How misfit drugs cross barriers

DRA lecture held by Post Doc Lianne Wieske, Centre for Targeted Protein Degradation, University of Dundee, UK

Lianne's work sits at the interface of molecular biology and medicinal chemistry with a strong emphasis on structure elucidation. In this seminar, she will talk about the conformational investigation of beyond Rule of five drugs. Extensive NMR experiments were used to study macrocyclic drugs, synthetic peptidomimetics, and PROTACs to gain insights into their chameleonic behaviour.

Abstract
Most drugs on the market today are small organic compounds that fall within the Lipinski’s rule of five (Ro5) and bind targets with well-defined binding-pockets. However, targets that lack a clear binding site are difficult to drug with Ro5 compliant compounds. These difficult-to-drug targets can sometimes be modulated by compounds occupying the space beyond the rule of five (bRo5). Despite the improved binding affinity and target selectivity of these drugs, their increased size poses additional synthetic challenges and complicates oral availability. Within the bRo5 space macrocycles and Proteolysis Targeting Chimeras (PROTACs) have received special attention, signified by an exponential growth of research since the 2000s. About 30-40% of the macrocyclic drugs have shown to be orally available, and PROTACs seem to be following a similar trend.

Extensive NMR studies have been used to study the mechanism by which these bRo5 drugs are able to permeate the cell. The obtained results give insight into the different types of chameleonic behaviour. Furthermore, this allowed us to have a closer look at the conformational journey two macrocycles took from crystal formulation, into solution, across the membrane, to its target.

The linker composition of PROTACs is of crucial importance when it comes to oral absorption. Thorough NMR investigations indicate how certain linker components modulate the chameleonic behaviour of the investigated PROTACs.

The lecture is organised on behalf of the graduate programme in pharmaceutical sciences, Drug Research Academy, by Assistant Professor Francesco Bavo, Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen.

The DRA lecture is free of charge and open for attendance by all interested parties. It is not necessary to pre-register.