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Gabriela Barreiro

Gabriela Barreiro
Eurofarma, São Paulo, Brazil · Innovation

About

32
Publications
2,598
Reads
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1,227
Citations
Additional affiliations
October 2007 - March 2014
Pfizer
Position
  • Principal Investigator

Publications

Publications (32)
Article
A major challenge in the development of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors for the treatment of Alzheimer's disease is the alignment of potency, drug-like properties, and selectivity over related aspartyl proteases such as Cathepsin D (CatD) and BACE2. The potential liabilities of inhibiting BACE2 chronically has...
Article
Full-text available
We previously observed a cutaneous type IV immune response in non-human primates (NHP) with the mGlu5 negative allosteric modulator (NAM) 7. To determine if this adverse event was chemotype- or mechanism-based, we evaluated a distinct series of mGlu5 NAMs. Increasing the sp(3) character of high-throughput screening hit 40 afforded a novel morpholin...
Article
A growing subset of β-secretase (BACE1) inhibitors for the treatment of Alzheimer’s disease (AD) utilizes an anilide chemotype that engages a key residue (Gly230) in the BACE1 binding site. Although the anilide moiety affords excellent potency, it simultaneously introduces a third hydrogen bond donor that limits brain availability and reveals a pot...
Article
Macrocycles pose challenges for computer-aided drug design due to their conformational complexity. One fundamental challenge is identifying all low-energy conformations of the macrocyclic ring, which is important for modeling target binding, passive membrane permeation, and other conformation-dependent properties. Macrocyclic polyketides are medica...
Article
In recent years, the first generation of β-secretase (BACE1) inhibitors advanced into clinical development for the treatment of Alzheimer's disease (AD). However, the alignment of drug-like properties and selectivity remains a major challenge. Herein, we describe the discovery of a novel class of potent, low clearance, CNS penetrant BACE1 inhibitor...
Article
The identification of centrally efficacious β-secretase (BACE1) inhibitors for the treatment of Alzheimer's disease (AD) has historically been thwarted by an inability to maintain alignment of potency, brain availability, and desired ADME properties. In this paper, we describe a series of truncated, fused thioamidines that are efficiently selective...
Article
A novel series of pyrazolopyrazines is herein disclosed as mGluR5 negative allosteric modulators (NAMs). Starting from a high-throughput screen (HTS) hit (1), a systematic structure-activity relationship (SAR) study was conducted with a specific focus on balancing pharmacological potency with physicochemical and pharmacokinetic (PK) properties. Thi...
Article
β-Secretase 1 (BACE-1) is an attractive therapeutic target for the treatment and prevention of Alzheimer's disease (AD). Herein, we describe the discovery of a novel class of BACE-1 inhibitors represented by sulfamide 14g, using a medicinal chemistry strategy to optimize central nervous system (CNS) penetration by minimizing hydrogen bond donors (H...
Article
As part of efforts directed at the G protein-coupled receptor 119 agonist program for type 2 diabetes, a series of cyanopyridine derivatives exemplified by isopropyl-4-(3-cyano-5-(quinoxalin-6-yl)pyridine-2-yl)piperazine-1-carboxylate (1) were identified as novel chemotypes worthy of further hit-to-lead optimization. Compound 1, however, was found...
Article
Dihydrofolate reductase (DHFR) is the enzyme responsible for the NADPH-dependent reduction of 5,6-dihydrofolate to 5,6,7,8-tetrahydrofolate, an essential cofactor in the synthesis of purines, thymidylate, methionine, and other key metabolites. Because of its importance in multiple cellular functions, DHFR has been the subject of much research targe...
Article
Full-text available
Newly generated actin free barbed ends at the front of motile cells provide sites for actin filament assembly driving membrane protrusion. Growth factors induce a rapid biphasic increase in actin free barbed ends, and we found both phases absent in fibroblasts lacking H(+) efflux by the Na-H exchanger NHE1. The first phase is restored by expression...
Article
Full-text available
Actin filament binding by the focal adhesion (FA)-associated protein talin stabilizes cell-substrate adhesions and is thought to be rate-limiting in cell migration. Although F-actin binding by talin is known to be pH-sensitive in vitro, with lower affinity at higher pH, the functional significance of this pH dependence is unknown. Because increased...
