Publications by authors named "Carlos Henrique Tomich de Paula da Silva"

32 Publications

Potential beneficial effects of kefir and its postbiotic, kefiran, on child food allergy.

Food Funct 2021 May;12(9):3770-3786

Laboratory of Pharmaceutical and Medicinal Chemistry (PharMedChem), Federal University of Amapá, Macapá, Brazil.

Food allergies are known as the public health problem, affecting people of all age groups, but more commonly in babies and children, with consequences for nutritional status and quality of life. The increase in the consumption of healthy foods has consequently led to an increased demand for functional foods with specific health benefits. Thus, the pharmaceutical industry's interest in natural products has grown every time and is therefore considered as an alternative to synthetic drugs. Kefir has been outstanding for several years as promising in the manufacture of various pharmaceutical products, due to its nutritional and therapeutic properties for the treatment of many diseases. Currently, a wide variety of new functional foods are appearing on the market, representing an important segment. Postbiotics, for example, has stood out for being a product with action similar to probiotics, without offering side effects. The kefiran is the postbiotic from kefir that promotes potential beneficial effects on food allergy from the intestinal microbiome to the immune system. In this context, it is necessary to know the main promoting component of this functional effect. This review compiles the benefits that kefir, and especially its postbiotic, kefiran, can bring to food allergy. In addition, it serve as a subsidy for studies on the development of innovative nutraceutical products, including the use of kefiran as an alternative therapy in food allergy.
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http://dx.doi.org/10.1039/d0fo03182hDOI Listing
May 2021

Identification of novel αβ-tubulin modulators with antiproliferative activity directed to cancer therapy using ligand and structure-based virtual screening.

Int J Biol Macromol 2020 Dec 22;165(Pt B):3040-3050. Epub 2020 Oct 22.

Computational Laboratory of Pharmaceutical Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Av. do Café, s/n, Ribeirão Preto, SP 14040-903, Brazil; Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, 14040-901 Ribeirão Preto, SP, Brazil.

Among several strategies related to cancer therapy targeting the modulation of αβ-tubulin has shown encouraging findings, more specifically when this is achieved by inhibitors located at the colchicine binding site. In this work, we aim to fish new αβ-tubulin modulators through a diverse and rational VS study, and thus, exhibiting the development of two VS pipelines. This allowed us to identify two compounds 5 and 9 that showed IC values of 19.69 and 21.97 μM, respectively, towards possible modulation of αβ-tubulin, such as assessed by in vitro assays in C6 glioma and HEPG2 cell lines. We also evaluated possible mechanisms of action of obtained hits towards the colchicine binding site of αβ-tubulin by using docking approaches. In addition, assessment of the stability of the active (5 and 9) and inactive compounds (3 and 13) within the colchicine binding site was carried out by molecular dynamics (MD) simulations, highlighting the solvent effect and revealing the compound 5 as the most stable in the complex. At last, deep analysis of these results provided some valuable insights on the importance of using mixed ligand- and structure-based strategies in VS campaigns, in order to achieve higher chemical diversity and biological effect as well.
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http://dx.doi.org/10.1016/j.ijbiomac.2020.10.136DOI Listing
December 2020

Molecular Docking, Physicochemical Properties, Pharmacokinetics and Toxicity of Flavonoids Present in Euterpe Oleracea Martius.

Curr Comput Aided Drug Des 2020 Jun 19. Epub 2020 Jun 19.

Laboratory of Medicinal and Pharmaceutical Chemistry (PharMedChem), Federal University of Amapá, Macapá, Amapá. Brazil.

Background: Euterpe oleracea Martius, popularly known as açaí, is a fruit rich in α-tocopherols, fibers, lipids, mineral ions and polyphenols. It is believed that the high content of polyphenols, specially flavonoids, provides several health-promoting effects to the açaí fruit, including anti-inflammatory, immunomodulatory, antinociceptive and antioxidant properties. Most of flavonoids are antioxidant molecules from vegetable origin that act as a trap for free radicals, reacting and neutralizing them, thus offering perspectives in preventing oxidative damage.

Objective: In this study we aim to perform an in silico evaluation of flavonoids present in the pulp and in the oil of Euterpe oleracea Martius, and their potential to represent antioxidant agents.

Methods: First, we selected 16 flavonoid molecules present in Euterpe oleracea Martius pulp and oil, and then their physicochemical properties were analysed with respect to the Lipinski's rule of five. Moreover, we evaluated their pharmacokinetic properties using the QikProp module of the Schrödinger software and their toxicity profile using the DEREK software. Docking simulations in the GOLD 4.1 software and calculation of the pharmacophore hypothesis of molecules were also performed.

Results: Flavonoids present in the açaí pulp, catechin, epicatechin, luteolin, chrisoeriol, taxifolin, apigenin, dihydrokaempferol, isovitexin and vitexin presented good oral bioavailability. Regarding pharmacokinetic properties, the compounds catechin, epicatechin, isovitexin, luteolin, chrisoeriol, taxifolin and isorhamnetina rutinoside presented the best results and high human oral absorption. In the prediction of toxicological properties, compounds isorhamnetin rutinoside and rutin presented alert concerning mutagenicity for hydroxynaphthalene or derivate, and in docking simulations all the compounds presented key interactions with the corresponding targets tested.

Conclusion: The flavonoids catechin, chrysoeriol and taxifolin presented overall best results, allowing such computational results to serve as a theoretical basis for future studies of developing drug candidates for biological tests in vitro and in vivo, which can contribute to the treatment of neurodegenerative diseases.
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http://dx.doi.org/10.2174/1573409916666200619122803DOI Listing
June 2020

Virtual screening, ADME/Tox predictions and the drug repurposing concept for future use of old drugs against the COVID-19.

