Diseño racional de fármacos del proteosoma para mieloma múltiple

Abstract

The objective of this research is to theoretically and rationally design a new drug for a molecular target such as the proteasome by means of computational methods for chemotherapy treatment in patients with Multiple Myeloma (MM). To achieve this, a protein provided by the Protein Data Bank (6XMJ) was used and all the drugs from the family of proteasome inhibitors that are commercial or in preclinical and clinical phases were analyzed, including Bortezomib, Ixazomib, Carfilzomib, Oprozomib, Marizomib and Delanzomib. Each of them acted as a ligand and had an interaction between the β5 subunit of the proteasome. Different software such as ChemSketch, Avogadro, Autodock Vina, Discovery Studio and PreADMET were used to determine variables such as interactions (SAR), molecular docking and toxicity. After this, Delanzomib was chosen as the leading drug, which would be structurally modified, respecting the pharmacophore and modifying the auxophore, where the pertinent isosteric changes were made. 21 compounds were analyzed through computational methods and a new drug prototype called INA-216 was generated whose functional group is an amide and achieved interaction with 14 amino acids of the proteasome and had much better toxicity values ​​compared to Delanzomib. INA-216 may function as a potential drug for the treatment of MM as it was determined that inhibition of the proteasome results in the stabilization of signaling pathways that are affected by MM, which may have effects on decreased proliferation. cell and increased apoptosis.