Design of a new class of PKM2 pharmacological inhibitors using docking based virtual library screening

VELEZ RUEDA A; SANCHEZ M; LORENZANO-MENNA P; GONZALES N; FERNANDEZ N; CABRERA M; CHINESTREAD P; ZINNI A

Bariloche

Simposio; The fourth South American Spring Symposium in Signal Trasducction and Molecular Medicine. (SISTAM 2018); 2018

The aerobic glycolysis (i.e. Warburg effect) is one of the major metabolic alterations observed in cancer. This metabolic reprogramming is associated to the re-expression of M2 isoform of Pyruvate Kinase (PKM2), a rate-limiting enzyme mainly expressed in embryonic and cancer cells.In normal tissues, the M1 isoform is expressed over M2 through alternative splicing of the mutually exclusive exons 9 and 10. Unlike the other isoforms, PKM2 exists in a quaternary-active and dimer-inactive glycolytic structure. The relatively inactive dimer allows the accumulation of glycolytic intermediates and several moonlight functions such as gene transcription, protein kinase activity and redox balance. The regulation of this oligomeric balance by protein-protein interaction pharmacologic modulation is a new therapeutic strategy for cancer treatment.A meta-analysis of clinical expression data over 3000 samples of mama and lung cancer patients from GEO (Gene Expression Omnibus) database was performed. Consistently with the state of art, results indicate a significative overexpression of PKM2 on both tumors compared to normal tissues. In addition, PKM2 expression is significantly associated with poor overall survival. The aim of this work is to discover novel selective compounds whose would be able to modulate the oligomeric dynamics of PKM2. Selection of PKM2 structure was based on conformational diversity evaluation of all crystal structures using CoDNas database. Docking based Virtual Library Screening was performed using about 500.000 drug like compounds, focusing on key residues involved in the inter-subunit contacts. After an exhaustive visual inspection focused on the interactions between the compounds with key residues involved in the oligomerization states of PKM2, 10 potential new classes of PKM2 inhibitors were selected. These one were with free energy values between -10.1 and -9.7.Future perspectives of this research involve the biological evaluation of the selected compounds onto mama and lung cancer model in order to identify the lead compound.