Exploiting Matched Molecular Pairs to Design New Cores Using CoreDesign®
Jess Stacey, Al Dossetter, Ed Griffen, Andrew Leach, Lauren Reid, Phillip de Sousa, Bashy Khan, Dan James, David Cousins and Jacqui Clarkson
MedChemica Ltd. MedChemica Ltd, The Motorworks, Chestergate, Macclesfield, SK11 6DU
Within the drug discovery process, typically an active core structure is established and alterations around the core are performed to improve properties of interest. Scaffold hopping is an approach used to explore new chemistry around the core (/scaffold) of interest in the hope to retain similar properties with slight structural changes. Scaffolds are typically a ring system or systems that can sometimes be connected by linkers. There have been several studies examining the potential ring chemical space and replacements1-3.
MedChemica Ltd is a pioneer and advocate of using Matched Molecular Pairs (MMPs) within the drug discovery process4-7. By exploiting MMPs MedChemica have developed software called RuleDesign® that performs small chemical transformations to improve the properties of an input molecule. Within RuleDesign® only transformations are applied if there is a high certainty of improvement in the property of interest. This is determined using statistical analysis on the MMPs and measurement data. CoreDesign® is an extension of RuleDesign®, where the probability of a successful transformation improving the property of interest is relaxed by including all possible transformations that have an associated reference, with a focus on core changes, whether the alteration is to the ring system or linker of the core. Therefore, CoreDesign® prioritises core exchanges with good synthetic tractability alongside a bibliography of other instances where this transformation occurred so users can understand whether this transformation is applicable.
This talk will explain the process of CoreDesign® and how we have used our new tool to suggest new PROTACs using ARV-110 and ARV-471 as starting points.
 Pitt, W., et al., Heteroaromatic Rings of the Future., J. Med. Chem., 2009, 52, 2952-2963
 Tu, M., et al., Exploring Aromatic Chemical Space with NEAT: Novel and Electronically Equivalent Aromatic Template., J. Chem. Inf. Model., 2012, 52, 1114-1123
 Ertl, P. Magic Rings: Navigation in the Ring Chemical Space Guided by the Bioactive Rings., J. Chem. Inf. Model., 2021, DOI: 10.1021/acs.jcim.1c00761
 Leach, A. G., et al., Matched Molecular Pairs as a guide in the Optimization of Pharmaceutical Properties; a Study of Aqueous Solubility, Plasma Protein Binding and Oral Exposure., J. Med. Chem., 2006, 49, 23, 6672-6682
 Hussain, J., et al., Computationally Efficient Algorithm to Identify Matched Molecular Pairs (MMPs) in Large Data Sets., J. Chem. Inf. Model., 2010, 50, 3, 339-348
 Griffen, E., et al., Matched Molecular Pairs as a Medicinal Chemistry Tool., J. Med. Chem., 2011, 54, 22, 7739-7750
 Dossetter, A. G., et al., Matched Molecular Pair Analysis in Drug Discovery., Drug Disco. Today., 2013, 18, 15, 724-731