RESUMO
Ab initio derived atomic partial charges offer a simple, yet informative representation of the molecular electron density. We demonstrate the potential of different partial charge schemes for molecular descriptor construction. NPA and CM5 charges turned out to be largely conformation-independent and constitute representations of choice for molecular modelling and design.
RESUMO
We have identified dihydroxythiophenes (DHT) as a novel series of human immunodeficiency virus type 1 (HIV-1) integrase inhibitors with broad antiviral activities against different HIV isolates in vitro. DHT were discovered in a biochemical integrase high-throughput screen searching for inhibitors of the strand transfer reaction of HIV-1 integrase. DHT are selective inhibitors of integrase that do not interfere with virus entry, as shown by the inhibition of a vesicular stomatitis virus G-pseudotyped retroviral system. Moreover, in quantitative real-time PCR experiments, no effect on the synthesis of viral cDNA could be detected but rather an increase in the accumulation of 2-long-terminal-repeat cycles was detected. This suggests that the integration of viral cDNA is blocked. Molecular modeling and the structure activity relationship of DHT demonstrate that our compound fits into a two-metal-binding motif that has been suggested as the essential pharmacophore for diketo acid (DKA)-like strand transfer inhibitors (Grobler et al., Proc. Natl. Acad. Sci. USA 99:6661-6666, 2002.). This notion is supported by the profiling of DHT on retroviral vectors carrying published resistance mutations for DKA-like inhibitors where DHT showed partial cross-resistance. This suggests that DHT bind to a common site in the catalytic center of integrase, albeit with an altered binding mode. Taken together, our findings indicate that DHT are novel selective strand transfer inhibitors of integrase with a pharmacophore homologous to DKA-like inhibitors.
Assuntos
Infecções por HIV/metabolismo , Inibidores de Integrase de HIV/farmacologia , Integrase de HIV/metabolismo , HIV-1/metabolismo , Integração Viral/efeitos dos fármacos , Motivos de Aminoácidos , Sítios de Ligação/efeitos dos fármacos , Sítios de Ligação/genética , Linhagem Celular , DNA Complementar/biossíntese , DNA Complementar/genética , DNA Viral/biossíntese , DNA Viral/genética , Farmacorresistência Viral/efeitos dos fármacos , Farmacorresistência Viral/genética , Infecções por HIV/tratamento farmacológico , Infecções por HIV/genética , Integrase de HIV/genética , Inibidores de Integrase de HIV/química , Inibidores de Integrase de HIV/uso terapêutico , HIV-1/genética , Humanos , Modelos Moleculares , Estrutura Molecular , Mutação , Ligação Proteica , Relação Estrutura-Atividade , Vírus da Estomatite Vesicular Indiana/genética , Vírus da Estomatite Vesicular Indiana/metabolismo , Integração Viral/genéticaRESUMO
Semiempirical AM1 studies on phycocyanobilin, the most abundant chromophore in the light-harvesting phycobiliproteins and a suitable model of the phytochrome chromophore, have been carried out. For the all-Z isomer, the structures and energies of all possible conformers, which arise from rotation about the single bonds of the exocyclic methine bridges, were calculated. In addition, the rotational barriers between the different conformers were deduced from the computed energy hypersurfaces. The cyclic helical SSS conformation is the most stable structure. Other minimum-energy structures with well-separated local minima on the energy hypersurface are the partially extended ASS and SAS conformations, although the conformational situation is characterized by a high degree of kinetic flexibility. The energy of the different conformers is mainly governed by intramolecular hydrogen bonding and steric repulsion of the substituents at the tetrapyrrolic backbone. It is very likely that the energetically most favorable conformers, SSS, ASS, and SAS, correspond with the three ground-state conformers of phycocyanobilin detected in previous time-resolved absorption studies.