Life Sci 2020 Sep 11;256:117963. Epub 2020 Jun 11.

Computational Laboratory of Pharmaceutical Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil; Department of Chemistry, School of Philosophy, Sciences and Letters of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.

The new Coronavirus (SARS-CoV-2) is the cause of a serious infection in the respiratory tract called COVID-19. Structures of the main protease of SARS-CoV-2 (M), responsible for the replication of the virus, have been solved and quickly made available, thus allowing the design of compounds that could interact with this protease and thus to prevent the progression of the disease by avoiding the viral peptide to be cleaved, so that smaller viral proteins can be released into the host's plasma. These structural data are extremely important for in silico design and development of compounds as well, being possible to quick and effectively identify potential inhibitors addressed to such enzyme's structure. Therefore, in order to identify potential inhibitors for M, we used virtual screening approaches based with the structure of the enzyme and two compounds libraries, targeted to SARS-CoV-2, containing compounds with predicted activity against M. In this way, we selected, through docking studies, the 100 top-ranked compounds, which followed to subsequent studies of pharmacokinetic and toxicity predictions. After all the simulations and predictions here performed, we obtained 10 top-ranked compounds that were again in silico analyzed inside the M catalytic site, together some drugs that are being currently investigated for treatment of COVID-19. After proposing and analyzing the interaction modes of these compounds, we submitted one molecule then selected as template to a 2D similarity study in a database containing drugs approved by FDA and we have found and indicated Apixaban as a potential drug for future treatment of COVID-19.
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http://dx.doi.org/10.1016/j.lfs.2020.117963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289103PMC
September 2020

1,2,3-Triazole tethered 2-mercaptobenzimidazole derivatives: design, synthesis and molecular assessment toward C6 glioma cell line.

Future Med Chem 2020 04 20;12(8):689-708. Epub 2020 Mar 20.

Departamento de Química Farmacéutica y Orgánica, Facultad de Farmacia, Universidad de Granada, Granada, 18071, Spain.

Glioblastoma multiforme (GBM) is an aggressive cancer with very limited clinical therapies. Herein, we have designed novel mercaptobenzimidazole derivatives () as multitarget antineoplastic drugs and assessed their antiproliferative profiles on an experimental model for GBM, the C6 glioma line. The target compounds were synthesized in few steps with reasonable yields (33-90%). Compounds (∼18 μM) and (∼20 μM) showed dose-dependent antiproliferative effects on C6 glioma and significantly increased early apoptosis, but only disrupted the cell cycle progression and did not induce autophagy. Docking simulations suggested these compounds as dual kinase and colchicine binding site inhibitors.  In spite of the limited selective toxicity, hold the potential to be further optimized for the treatment of GBM.
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http://dx.doi.org/10.4155/fmc-2019-0227DOI Listing
April 2020

The Aspergillus fumigatus Phosphoproteome Reveals Roles of High-Osmolarity Glycerol Mitogen-Activated Protein Kinases in Promoting Cell Wall Damage and Caspofungin Tolerance.

mBio 2020 02 4;11(1). Epub 2020 Feb 4.

Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, Brazil

The filamentous fungus can cause a distinct set of clinical disorders in humans. Invasive aspergillosis (IA) is the most common life-threatening fungal disease of immunocompromised humans. The mitogen-activated protein kinase (MAPK) signaling pathways are essential to the adaptation to the human host. Fungal cell survival is highly dependent on the organization, composition, and function of the cell wall. Here, an evaluation of the global phosphoproteome under cell wall stress caused by the cell wall-damaging agent Congo red (CR) revealed 485 proteins potentially involved in the cell wall damage response. Comparative phosphoproteome analyses with the Δ, Δ, and Δ Δ mutant strains from the osmotic stress MAPK cascades identify their additional roles during the cell wall stress response. Our phosphoproteomics allowed the identification of novel kinases and transcription factors (TFs) involved in osmotic stress and in the cell wall integrity (CWI) pathway. Our global phosphoproteome network analysis showed an enrichment for protein kinases, RNA recognition motif domains, and the MAPK signaling pathway. In contrast to the wild-type strain, there is an overall decrease of differentially phosphorylated kinases and phosphatases in Δ, Δ, and Δ Δ mutants. We constructed phosphomutants for the phosphorylation sites of several proteins differentially phosphorylated in the wild-type and mutant strains. For all the phosphomutants, there is an increase in the sensitivity to cell wall-damaging agents and a reduction in the MpkA phosphorylation upon CR stress, suggesting these phosphosites could be important for the MpkA modulation and CWI pathway regulation. is an opportunistic human pathogen causing allergic reactions or systemic infections, such as invasive pulmonary aspergillosis in immunocompromised patients. The mitogen-activated protein kinase (MAPK) signaling pathways are essential for fungal adaptation to the human host. Fungal cell survival, fungicide tolerance, and virulence are highly dependent on the organization, composition, and function of the cell wall. Upon cell wall stress, MAPKs phosphorylate multiple target proteins involved in the remodeling of the cell wall. Here, we investigate the global phosphoproteome of the Δ and Δ and high-osmolarity glycerol (HOG) pathway MAPK mutants upon cell wall damage. This showed the involvement of the HOG pathway and identified novel protein kinases and transcription factors, which were confirmed by fungal genetics to be involved in promoting tolerance of cell wall damage. Our results provide understanding of how fungal signal transduction networks modulate the cell wall. This may also lead to the discovery of new fungicide drug targets to impact fungal cell wall function, fungicide tolerance, and virulence.
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http://dx.doi.org/10.1128/mBio.02962-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002344PMC
February 2020

Allosteric Modulators of Potential Targets Related to Alzheimer's Disease: a Review.

