In search of AKT kinase inhibitors as anticancer agents: structure-based design, docking, and molecular dynamics studies of 2,4,6-trisubstituted pyridines.
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 11), 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.
a Facultad de Química, Departamento de Farmacia , Universidad Nacional Autónoma de México , Ciudad de México 04510 , Mexico.
Pedro Josué
PJ
Trejo-Soto
a Facultad de Química, Departamento de Farmacia , Universidad Nacional Autónoma de México , Ciudad de México 04510 , Mexico.
Alicia
A
Hernández-Campos
b Facultad de Química, División de Estudios de Posgrado , Universidad Autónoma de Querétaro , Santiago de Querétaro 07610 , Mexico.
Antonio
0000-0003-2869-588X
A
Romo-Mancillas
a Facultad de Química, Departamento de Farmacia , Universidad Nacional Autónoma de México , Ciudad de México 04510 , Mexico.
José L
JL
Medina-Franco
a Facultad de Química, Departamento de Farmacia , Universidad Nacional Autónoma de México , Ciudad de México 04510 , Mexico.
Rafael
R
Castillo
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009369:Neoplasms / Q000188:drug therapy*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011725:Pyridines / Q000737:chemistry* / Q000627:therapeutic use; D013329:Structure-Activity Relationship
D000970:Antineoplastic Agents; D011725:Pyridines; C007106:gamma-collidine; D051057:Proto-Oncogene Proteins c-akt
2,4,6-trisubstituted pyridines; AKT; cancer; molecular dynamics; serine-threonine kinase B