Magaly Girão Albuquerque

Snake venom thrombin-like enzymes: from reptilase to now.

The snake venom thrombin-like enzymes (SVTLEs) comprise a number of serine proteases functionally and structurally related to thrombin. Until recently, only nine complete sequences of this subgroup of the serine protease family were known. Over the past 5 years, the primary structure of several SVTLEs has been characterized, and now this family includes several members. Of particular interest is their possible use in pathologies such as thrombosis. The aim of the present review is to summarize the state of the art concerning the evolutionary, structural and biological features of the SVTLEs.

Synthesis, antichagasic in vitro evaluation, cytotoxicity assays, molecular modeling and SAR/QSAR studies of a 2-phenyl-3-(1-phenyl-1H-pyrazol-4-yl)-acrylic acid benzylidene-carbohydrazide series.

Chagas disease (American trypanosomiasis) is one of the most important parasitic diseases with serious social and economic impacts mainly on Latin America. This work reports the synthesis, in vitro trypanocidal evaluation, cytotoxicity assays, and molecular modeling and SAR/QSAR studies of a new series of N-phenylpyrazole benzylidene-carbohydrazides. The results pointed 6k (X=H, Y=p-NO2, pIC(50)=4.55 M) and 6l (X=F, Y=p-CN, pIC(50)=4.27 M) as the most potent derivatives compared to crystal violet (pIC(50)=3.77 M). The halogen-benzylidene-carbohydrazide presented the lowest potency whereas 6l showed the most promising profile with low toxicity (0% of cell death). The best equation from the 4D-QSAR analysis (Model 1) was able to explain 85% of the activity variability. The QSAR graphical representation revealed that bulky X-substituents decreased the potency whereas hydrophobic and hydrogen bond acceptor Y-substituents increased it.

Docking of the alkaloid geissospermine into acetylcholinesterase: a natural scaffold targeting the treatment of Alzheimer’s disease

AbstractPharmacological studies from our group [Lima et al. Pharmacol Biochem Behav 92:508, (2009)] revealed that geissospermine (GSP), the major alkaloid of the bark extract of Brazilian Geissospermum vellosii, inhibits acetylcholinesterases (AChEs) in the brains of rats and electric eels (Electrophorus electricus). However, the binding mode (i.e., conformation and orientation) of this indole-indoline alkaloid into the AChE active site is unknown. Therefore, in order to propose a plausible binding mode between GSP and AChE, which might explain the observed experimental inhibitory activity, we performed comparative automatic molecular docking simulations using the AutoDock and Molegro Virtual Docker (MVD) programs. A sample of ten crystal structures of the Pacific electric ray (Torpedo californica) TcAChE, in complex with ten diverse active site ligands, was selected as a robust re-docking validation test, and also for GSP docking. The MVD results indicate a preferential binding mode between GSP and AChE, in which GSP functional groups may perform specific interactions with residues in the enzyme active site, according to the ligand–protein contacts detected by the LPC/CSU server. Four hydrogen bonds were detected between GSP and Tyr121, Ser122, Ser200, and His440, in which the last two residues belong to the catalytic triad (Ser200···His440···Glu327). Hydrophobic and π–π stacking interactions were also detected between GSP and Phe330 and Trp84, respectively; these are involved in substrate stabilization at the active site. This study provides the basis to propose structural changes to the GSP structure, such as molecular simplification and isosteric replacement, in order to aid the design of new potential AChE inhibitors that are relevant to the treatment of Alzheimer’s disease. FigureGSP/1DX6 (Molegro Virtual Docker)

3D-QSAR CoMFA/CoMSIA models based on theoretical active conformers of HOE/BAY-793 analogs derived from HIV-1 protease inhibitor complexes

The three-dimensional quantitative structure-activity relationships (3D-QSAR) of a series of HOE/BAY-793 analogs (C(2)-symmetric diol peptidomimetics), developed by Budt and co-workers [Bioorg. Med. Chem. 3 (1995) 559] as inhibitors of HIV-1 protease (HIV-PR), were studied using Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA). Theoretical active conformers for these peptidomimetics were generated, derived from modeled protease inhibitor complexes, in order to orient the compounds superposition and to afford a consistent alignment. The best CoMFA model (N=27, q(2)=0.637, R(2)=0.991) showed contributions of the steric (45.7%) and electrostatic (54.3%) fields to the activity, while the best CoMSIA model (N=27, q(2)=0.511, R(2)=0.987) showed contributions of the electrostatic (68.5%) and hydrogen bond donor (37.5%) fields. The models were also external validated using four compounds (test set) not included in the model generation process. The statistical parameters from both models indicate that the data are well fitted and have high predictive ability. Moreover, the resulting 3D CoMFA/CoMSIA contour maps provide useful guidance for designing highly active ligands. The CoMFA/CoMSIA models were also compared with previous 4D-QSAR models [E.F.F. da Cunha, M.G. Albuquerque, O.A.C. Antunes, R.B. de Alencastro, QSAR Comb. Sci. 24 (2005), 240-253.].

