RESUMO
This paper reports the synthesis and the antiviral properties of new diarylpyrimidine (DAPY) compounds as nonnucleoside reverse transcriptase inhibitors (NNRTIs). The synthesis program around this new DAPY series was further optimized to produce compounds displaying improved activity against a panel of eight clinically relevant single and double mutant strains of human immunodeficiency virus type 1 (HIV-1).
Assuntos
Fármacos Anti-HIV/síntese química , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , Pirimidinas/síntese química , Inibidores da Transcriptase Reversa/síntese química , Fármacos Anti-HIV/farmacologia , Fármacos Anti-HIV/toxicidade , Linhagem Celular , Farmacorresistência Viral , Transcriptase Reversa do HIV/genética , HIV-1/genética , Humanos , Mutação , Pirimidinas/farmacologia , Pirimidinas/toxicidade , Inibidores da Transcriptase Reversa/farmacologia , Inibidores da Transcriptase Reversa/toxicidade , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
The docking of small molecules into the binding site of a target protein is an important but difficult step in structure-based drug design. The performance of a docking algorithm is usually evaluated by re-docking ligands into their native binding sites. We have explored the cross-docking of 18 HIV-NNRTIs (non-nucleoside inhibitors of HIV reverse transcriptase) of which the ligand-protein structure has been determined: each of the 18 ligands was docked into each of the 18 binding sites. The docking algorithms studied are an energy-based simulated annealing algorithm and a novel pharmacophore docking algorithm. It turns out that the energy-based docking of the ligands into non-native pockets is far less successful than the docking into their native pockets. The results can be improved by using explicit pharmacophore information, and by docking a ligand into a panel of protein structures and selecting the ligand-protein combination with the lowest interaction energy as the final result.