ChemMedChem 2019 08 1;14(16):1467-1483. Epub 2019 Aug 1.

Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Av. do Café, s/n, 14040-903, Ribeirão Preto, Brazil.

Among neurodegenerative disorders, Alzheimer's disease (AD) is the most common type of dementia, and there is an urgent need to discover new and efficacious forms of treatment for it. Pathological patterns of AD include cholinergic dysfunction, increased β-amyloid (Aβ) peptide concentration, the appearance of neurofibrillary tangles, among others, all of which are strongly associated with specific biological targets. Interactions observed between these targets and potential drug candidates in AD most often occur by competitive mechanisms driven by orthosteric ligands that sometimes result in the production of side effects. In this context, the allosteric mechanism represents a key strategy; this can be regarded as the selective modulation of such targets by allosteric modulators in an advantageous manner, as this may decrease the likelihood of side effects. The purpose of this review is to present an overview of compounds that act as allosteric modulators of the main biological targets related to AD.
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http://dx.doi.org/10.1002/cmdc.201900299DOI Listing
August 2019

In silico study of the mechanism of action, pharmacokinetic and toxicological properties of some N-methylanthranilates and their analogs.

Food Chem Toxicol 2019 Sep 7;131:110556. Epub 2019 Jun 7.

School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin 2, Ireland. Electronic address:

The in silico evaluation for the three previously synthesized compounds (Methyl (MMA), propyl (PMA) and isopropyl (IMA) N-methylanthranilate), MMA and IMA originally found in the leaf essential oil of Choisya ternata, provided a very good confirmation for the in vivo pharmacological results obtained with such compounds for a number of pharmacological targets. This manuscript dealt with their assessment in six pharmacological targets to understanding anti-inflammatory, antinociceptive, anxiolytic, antidepressant and anti-allergic activities using docking molecular as well as their pharmacokinetics and toxicological parameters prediction. The compound IMA seems to be the best one when all the combined parameters are put together. Interestingly this compound presented the best in vivo profile in previous studies by the group. Derivatives of the three original molecules were proposed. Overall the second modification (5-[2-(methoxycarbonyl)anilino]pentanoic acid, 5-[2-(propoxycarbonyl)anilino]pentanoic acid and 5-(2-{[(propan-2-yl)oxy]carbonyl}anilino)pentanoic acid) of all three original molecules was the one that achieved highest score in molecular docking and a better combination of the other parameters. Further research as in the obtaining of such derivatives via synthesis and their in vivo testing to confirm their higher pharmacological potential is currently on the way.
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http://dx.doi.org/10.1016/j.fct.2019.06.003DOI Listing
September 2019

Antioxidant Effect of Flavonoids Present in Euterpe oleracea Martius and Neurodegenerative Diseases: A Literature Review.

Cent Nerv Syst Agents Med Chem 2019 ;19(2):75-99

Laboratory of Pharmaceutical and Medicinal Chemistry (PharMedChem), Federal University of Amapa, Macapa, Brazil.

Introduction: Neurodegenerative diseases (NDDs) are progressive, directly affecting the central nervous system (CNS), the most common and recurrent are Alzheimer's disease (AD) and Parkinson's disease (PD). One factor frequently mentioned in the etiology of NDDs is the generation of free radicals and oxidative stress, producing cellular damages. Studies have shown that the consumption of foods rich in polyphenols, especially those of the flavonoid class, has been related to the low risk in the development of several diseases. Due to the antioxidant properties present in the food, a fruit that has been gaining prominence among these foods is the Euterpe oleracea Mart. (açaí), because it presents in its composition significant amounts of a subclass of the flavonoids, the anthocyanins.

Methods: In the case review, the authors receive a basic background on the most common NDDs, oxidative stress and antioxidants. In addition, revisiting the various studies related to NDDs, including flavonoids and consumption of açaí.

Results: Detailed analysis of the recently reported case studies reveal that dietary consumption of flavonoid-rich foods, such as açaí fruits, suggests the efficacy to attenuate neurodegeneration and prevent or reverse the age-dependent deterioration of cognitive function.

Conclusion: This systematic review points out that flavonoids presenting in açaí have the potential for the treatment of diseases such as PD and AD and are candidates for drugs in future clinical research. However, there is a need for in vitro and in vivo studies with polyphenol that prove and ratify the therapeutic potential of this fruit for several NDDs.
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http://dx.doi.org/10.2174/1871524919666190502105855DOI Listing
January 2020

Identification of Potential Inhibitors from Pyriproxyfen with Insecticidal Activity by Virtual Screening.

Pharmaceuticals (Basel) 2019 Jan 25;12(1). Epub 2019 Jan 25.