Trypanosoma cruzi: Insights into naphthoquinone effects on growth and proteinase activity

In this study we compared the effects of naphthoquinones (α-lapachone, β-lapachone, nor-β-lapachone and Epoxy-α-lap) on growth of Trypanosoma cruzi epimastigotes forms, and on viability of VERO cells. In addition we also experimentally analyzed the most active compounds inhibitory profile against T. cruzi serine- and cysteine-proteinases activity and theoretically evaluated them against cruzain, the major T. cruzi cysteine proteinase by using a molecular docking approach. Our results confirmed β-lapachone and Epoxy-α-lap with a high trypanocidal activity in contrast to α-lapachone and nor-β-lapachone whereas Epoxy-α-lap presented the safest toxicity profile against VERO cells. Interestingly the evaluation of the active compounds effects against T. cruzi cysteine- and serine-proteinases activities revealed different targets for these molecules. β-Lapachone is able to inhibit the cysteine-proteinase activity of T. cruzi proteic whole extract and of cruzain, similar to E-64, a classical cysteine-proteinase inhibitor. Differently, Epoxy-α-lap inhibited the T. cruzi serine-proteinase activity, similar to PMSF, a classical serine-proteinase inhibitor. In agreement to these biological profiles in the enzymatic assays, our theoretical analysis showed that E-64 and β-lapachone interact with the cruzain specific S2 pocket and active site whereas Epoxy-α-lap showed no important interactions. Overall, our results infer that β-lapachone and Epoxy-α-lap compounds may inhibit T. cruzi epimastigotes growth by affecting T. cruzi different proteinases. Thus the present data shows the potential of these compounds as prototype of protease inhibitors on drug design studies for developing new antichagasic compounds.

Hologram QSAR models of 4-[(diethylamino)methyl]-phenol inhibitors of acetyl/butyrylcholinesterase enzymes as potential anti-Alzheimer agents.

Hologram QSAR models were developed for a series of 36 inhibitors (29 training set and seven test set compounds) of acetyl/butyrylcholinesterase (AChE/BChE) enzymes, an attractive molecular target for Alzheimer’s disease (AD) treatment. The HQSAR models (N = 29) exhibited significant cross-validated (AChE, q2 = 0.787; BChE, q2 = 0. 904) and non-cross-validated (AChE, r2 = 0.965; BChE, r2 = 0.952) correlation coefficients. The models were used to predict the inhibitory potencies of the test set compounds, and agreement between the experimental and predicted values was verified, exhibiting a powerful predictive capability. Contribution maps show that structural fragments containing aromatic moieties and long side chains increase potency. Both the HQSAR models and the contribution maps should be useful for the further design of novel, structurally related cholinesterase inhibitors.

Molecular modeling studies of the structural, electronic, and UV absorption properties of benzophenone derivatives.

Benzophenone derivatives (BZP), an important class of organic UV filters, are widely used in sunscreen products due to their ability to absorb in the UVA and UVB ranges. The structural, electronic, and spectral properties of BZP derivatives have been studied by density functional theory (DFT) and time-dependent DFT (TD-DFT) methods. DFT/B3LYP with the 6-31G(d) basis set is an accurate method for optimizing the geometry of BZPs. The absorption maxima obtained from the TD-DFT calculations in a vacuum were in agreement with the experimental absorption bands and showed that the main electronic transitions in the UVA/UVB range present π → π* character, the major transition being HOMO → LUMO. The oscillator strength seems to increase in the presence of disubstitution at the para position. For protic substituents, the position appears to be related to the absorption band. Absorption in the UVB range occurs in the presence of para substitution, whereas ortho substitution leads to absorption in the UVA spectral region. The obtained results provide some features for BZP derivatives that can be useful for customizing absorption properties (wavelengths and intensities) and designing new BZP derivatives as sunscreens.

N-t-Boc-amino acid esters of isomannide Potential inhibitors of serine proteases

Summary.Hepatitis C, Dengue and West Nile virus are some of the most important flaviviruses, that share one important serine protease enzyme. Serine proteases are the most studied class of proteolytic enzyme and, in these cases, a primary target for drug discovery. In this paper, we describe the synthesis and preliminary molecular modeling studies of a novel class of N-t-Boc amino acid esters derived of isomannide as potential serine proteases inhibitors.

Pseudo-peptides derived from isomannide as potential inhibitors of serine proteases.

Summary.Hepatitis C, Dengue and West Nile virus are among of the most important flaviviruses that share one important serine protease enzyme. Serine proteases belong to the most studied class of proteolytic enzymes, and are a primary target in the drug development field. In this paper, we describe the synthesis and preliminary molecular modeling studies of a novel class of N-t-Boc amino acid amides derived of isomannide as potential serine proteases inhibitors.

Modelagem Molecular: Uma Ferramenta para o Planejamento Racional de Fármacos em Química Medicinal

The molecular basis of modern therapeutics consist in the modulation of cell function by the interaction of microbioactive molecules as drug cells macromolecules structures. Molecular modeling is a computational technique developed to access the chemical structure. This methodology, by means of the molecular similarity and complementary paradigm, is the basis for the computer-assisted drug design universally employed in pharmaceutical research laboratories to obtain more efficient, more selective, and safer drugs. In this work, we discuss some methods for molecular modeling and some approaches to evaluate new bioactive structures in development by our research group.