In search of AKT kinase inhibitors as anticancer agents: structure-based design, docking, and molecular dynamics studies of 2,4,6-trisubstituted pyridines

<p>The AKT isoforms are a group of key kinases that play a critical role in tumorigenesis. These enzymes are overexpressed in different types of cancers, such as breast, colon, prostate, ovarian, and lung. Because of its relevance the AKT isoforms are attractive targets for the design of anticancer molecules. However, it has been found that AKT1 and AKT3 isoforms have a main role in tumor progression and metastasis; thus, the identification of AKT isoforms specific inhibitors seems to be a challenge. Previously, we identified an ATP binding pocket pan-AKT inhibitor, this compound is a 2,4,6-trisubstituted pyridine (compound <b>11</b>), which represents a new interesting scaffold for the developing of AKT inhibitors. Starting from the 2,4,6-trisubstituted pyridine scaffold, and guided by structure-based design technique, 42 new inhibitors were designed and further evaluated in the three AKT isoforms by multiple docking approach and molecular dynamics. Results showed that seven compounds presented binding selectivity for AKT1 and AKT3, better than for AKT2. The binding affinities of these seven compounds on AKT1 and AKT3 isoforms were mainly determined by hydrophobic contributions between the aromatic portion at position 4 of the pyridine ring with residues Phe236/234, Phe237/235, Phe438/435, and Phe442/439 in the ATP binding pocket. Results presented in this work provide an addition knowledge leading to promising selective AKT inhibitors.</p

Insights into the structure and inhibition of <i>Giardia intestinalis</i> arginine deiminase: homology modeling, docking, and molecular dynamics studies

<p><i>Giardia intestinalis</i> arginine deiminase (<i>GiADI</i>) is an important metabolic enzyme involved in the energy production and defense of this protozoan parasite. The lack of this enzyme in the human host makes <i>GiADI</i> an attractive target for drug design against <i>G. intestinalis</i>. One approach in the design of inhibitors of <i>GiADI</i> could be computer-assisted studies of its crystal structure, such as docking; however, the required crystallographic structure of the enzyme still remains unresolved. Because of its relevance, in this work, we present a three-dimensional structure of <i>GiADI</i> obtained from its amino acid sequence using the homology modeling approximation. Furthermore, we present an approximation of the most stable dimeric structure of <i>GiADI</i> identified through molecular dynamics simulation studies. An <i>in silico</i> analysis of druggability using the structure of <i>GiADI</i> was carried out in order to know if it is a good target for design and optimization of selective inhibitors. Potential <i>GiADI</i> inhibitors were identified by docking of a set of 3196 commercial and 19 <i>in</i>-<i>house</i> benzimidazole derivatives, and molecular dynamics simulation studies were used to evaluate the stability of the ligand–enzyme complexes.</p