Postgraduate Program in Biotechnology and Biodiversity-Network BIONORTE, Federal University of Amapá, Macapá, Amapá 68903-419, Brazil.

is the main vector of dengue fever transmission, yellow fever, Zika, and chikungunya in tropical and subtropical regions and it is considered to cause health risks to millions of people in the world. In this study, we search to obtain new molecules with insecticidal potential against via virtual screening. Pyriproxyfen was chosen as a template compound to search molecules in the database Zinc_Natural_Stock (ZNSt) with structural similarity using ROCS (rapid overlay of chemical structures) and EON (electrostatic similarity) software, and in the final search, the top 100 were selected. Subsequently, in silico pharmacokinetic and toxicological properties were determined resulting in a total of 14 molecules, and these were submitted to the PASS online server for the prediction of biological insecticide and acetylcholinesterase activities, and only two selected molecules followed for the molecular docking study to evaluate the binding free energy and interaction mode. After these procedures were performed, toxicity risk assessment such as LD values in mg/kg and toxicity class using the PROTOX online server, were undertaken. Molecule ZINC00001624 presented potential for inhibition for the acetylcholinesterase enzyme (insect and human) with a binding affinity value of -10.5 and -10.3 kcal/mol, respectively. The interaction with the juvenile hormone was -11.4 kcal/mol for the molecule ZINC00001021. Molecules ZINC00001021 and ZINC00001624 had excellent predictions in all the steps of the study and may be indicated as the most promising molecules resulting from the virtual screening of new insecticidal agents.
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http://dx.doi.org/10.3390/ph12010020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469432PMC
January 2019

An In Silico Study of the Antioxidant Ability for Two Caffeine Analogs Using Molecular Docking and Quantum Chemical Methods.

Molecules 2018 Oct 29;23(11). Epub 2018 Oct 29.

Laboratory of Modeling and Computational Chemistry, Department of Biological Sciences, Federal University of Amapá, Rod. Juscelino Kubitschek, Km 02, s/n, Macapá, Amapá 68902-280, Brazil.

The antioxidant activity of molecules constitutes an important factor for the regulation of redox homeostasis and reduction of the oxidative stress. Cells affected by oxidative stress can undergo genetic alteration, causing structural changes and promoting the onset of chronic diseases, such as cancer. We have performed an in silico study to evaluate the antioxidant potential of two molecules of the zinc database: ZINC08706191 (Z91) and ZINC08992920 (Z20). Molecular docking, quantum chemical calculations (HF/6-31G**) and Pearson's correlation have been performed. Molecular docking results of Z91 and Z20 showed both the lower binding affinity (BA) and inhibition constant (Ki) values for the receptor-ligand interactions in the three tested enzymes (cytochrome P450-CP450, myeloperoxidase-MP and NADPH oxidase-NO) than the control molecules (5-fluorouracil-FLU, melatonin-MEL and dextromethorphan-DEX, for each receptor respectively). Molecular descriptors were correlated with Ki and strong correlations were observed for the CP450, MP and NO receptors. These and other results attest the significant antioxidant ability of Z91 and Z20, that may be indicated for further analyses in relation to the control of oxidative stress and as possible antioxidant agents to be used in the pharmaceutical industry.
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http://dx.doi.org/10.3390/molecules23112801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6278550PMC
October 2018

Alzheimer's Disease: A Review from the Pathophysiology to Diagnosis, New Perspectives for Pharmacological Treatment.

Curr Med Chem 2018 ;25(26):3141-3159

Laboratorio de Quimica Farmaceutica e Medicinal (PharMedChem), Universidade Federal do Amapa, Macapa, Brazil.

Dementia is characterized by the impairment of cognition and behavior of people over 65 years. Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder in the world, as approximately 47 million people are affected by this disease and the tendency is that this number will increase to 62% by 2030. Two microscopic features assist in the characterization of the disease, the amyloid plaques and neurofibrillary agglomerates. All these factors are responsible for the slow and gradual deterioration of memory that affect language, personality or cognitive control. For the AD diagnosis, neuropsychological tests are performed in different spheres of cognitive functions but since not all cognitive functions may be affected, cerebrospinal fluid biomarkers are used along with these tests. To date, cholinesterase inhibitors are used as treatment, they are the only drugs that have shown significant improvements in the cognitive functions of AD patients. Despite the proven effectiveness of cholinesterase inhibitors, an AD carrier, even while being treated, is continually subjected to progressive degeneration of the neuronal tissue. For this reason, other biochemical pathways associated with the pathophysiology of AD have been explored as alternatives to the treatment of this condition such as inhibition of β-secretase and glycogen synthase kinase-3β. The present study aims to conduct a review of the epidemiology, pathophysiology, symptoms, diagnosis and treatment of Alzheimer's disease, emphasizing the research and development of new therapeutic approaches.
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http://dx.doi.org/10.2174/0929867323666161213101126DOI Listing
September 2018

An Antioxidant Potential, Quantum-Chemical and Molecular Docking Study of the Major Chemical Constituents Present in the Leaves of Linn.

Pharmaceuticals (Basel) 2018 Jul 20;11(3). Epub 2018 Jul 20.

Posgraduate Program of Pharmaceutical Innovation, Federal University of Amapá, 68902-280 Macapá, AP, Brazil.

Reactive oxygen species (ROS) are continuously generated in the normal biological systems, primarily by enzymes as xanthine oxidase (XO). The inappropriate scavenging or inhibition of ROS has been considered to be linked with aging, inflammatory disorders, and chronic diseases. Therefore, many plants and their products have been investigated as natural antioxidants for their potential use in preventive medicine. The leaves and bark extracts of Linn. were described in scientific research as anti-inflammatory, vasodilator, anti-ulcerogenic, and hypolipidemic effects. So, the aim of this study was to evaluate the antioxidant potentials of leaf hydroalcoholic extract from (HECA) through the scavenging DPPH assay and their main chemical constituents, evaluated by the following quantum chemical approaches (DFT B3LYP/6-31G**): Maps of Molecular Electrostatic Potential (MEP), Frontier Orbital's (HOMO and LUMO) followed by multivariate analysis and molecular docking simulations with the xanthine oxidase enzyme. The hydroalcoholic extract showed significant antioxidant activity by free radical scavenging probably due to the great presence of flavonoids, which were grouped in the PCA and HCA analysis with the standard gallic acid. In the molecular docking study, the compounds studied presented the binding free energy (ΔG) values close each other, due to the similar interactions with amino acids residues at the activity site. The descriptors Gap and softness were important to characterize the molecules with antioxidant potential by capturing oxygen radicals.
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http://dx.doi.org/10.3390/ph11030072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6161303PMC
July 2018

Discovery of novel dual acetylcholinesterase inhibitors with antifibrillogenic activity related to Alzheimer's disease.