Article
Virtual screening of the Maybridge library of ca. 70 000 compounds was performed using a similarity filter, docking, and molecular mechanics-generalized Born/surface area postprocessing to seek potential non-nucleoside inhibitors of human immunodeficiency virus-1 (HIV-1) reverse transcriptase (NNRTIs). Although known NNRTIs were retrieved well, pur...
Article
A virtual screening protocol has been applied to seek non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) and its K103N mutant. First, a chemical similarity search on the Maybridge library was performed using known NNRTIs as reference structures. The top-ranked molecules obtained from this procedure plus 26 known NNRTIs were then dock...
Article
Human cytomegalovirus (HCMV) is a pathogenic agent responsible for morbidity and mortality in immunocompromised and immunosuppressed individuals. HCMV encodes a serine protease that is essential for the production of infectious virions. In this work, we applied molecular dynamics (MD) simulations on HCMV protease models in order to investigate the...
Article
Full-text available
We describe herein a computationally intensive project aimed at carrying out molecular dynamics (MD) simulations including water and counterions on B-DNA oligomers containing all 136 unique tetranucleotide base sequences. This initiative was undertaken by an international collaborative effort involving nine research groups, the "Ascona B-DNA Consor...
Article
Full-text available
Computer simulations of biomolecular systems have achieved a significant importance in science as they provide information regarding structure, dynamics, and energetics of biomolecules that are inaccessible to experimental measuring techniques. In this work, some important aspects of the simulation of biomolecular systems are described. An overview...
Article
Recent studies of DNA axis curvature and flexibility based on molecular dynamics (MD) simulations on DNA are reviewed. The MD simulations are on DNA sequences up to 25 base pairs in length, including explicit consideration of counterions and waters in the computational model. MD studies are described for ApA steps, A-tracts, for sequences of A-trac...
Article
Human cytomegalovirus (HCMV) is a highly species-specific DNA virus infecting up to 80% of the general population. The viral genome contains the open reading frame UL80, which encodes the full-length 80 kDa HCMV serine protease and its substrate. Full-length HCMV protease is composed of an N-terminal 256-amino-acid proteolytic domain, called assemb...
Article
Full-text available
To understand the mechanisms of Na(+)/Li(+) permeation at submicromolar Ca(2+) concentrations, Na(+)/Li(+) blocking at higher Ca(2+) concentrations (10(-6)-10(-4) M) and Ca(2+) permeation at millimolar Ca(2+) concentrations, we used our recently described L-type calcium channel model. For this purpose, we obtained potential of mean force (pmf) curv...
Article
In this work, we propose a molecular model of the L-type calcium channel pore from the human cardiac alpha1 subunit. Four glutamic acid residues, the EEEE locus, located at highly conserved P loops (also called SS1-SS2 segments) of the alpha1 subunit, molecularly express the calcium channel selectivity. The proposed alpha-helix structure for the SS...
Article
In this work, we developed a nicotinic acetylcholine receptor (nAChR) model using the minireceptor modeling technique. For the construction of the minireceptor model, we elected some known nicotinic agonists according to their structural characteristics and binding constants (Ki) values. The results show an orientation pattern for the probes’ dista...
Article
In this work, we modeled leupeptin (Ac.Leu.Leu.Arg.CHO), a natural inhibitor of proteases, and the active site of papain, a cysteine protease, using as a template the crystal structure of a leupeptin–papain complex recently obtained by Schroder and co-workers [FEBS Lett. 135(1), 38 (1993)] and including 11 amino acids relevant to the proteolytic ac...
Article
In this work, we evaluated structural and electronic similarities between a new class of acylhydrazones, recently presented as effective inhibitors of a Plasmodium falciparum cysteine protease, and a series of pyrazole arylacylhydrazones with analgesic and antiaggregating (antithrombotic) properties, using AM1. The calculated results suggest that a...

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