From Synthesis to DFT Calculations: Computational and Experimental Approaches in Drug Discovery

This work combines organic synthesis and computational chemistry to address diverse drug discovery challenges. In the Maytansinol project, bifunctional compounds linking maytansinol to a tubulin-binding peptide were synthesized via click chemistry, and three are now under biological evaluation. In the PHOX15 project, molecular dynamics identified a derivatizable site on TAU fibrils, guiding the design of polypharmacological PROTACs targeting TAU, GSK3β and Cdk5, supported by a library of lenalidomide derivatives. In the ASIC3 project, novel ligands targeting glioblastoma cancer stem cells were prepared. Finally, the absolute configurations of ARN2011 enantiomers (an Nfix inhibitor) and a CBD diaryl dimer were assigned by combining chiral separation, circular dichroism and TDDFT-calculated ECD spectra.