Dual inhibitors of the dengue and West Nile virus NS2B-NS3 proteases: Synthesis, biological evaluation and docking studies of novel peptide-hybrids.

Dengue virus (DENV) and West Nile virus (WNV) are mosquito-borne arboviruses responsible for causing acute systemic diseases and severe health conditions in humans. The discovery of therapies capable to prevent infections or treat infected individuals remains an important challenge, since no vaccine or specific efficient treatment could be developed so far. In this context, we present herein the synthesis, characterization, biological evaluation and docking studies of novel peptide-hybrids based on 2,4-thiazolidinedione scaffolds containing non-polar groups. The most promising compound has an IC50 of 0.75 µM against WNV protease, which represents a seventyfold improvement in activity compared to our previously reported compounds. Experimental results and docking studies are in agreement with the hypothesis that a non-polar group in the scaffold is important to obtain interactions between the inhibitors and a hydrophobic pocket in the substrate recognition region of the DENV and WNV NS2B-NS3 serine proteases.

C-terminal residue optimization and fragment merging: discovery of a potent Peptide-hybrid inhibitor of dengue protease.

Dengue virus protease is a promising target for the development of antiviral drugs. We describe here a two-step rational optimization that led to the discovery of the potent inhibitor 35 with nanomolar binding affinity at dengue protease serotype 2 (IC50 = 0.6 µM, K i = 0.4 µM). First, a large number of natural and non-natural amino acids were screened at the C-terminal position of the previously reported, canonical peptide sequence (Cap-Arg-Lys-Nle-NH2). Compared to the reference compound 1 (Bz-Arg-Lys-Nle-NH2, IC50 = 13.3 µM), a 4-fold higher inhibitory potential was observed with the incorporation of a C-terminal phenylglycine (compound 9, IC50 = 3.3 µM). Second, we applied fragment merging of 9 with the previously reported thiazolidinedione peptide hybrid 33 (IC50 = 2.5 µM). This approach led to the fusion of two inhibitor-fragments with micromolar affinity into a 20-fold more potent, competitive inhibitor of dengue protease.

Molecular-dynamics simulations of dimethylsulfoxide-methanol mixtures.

We present molecular-dynamics (MD) computer simulation results for the local structures, hydrogen (H)-bond distribution, and dynamical properties of methanol (MeOH) and dimethylsulfoxide (DMSO) binary mixtures at ambient conditions over the entire composition range. The simulated heat of mixing and site-site pair distribution functions suggest that the intermolecular structures of the pure liquids are not markedly altered upon mixing. Nevertheless, H-bonding statistics show that aggregates of the type 1DMSO:1MeOH are formed and represent the predominant form of molecular association in these mixtures. Only a small fraction (10%) of DMSO molecules in MeOH-rich mixtures (85% in mole) forms H-bonding trimers of type 1DMSO:2MeOH. No evidence of other types of interspecies association is found. The self-diffusion coefficient for DMSO (MeOH) increases (decreases) upon mixing. The characteristic reorientation time tau1 of both species increases in the mixture, but the composition dependence is weak. The frequency spectrum of MeOH reorientational time-correlation function shows significant redshifts of the principal librational band as DMSO is added to the system, whereas the librational band of DMSO shows small alterations upon mixing. Our results are discussed in the light of previous simulation analyses for a similar system, DMSO-water mixtures, and compared with available experimental results.

A simulation study of the optical Kerr effect in liquid water.

A molecular dynamics simulation study is presented for the dynamics of the polarizability anisotropy of liquid water using the SPC/E model and a dipolar induction scheme that involves the intrinsic polarizability and first hyperpolarizability tensors obtained from ab initio quantum chemical calculations at the MP2/6-311++G(d,p) level. The time-correlation functions for the collective polarizability anisotropy, the optical Kerr effect response, and the frequency spectra are analyzed in terms of the intrinsic and induced polarizability contributions. At short times, the simulated Kerr nuclear response exhibits maxima near 15, 50 and 180 fs, followed by a diffusive tail which has been fitted by a bi-exponential with time constants ca. 0.4 and 2.5 ps. The short time features are in good agreement with available simulation and experimental results. The agreement with experiments is less satisfactory for the diffusive components. The main features of the frequency spectrum include a rotational-diffusion peak centered around 3 cm(-1), a collision-induced (hindered translations) band near 200 cm(-1), and a broad librational band at 450 cm(-1). The simulation results are in good agreement with experimental frequency spectra obtained from Kerr effect and related spectroscopies, but fail to reproduce the experimental band near 60 cm(-1).