Future Med Chem 2018 05 20;10(9):1037-1053. Epub 2018 Apr 20.

Departamento de Ciências Farmacêuticas, Universidade de São Paulo, Av. do Café, s/n - Ribeirão Preto - SP, CEP 14040-903, Brazil.

Aim: Alzheimer's disease is a progressive and neurodegenerative disorder of the CNS, affecting elderly people. The current pharmacological approach is based on the improvement of cholinergic neurotransmission by inhibiting acetylcholinesterase (AChE) with AChE inhibitors. The disease is also characterized by the accelerated accumulation of β-amyloid plaques around neurons. Furthermore, in vitro studies revealed that AChE can induce β-amyloid peptide (Aβ) aggregation.

Methodology: Computer-aided molecular design by virtual screening was here employed to discover novel potential AChE inhibitors, with antifibrillogenic properties, in other words, inhibiting Aβ aggregation.

Results: Compounds 1, 4 and 6 showed interesting AChE inhibition. In addition, they particularly inhibit Aβ aggregation in vitro, indicating to be promising novel anti-Alzheimer agents.
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http://dx.doi.org/10.4155/fmc-2017-0201DOI Listing
May 2018

Virtual Screening and Statistical Analysis in the Design of New Caffeine Analogues Molecules with Potential Epithelial Anticancer Activity.

Curr Pharm Des 2018 ;24(5):576-594

Laboratory of Molecular Modeling and Simulation System, Federal Rural University of Amazonia, Rua Joao Pessoa, 121, Campus Capanema-Centro, Capanema, Para 68700-030, Brazil.

About 132 thousand cases of melanoma (more severe type of skin cancer) were registered in 2014 according to the World Health Organization. This type of cancer significantly affects the quality of life of individuals. Caffeine has shown potential inhibitory effect against epithelial cancer. In this study, it was proposed to obtain new caffeine-based molecules with potential epithelial anticancer activity. For this, a training set of 21 molecules was used for pharmacophore perception procedures. Multiple linear regression analyses were used to propose mono-, bi-, tri-, and tetra-parametric models applied in the prediction of the activity. The generated pharmacophore was used to select 350 molecules available at the ZINCpharmer server, followed by reduction to 24 molecules, after selection using the Tanimoto index, yielding 10 molecules after final selection by predicted activity values > 1.5229. These ten molecules had better pharmacokinetic properties than the other ones used as reference and within the clinically significant limits. Only two molecules show minor hits of toxicity and were submitted to molecular docking procedures, showing BFE (binding free energy) values lower than the reference values. Statistical analyses indicated strong negative correlations between BFE and pharmacophoric properties (high influence on BFE lowering) and practically null correlation between BFE and BBB. The two most promising molecules can be indicated as candidates for further in vitro and in vivo analyzes.
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http://dx.doi.org/10.2174/1381612823666170711112510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5944109PMC
September 2019

New Horizons on Molecular Pharmacology Applied to Drug Discovery: When Resonance Overcomes Radioligand Binding.

Curr Radiopharm 2017 ;10(1):16-20

Department of Biosciences Applied to Pharmacy, Faculty of Pharmaceutical Sciences from Ribeirao Preto, University of Sao Paulo, Ribeirao Preto, SP, Brazil.

One of the cornerstones of rational drug development is the measurement of molecular parameters derived from ligand-receptor interaction, which guides therapeutic windows definition. Over the last decades, radioligand binding has provided valuable contributions in this field as key method for such purposes. However, its limitations spurred the development of more exquisite techniques for determining such parameters. For instance, safety risks related to radioactivity waste, expensive and controlled disposal of radioisotopes, radiotracer separation-dependence for affinity analysis, and one-site mathematical models-based fitting of data make radioligand binding a suboptimal approach in providing measures of actual affinity conformations from ligands and G proteincoupled receptors (GPCR). Current advances on high-throughput screening (HTS) assays have markedly extended the options of sparing sensitive ways for monitoring ligand affinity. The advent of the novel bioluminescent donor NanoLuc luciferase (Nluc), engineered from Oplophorus gracilirostris luciferase, allowed fitting bioluminescence resonance energy transfer (BRET) for monitoring ligand binding. Such novel approach named Nluc-based BRET (NanoBRET) binding assay consists of a real-time homogeneous proximity assay that overcomes radioligand binding limitations but ensures the quality in affinity measurements. Here, we cover the main advantages of NanoBRET protocol and the undesirable drawbacks of radioligand binding as molecular methods that span pharmacological toolbox applied to Drug Discovery. Also, we provide a novel perspective for the application of NanoBRET technology in affinity assays for multiple-state binding mechanisms involving oligomerization and/or functional biased selectivity. This new angle was proposed based on specific biophysical criteria required for the real-time homogeneity assigned to the proximity NanoBRET protocol.
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http://dx.doi.org/10.2174/1874471010666170208152420DOI Listing
February 2018

3D descriptors calculation and conformational search to investigate potential bioactive conformations, with application in 3D-QSAR and virtual screening in drug design.

