ADMET properties, database screening, molecular dynamics, density functional, and docking studies of novel potential anti-cancer compounds.
Database screening was performed in a large database (hundreds of thousands of molecules which we optimized at the AM1 level) yielding a set of potential bioactive ligands. One new ligand was selected among the top solutions and optimized at the B3LYP/6-31G* level, yielding also NBO (Natural Bond Order) charges. A flexible docking program was used to investigate the interactions between the receptor and the new ligand. The stability as well as the main protein-ligand contacts of our proposed novel ligand as well as the crystallographic RAR ligand was investigated by molecular dynamics. The ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) properties as well as the parameters of the Rule of Five were investigated. The result of this work is compared with a crystallographic ligand of RAR. Our novel proposed anti-cancer ligand indicates hydrophobic interactions and strong polar interactions with the receptor.
Silva
Carlos H T P
CH
Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Av. do cafe, s/n, CEP 14040-903, Ribeirão Preto, SP, Brasil.
Taft
C A
CA
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D015195:Drug Design; D008024:Ligands; D008958:Models, Molecular; D011487:Protein Conformation; D011789:Quantum Theory; D018168:Receptors, Retinoic Acid / Q000737:chemistry / Q000378:metabolism; D047488:Retinoid X Receptors / Q000737:chemistry / Q000378:metabolism
D000970:Antineoplastic Agents; D008024:Ligands; D018168:Receptors, Retinoic Acid; D047488:Retinoid X Receptors