Insights for design of Trypanosoma cruzi GAPDH inhibitors: A QM/MM MD study of 1,3‐bisphospo‐D‐glyceric acid analogs

• DOI: 10.1002/qua.24253
• Publication Date: 2012-06-26T18:06:06Z
• Authors: José Rogério Araú...; Jerônimo Lameira; Cláudio Nahum Alves
• Keywords: 0303 health sciences; 03 medical and health sciences

AbstractGlyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) is a key‐enzyme for design of new drugs against Chagas disease. Herein, molecular inhibition mechanism of GAPDH involving 1,3‐bisphospho‐D‐glyceric acid (1,3‐BPGA) analogs were studied using the hybrid quantum mechanical/molecular mechanical (QM/MM) approach and molecular dynamic simulations. The analysis of the binding contribution of the individual residues shows that Lys209, Asp210, Arg212, Thr167, Thr197, Thr199, Ser224, Thr226, Ser247, Arg249, water molecules, and NAD+ are responsible for stabilization of the protein‐inhibitor complexes. The results obtained suggest that Arg249 plays an important role in the GAPDH‐inhibitor complex and might induce the compression of the 1,3‐BPGA analogs inside the active site of GAPDH. In addition, analysis of QM/MM molecular dynamics simulations have shown that the extended conformation 1,3‐BPGA analogs contribute to biological activity of these compounds. © 2012 Wiley Periodicals, Inc.