J Biomol Struct Dyn 2017 Oct 14;35(13):2966-2974. Epub 2016 Oct 14.

b Centro Brasileiro de Pesquisas Físicas , Rua Dr. Xavier Sigaud, 150, Urca, 22290-180, Rio de Janeiro , RJ , Brazil.

The knowledge of the bioactive conformation for an active hit is relevant because of the easier interpretation and the general quality of the recognition models of protein and ligand. With the aim of investigating potential bioactive conformations without previous structural knowledge of the molecular target, we present herewith a 'protocol' that could be used which includes generation of low-energy conformations, calculations of tridimensional descriptors and investigation of structural similarity via principal component analysis. The protocol was used in the search for potential bioactive conformations. An initial selection of targets was made from a set of protein-ligand complexes with structure deposited in the Protein Data Bank, which was systematically filtered by lead-like rules, resulting in 45 ligands of 8 important therapeutic targets. After extensive optimization of the protocol and parameters of both OMEGA and Pentacle softwares, the best results were obtained for series of compounds such as the beta-trypsin and urokinase inhibitors, which are more structurally related among each other, inside the respective therapeutic class. Future improvements of the protocol, including a suitable choice and combination of robust 3D descriptors, could yield more reliable and less restrictive results, with general and diverse applications in drug design, in particular for improving the 3D-QSAR methodologies as well as virtual screening experiments for a more reliable selection of new lead compounds for different molecular targets.
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http://dx.doi.org/10.1080/07391102.2016.1237382DOI Listing
October 2017

GRIND2-based 3D-QSAR and prediction of activity spectra for symmetrical bis-pyridinium salts with promastigote antileishmanial activity.

J Biomol Struct Dyn 2017 Aug 6;35(11):2430-2440. Epub 2016 Sep 6.

b Facultad de Farmacia, Departamento de Química Farmacéutica y Orgánica , Universidad de Granada , c/ Campus de Cartuja s/n, Granada 18071 , Spain.

Leishmaniasis is a major group of neglected tropical diseases caused by the protozoan parasite Leishmania. About 12 million people are affected in 98 countries and 350 million people worldwide are at risk of infection. Current leishmaniasis treatments rely on a relatively small arsenal of drugs, including amphotericin B, pentamidine and others, which in general have some type of inconvenience. Recently, we have synthesized antileishmanial bis-pyridinium derivatives and symmetrical bis-pyridinium cyclophanes. These compounds are considered structural analogues of pentamidine, where the amidino moiety, protonated at physiological pH, is replaced by a positively charged nitrogen atom as a pyridinium ring. In this work, a statistically significant GRIND2-based 3D-QSAR model was built and biological activity predictions were in silico carried out allowing rationalization of the different activities recently obtained against Leishmania donovani (in L. donovani promastigotes) for a data set of 19 bis-pyridinium compounds. We will emphasize the most important structural requirements to improve the biological activity and probable interactions with the biological receptor as a guide for lead and prototype optimization. In addition, since no information about the actual biological target for this series of active compounds is provided, we have used Prediction of Activity Spectra for Biologically Active Substances to propose our compounds as potential nicotinic α6β3β4α5 receptor antagonists. This proposal is reinforced by the high structural similarity observed between our compounds and several anthelmintic drugs in current clinical use, which have the same drug action mechanism here predicted. Such new findings would be confirmed with further and additional experimental assays.
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http://dx.doi.org/10.1080/07391102.2016.1221364DOI Listing
August 2017

Rational Design of Antimalarial Drugs Using Molecular Modeling and Statistical Analysis.

Curr Pharm Des 2015 ;21(28):4112-27

Laboratory of Modeling and Computational Chemistry, Federal University of Amapa, Macapa, Amapa, 68902-280, Brazil.

Artemisinin is an antimalarial compound isolated from Artemisia annua L. that is effective against Plasmodium falciparum. This paper proposes the development of new antimalarial derivatives of artemisinin from a SAR study and statistical analysis by multiple linear regression (MLR). The HF/6-31G** method was used to determine the molecular properties of artemisinin and 10 derivatives with antimalarial action. MEP maps and molecular docking were used to study the interface between ligand and receptor (heme). The Pearson correlation was used to choose the most important properties interrelated to the antimalarial activity: Hydration Energy (HE), Energy of the Complex (Ecplex), bond length (FeO1), and maximum index of R/Electronegativity of Sanderson (RTe+). After the Pearson correlation, 72 MLR models were built between antimalarial activity and molecular properties; the statistical quality of the models was evaluated by means of correlation coefficient (r), squared correlation coefficient (r(2)), explained variance (adjusted R(2)), standard error of estimate (SEE), and variance ratio (F), and only four models showed predictive ability. The selected models were used to predict the antimalarial activity of ten new artemisinin derivatives (test set) with unknown activity, and only eight of these compounds were predicted to be more potent than artemisinin, and were therefore subjected to theoretical studies of pharmacokinetic and toxicological properties. The test set showed satisfactory results for six new artemisinin compounds which is a promising factor for future synthesis and biological assays.
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http://dx.doi.org/10.2174/1381612821666150528121423DOI Listing
July 2016

Structure- and ligand-based drug design of novel p38-alpha MAPK inhibitors in the fight against the Alzheimer's disease.

J Biomol Struct Dyn 2014 28;32(7):1047-63. Epub 2013 Jun 28.

a Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo , Av. do Café, s/n - Monte Alegre, Ribeirão Preto , SP 14040-903 , Brazil .

