No abstract

No abstract

No abstract

A novel coronavirus has been identified as an etiological agent of severe acute respiratory syndrome (SARS). To rapidly identify anti-SARS drugs available for clinical use, we screened a set of compounds that included antiviral drugs already in wide use. Here we report that the HIV-1 protease inhibitor, nelfinavir, strongly inhibited replication of the SARS coronavirus (SARS-CoV). Nelfinavir inhibited the cytopathic effect induced by SARS-CoV infection. Expression of viral antigens was much lower in infected cells treated with nelfinavir than in untreated infected cells. Quantitative RT-PCR analysis showed that nelfinavir could decrease the production of virions from Vero cells. Experiments with various timings of drug addition revealed that nelfinavir exerted its effect not at the entry step, but at the post-entry step of SARS-CoV infection. Our results suggest that nelfinavir should be examined clinically for the treatment of SARS and has potential as a good lead compound for designing anti-SARS drugs.

No abstract

No abstract

We have theoretically examined the relative binding affinities (RBA) of typical ligands, 17beta-estradiol (EST), 17alpha-estradiol (ESTA), genistein (GEN), raloxifene (RAL), 4-hydroxytamoxifen (OHT), tamoxifen (TAM), clomifene (CLO), 4-hydroxyclomifene (OHC), diethylstilbestrol (DES), bisphenol A (BISA), and bisphenol F (BISF), to the alpha-subtype of the human estrogen receptor ligand-binding domain (hERalpha LBD), by calculating their binding energies. The ab initio fragment molecular orbital (FMO) method, which we have recently proposed for the calculations of macromolecules such as proteins, was applied at the HF/STO-3G level. The receptor protein was primarily modeled by 50 amino acid residues surrounding the ligand. The number of atoms in these model complexes is about 850, including hydrogen atoms. For the complexes with EST, RAL, OHT, and DES, the binding energies were calculated again with the entire ERalphaLBD consisting of 241 residues or about 4000 atoms. No significant difference was found in the calculated binding energies between the model and the real protein complexes. This indicates that the binding between the protein and its ligands is well characterized by the model protein with the 50 residues. The calculated binding energies relative to EST were very well correlated with the experimental RBA (the correlation coefficient r=0.837) for the ligands studied in this work. We also found that the charge transfer between ER and ligands is significant on ER-ligand binding. To our knowledge, this is the first achievement of ab initio quantum mechanical calculations of large molecules such as the entire ERalphaLBD protein.

Studies of the genetic regulation involved in drug metabolizing enzymes and drug transporters are of great interest to understand the molecular mechanisms of drug response and toxic events. Recent reports have revealed that hydrophobic ligands and several nuclear receptors are involved in the induction or down-regulation of various enzymes and transporters involved in Phase I, II, and III xenobiotic metabolizing systems. Nuclear receptors (NRs) form a family of ligand-activated transcription factors (TFs). These proteins modulate the regulation of target genes by contacting their promoter or enhancer sequences at specific recognition sites. These target genes include metabolizing enzymes such as cytochrome P450s (CYPs), transporters, and NRs. Thus it was now recognized that these NRs play essential role in sensing processing xenobiotic substances including drugs, environmental chemical pollutants and nutritional ingredients. From literature, we picked up target genes of each NR in xenobiotic response systems. Possible cross-talk, by which xenobiotics may exert undesirable effects, was listed. For example, the role of NRs was comprehensively drawn up in cholesterol and bile acid homeostasis in human hepatocyte. Summarizing current states of related research, especially for in silico response element search, we tried to elucidate nuclear receptor mediated xenobiotic processing loops and direct future research.