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 (IC 50 = 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-NH 2 ). Compared to the reference compound 1 (Bz-Arg-Lys-Nle-NH 2 , IC 50 = 13.3 μM), a 4-fold higher inhibitory potential was observed with the incorporation of a C-terminal phenylglycine (compound 9, IC 50 = 3.3 μM). Second, we applied fragment merging of 9 with the previously reported thiazolidinedione peptide hybrid 33 (IC 50 = 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. KEYWORDS: Dengue virus, protease inhibitor, peptide, fragment merging D engue virus (DENV), with its four common serotypes (DENV 1−4), is considered the most important diseasecausing arbovirus in tropical and subtropical regions and a major public health concern. A recent study estimates a global infection burden of 390 million cases in 2010, a more than 3-fold higher number than reported previously by the World Health Organization. 1,2 Increasing prevalence of dengue infections worldwide has been associated with the geographical spread of Aedes mosquitoes, the primary transmitting vector, probably as a result of global warming and climate changes. 3 Currently, vaccines or antiviral agents against DENV remain unavailable. Viral proteases are extremely relevant for the development of antiviral drugs. 4 Highly successful examples are the hepatitis C virus (HCV) NS3 protease inhibitors, such as boceprevir and telaprevir, 5 and the HIV protease inhibitors. 6 DENV protease is regarded as a similarly promising target for drug discovery efforts against dengue virus infections. 7 The enzyme is critical for the viral replication cycle. It posttranslationally cleaves the viral polyprotein, encoded by a single stranded RNA, into three structural and seven nonstructural (NS) proteins. The proteolytically competent NS3-NS2B complex consists of the NS3 serine protease domain and the hydrophilic core sequence of NS2B as cofactor. 8,9 Published inhibitors against DENV protease range from small molecule nonpeptidic inhibitors, 10−13 so far not capable of achieving sufficient target inhibition, to substrate-mimicking peptidic inhibitors. 14−18 The latter class benefits from improved molecular recognition because of its similarity to the natural substrate, which offers higher selectivity and activity, reaching the low micromolar range and even the nanomolar range when combined with an electrophilic warhead. 18 However, the promising in vitro binding affinities come at the expense of pharmacokinetic properties, such as membrane permeability and metabolic stability, which is challenged by ...

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).

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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.