Alzheimer's disease (AD) is characterized microscopically by the presence of amyloid plaques, which are accumulations of beta-amyloid protein inter-neurons, and neurofibrillary tangles formed predominantly by highly phosphorylated forms of the microtubule-associated protein, tau, which form tangled masses that consume neuronal cell body, possibly leading to neuronal dysfunction and ultimately death. p38α mitogen-activated protein kinase (MAPK) has been implicated in both events associated with AD, tau phosphorylation and inflammation. p38α MAPK pathway is activated by a dual phosphorylation at Thr180 and Tyr182 residues. Drug design of p38α MAPK inhibitors is mainly focused on small molecules that compete for Adenosine triphosphate in the catalytic site. Here, we used different approaches of structure- and ligand-based drug design and medicinal chemistry strategies based on a selected p38α MAPK structure deposited in the Protein Data Bank in complex with inhibitor, as well as others reported in literature. As a result of the virtual screening experiments performed here, as well as molecular dynamics, molecular interaction fields studies, shape and electrostatic similarities, activity and toxicity predictions, and pharmacokinetic and physicochemical properties, we have selected 13 compounds that meet the criteria of low or no toxicity potential, good pharmacotherapeutic profile, predicted activities, and calculated values ​​comparable with those obtained for the reference compounds, while maintaining the main interactions observed for the most potent inhibitors.
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http://dx.doi.org/10.1080/07391102.2013.803441DOI Listing
April 2015

Novel aryl β-aminocarbonyl derivatives as inhibitors of Trypanosoma cruzi trypanothione reductase: binding mode revised by docking and GRIND2-based 3D-QSAR procedures.

J Biomol Struct Dyn 2012 ;29(6):702-16

Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Ribeirão Preto, SP, Brazil.

Trypanothione reductase has long been investigated as a promising target for chemotherapeutic intervention in Chagas disease, since it is an enzyme of a unique metabolic pathway that is exclusively present in the pathogen but not in the human host, which has the analog Glutathione reductase. In spite of the present data-set includes a small number of compounds, a combined use of flexible docking, pharmacophore perception, ligand binding site prediction, and Grid-Independent Descriptors GRIND2-based 3D-Quantitative Structure-Activity Relationships (QSAR) procedures allowed us to rationalize the different biological activities of a series of 11 aryl β-aminocarbonyl derivatives, which are inhibitors of Trypanosoma cruzi trypanothione reductase (TcTR). Three QSAR models were built and validated using different alignments, which are based on docking with the TcTR crystal structure, pharmacophore, and molecular interaction fields. The high statistical significance of the models thus obtained assures the robustness of this second generation of GRIND descriptors here used, which were able to detect the most important residues of such enzyme for binding the aryl β-aminocarbonyl derivatives, besides to rationalize distances among them. Finally, a revised binding mode has been proposed for our inhibitors and independently supported by the different methodologies here used, allowing further optimization of the lead compounds with such combined structure- and ligand-based approaches in the fight against the Chagas disease.
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http://dx.doi.org/10.1080/07391102.2011.672633DOI Listing
August 2012

Toxicophoric and metabolic in silico evaluation of benzimidazole and phenylbenzamide derivatives with potential application as anticancer agents.

Drug Metab Lett 2011 Dec;5(4):267-75

Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Monte Alegre, Ribeirão Preto-SP, Brasil.

Poor pharmacokinetics and toxicity are responsible for most drug candidate failures. In order to attempt to some degree of ADMET (Absorption, Distribution, Metabolism, Excrection and Toxicity) information, in silico predictions arise currently as an interesting alternative to evaluate prototypes during early stages of the drug design processes, especially for anticancer candidates that constitute a class of therapeutic agents that exhibit substantial toxicity. A benzimidazole and a phenylbenzamide derivatives, previously identified as novel anticancer lead compounds able to prevent DNA binding to hnRNP K protein, were evaluated in silico regarding their metabolic profile and toxicity potential in order to give insights to the design of drug candidates with an adequate pharmaceutical profile. Considering the structure of proposed metabolites for both molecules, the phenylbenzamide derivative seems to be a molecule with better pharmaceutic profile, since its possible metabolites present a milder degree of chemical structure toxic alerts than the benzimidazole derivative that can cause chromosome damage induced by the benzimidazole group. It would be desirable during optimization of the phenylbenzamide derivative to maintain these characteristics during generation of analogues with substituents that are not known as potent toxicophoric groups. For the benzimidazole derivative, if the toxic events are really severe as it seems, one possible strategy would be replace the benzimidazole ring system by bioisosteres with lower toxic potential, hoping to maintain or enhance biological activity.
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http://dx.doi.org/10.2174/187231211798472566DOI Listing
December 2011

Search for a platelet-activating factor receptor in the Trypanosoma cruzi proteome: a potential target for Chagas disease chemotherapy.

Mem Inst Oswaldo Cruz 2011 Dec;106(8):957-67

Departamento de Ciências Farmacêuticas, Universidade de São Paulo, 14040-903 Ribeirão Preto, SP, Brasil.

