Computational design and evaluation of LYTACS for the selective degradation of MMP-2

Abstract

LYTACs (LYsosome TArgeting Chimeras) are a novel pharmacological strategy based on the targeted protein degradation of extracellular and transmembrane proteins. Their mechanism of action is based on the use of a membrane receptor to internalize a target protein and mediate its lysosomal degradation. To date, its development has been focused on the use of antibodies for target binding, which has certain disadvantages from the pharmacokinetic and synthetic point of view. The aim of this work is to design a LYTAC capable of inducing the selective degradation of MMP-2 (LYTAC-MMP2), a matrix metalloprotease that is overexpressed in many types of cancer. LYTAC-MMP2 consists of a cation-independent mannose-6-phosphate receptor (CI-MPR) ligand and a selective MMP-2 inhibitor developed by our research group. Computational methods of homology modelling, docking and molecular dynamics have been used to study the CI-MPR receptor and its internalization mechanism, as well as for the comparison of the dynamic behaviour in water of a CI-MPR ligand described in the literature and LYTAC-MMP2.