The third MIDD student symposium will take place on November 4th at 2:30 pm in CHEM110 (Chemistry Building). The event will give student affiliated with the MIDD the opportunity to present their work to other UWM students. We hold this event six times a year, bimonthly on the first Wednesday of the month at 2:30 pm. The presentation are 20 minutes long with 5 min Q&A. We have the following presentations:
Absolute Binding Free Energy Calculations Reveal How Bruton’s Tyrosine Kinase (BTK) Mutations Disrupt Inhibitor Binding at the Molecular Level
Justice Josiah Mallen from the Research Group of Prof. Arjun Saha Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53211, United States
Kinases play a crucial role in controlling signaling pathways, and their dysregulation is directly linked to numerous diseases, including various cancers, thus making them highly significant targets for therapeutic intervention. Bruton’s tyrosine kinase (BTK) plays a critical role in B-cell development and signaling, and BTK inhibitors (BTKi) have shown significant clinical success in the treatment of B-cell malignancies, particularly chronic lymphocytic leukemia (CLL). Both covalent and non-covalent classes of BTK inhibitors represent promising strategies for kinase-targeted therapeutic intervention. However, the clinical landscape is marred by an escalating incidence of relapses and refractory cases in CLL, especially among those harboring BTK mutations within the catalytic domain. Recently, a novel therapeutic approach known as PROTAC (Proteolysis Targeting Chimeras) has been introduced, offering new avenues for treatment; however, it too is encountering resistance. In this work, we first conducted a computational study using the Molecular Mechanics-Poisson-Boltzmann Surface Area (MM-PBSA) method to predict the effects of mutations on inhibitor binding affinity. We then applied a more rigorous statistical mechanics approach (BFEE2) to achieve accurate predictions of protein-inhibitor binding affinities. This study aims to support the development and design of drugs capable of combating these mutations. The non-covalent inhibitors analyzed include Pirtobrutinib (PDB ID: 8FLL), Fenebrutinib (PDB ID: 5VFI), YDA (PDB ID: 7LTZ), 73T (PDB ID: 5T18), and L0Z (PDB ID:6S90). Our findings provide valuable molecular insights into the structural determinants, thermodynamics, and conformational energies that influence ligand binding for this clinically relevant biological target.