ciulli (University of Dundee, Dundee, UK) discussed their use of PROTACs and how this work could lead to a drastically new class of drugs.
3. Tipping the balance to trigger cell death
David Wilson (AstraZeneca) spoke on his team’s work in triggering the breakdown of cancer cells. BcI-2 is a class of proteins that regulates apoptosis in cells. BcI-2 proteins exist in a careful balance, with members either inducing the process or inhibiting it through protein-protein interactions.
Wilson’s team has identified motifs for interfering with these interactions and accentuated their effects through macrocyclisation techniques that allow for bioactive preorganisation. The hope is that by removing ‘pro-survival’ BcI-2 interactions in cancer cells, drugs could trigger an enzyme cascade, causing the cancer to break itself apart in a controlled and nondestructive manner.
4. Addressing complex targets in drug design through a more dynamic approach
At Sanofi, work on complex drug targets has found success in moving beyond static computational models for compound to target interactions. Laurent Schio (Paris, France) discussed how his team had studied the KRAS oncogene, which acts as a trigger to engage proteins for propagation. KRAS’s activity is controlled by the position of two ‘switches’, which are most stable when sitting in the ‘active’ conformation.
The team discovered that by using a rigid covalent structure to link the two switches, they could be stabilised in their inactive state, inhibiting the propagation trigger. Schio also talked about the overlooked role of water in ligand binding and the challenges in effectively using explicit solvation models.
5. A more nuanced approach to permeability
Towards the end of the day, Nick Terrett (Merck, Sharpe and Dohme, Lucerne, Switzerland) reviewed how drugs can move beyond Lipinski’s ‘rule of 5’. By studying how natural proteins pass through cell membranes, researchers in recent years have been looking into novel mechanisms for drug penetration, falling into two categories.
Charge shielding uses cationic peptide motifs to interact with charged phospholipid heads, guiding the protein to pass through the membrane. By designing conformationally fluid structures, drugs can expose charged groups to pass through membranes before flipping to the active conformation. The second method is through endocytosis, in which the peptide creates an endosome to enter the cell, stabilising its enthalpically costly formation.
The next Medicinal Chemistry Summit will take place September 17 – 18 in Boston. Take a look at the agenda.
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