Chagas disease (CD) causes the highest burden of parasitic diseases in the Western Hemisphere and is therefore a priority for drug research and development. Platelet-activating factor (PAF) causes the CD parasite Trypanosoma cruzi to differentiate, which suggests that the parasite may express PAF receptors. Here, we explored the T. cruzi proteome for PAF receptor-like proteins. From a total of 23,000 protein sequences, we identified 29 hypothetical proteins that are predicted to have seven transmembrane domains (TMDs), which is the main characteristic of the G protein-coupled receptors (GPCRs), including the PAF receptor. The TMDs of these sequences were independently aligned with domains from 25 animal PAF receptors and the sequences were analysed for conserved residues. The conservation score mean values for the TMDs of the hypothetical proteins ranged from 31.7-44.1%, which suggests that if the putative T. cruzi PAF receptor is among the sequences identified, the TMDs are not highly conserved. These results suggest that T. cruzi contains several GPCR-like proteins and that one of these GPCRs may be a PAF receptor. Future studies may further validate the PAF receptor as a target for CD chemotherapy.
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http://dx.doi.org/10.1590/s0074-02762011000800010DOI Listing
December 2011

In silico design and search for acetylcholinesterase inhibitors in Alzheimer's disease with a suitable pharmacokinetic profile and low toxicity.

Future Med Chem 2011 Jun;3(8):947-60

Departamento de Ciências Farmacêuticas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Av. do Café, s/n, Monte Alegre, 14040-903, Ribeirão Preto, São Paulo, Brazil.

Alzheimer's disease is a complex neurodegenerative disorder of the central nervous system, characterized by amyloid-β deposits, τ-protein aggregation, oxidative stress and reduced levels of acetylcholine in the brain. One pharmacological approach is to restore acetylcholine level by inhibiting acetylcholinesterase (AChE) with reversible inhibitors, such as galanthamine, thus helping to improve the cognitive symptoms of the disease. In order to design new galanthamine derivatives and search for novel, potential inhibitors with improved interactions, as well as a suitable pharmacokinetic profile and low toxicity, several molecular modeling techniques were applied. These techniques included the investigation of AChE-drug complexes (1QT1 and 1ACJ Protein Data Bank codes), ligand-binding sites calculation within the active site of the enzyme, pharmacophore perception of galanthamine derivatives, virtual screening, toxicophorical analysis and estimation of pharmacokinetics properties. A total of four galanthamine derivatives having a N-alkyl-phenyl chain were designed, since the tertiary amine substituents could reach the peripheral anionic site that is not occupied by galanthamine. In addition, 12 drug-like compounds from the Ilibdiverse database were selected by virtual screening as novel, hypothetical AChE inhibitors. The toxicophorical analysis revealed that only four proposed inhibitors have chemical groups able to develop mutagenicity and chromosome damage. The remaining compounds showed only mild or none toxicophorical alerts. At least three screened compounds presented theoric parameters consistent with good oral bioavailability. The designed molecules have the potential to become new lead compounds that might guide the design of drugs with optimized pharmacodynamic and pharmacokinetic properties in order to improve the treatment of Alzheimer's disease by creating new pharmacotherapeutic options.
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http://dx.doi.org/10.4155/fmc.11.67DOI Listing
June 2011

Computer-aided drug design and ADMET predictions for identification and evaluation of novel potential farnesyltransferase inhibitors in cancer therapy.

J Mol Graph Model 2010 Feb 4;28(6):513-23. Epub 2009 Dec 4.

Departamento de Ciências Farmacêuticas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Av. do Café, s/n, Monte Alegre, 14040-903, Ribeirão Preto-SP, Brazil.

We have used various computational methodologies including molecular dynamics, density functional theory, virtual screening, ADMET predictions and molecular interaction field studies to design and analyze four novel potential inhibitors of farnesyltransferase (FTase). Evaluation of two proposals regarding their drug potential as well as lead compounds have indicated them as novel promising FTase inhibitors, with theoretically interesting pharmacotherapeutic profiles, when compared to the very active and most cited FTase inhibitors that have activity data reported, which are launched drugs or compounds in clinical tests. One of our two proposals appears to be a more promising drug candidate and FTase inhibitor, but both derivative molecules indicate potentially very good pharmacotherapeutic profiles in comparison with Tipifarnib and Lonafarnib, two reference pharmaceuticals. Two other proposals have been selected with virtual screening approaches and investigated by us, which suggest novel and alternatives scaffolds to design future potential FTase inhibitors. Such compounds can be explored as promising molecules to initiate a research protocol in order to discover novel anticancer drug candidates targeting farnesyltransferase, in the fight against cancer.
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http://dx.doi.org/10.1016/j.jmgm.2009.11.011DOI Listing
February 2010

Psoralen and bergapten: in silico metabolism and toxicophoric analysis of drugs used to treat vitiligo.

J Pharm Pharm Sci 2009 ;12(3):378-87

Departamento de Ciências Farmacêuticas, Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, CEP 14040-903, Brazil.

Purpose: To discuss the contribution of psoralen and bergapten metabolites on psoralens toxicity.

Methods: Computational chemistry prediction of metabolic reactions and toxicophoric groups based on the expert systems Derek and Meteor.

Results: a total of 15 metabolites were suggested for both psoralen and bergapten based on phase 1 and 2 biotransformations until the 3rd generation. Five toxicophoric substructures were shared among psoralen, bergapten and their corresponding metabolites; one toxicophoric marker (resorcinol) was only identified in bergapten and its biotransformation products.

Conclusion: Although the toxic effects of psoralens are well known and documented, there is little information concerning the role of their metabolites in this process. We believe this work add to the knowledge of which molecular substructures are relevant to the process of metabolism and toxicity induction, thus guiding the search and development of more effective and less toxic drugs to treat vitiligo.
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http://dx.doi.org/10.18433/j3w01dDOI Listing
April 2010

Cubebin and derivatives as inhibitors of mitochondrial complex I. Proposed interaction with subunit B8.

J Enzyme Inhib Med Chem 2009 Apr;24(2):599-606

Departamento de Analises Clinicas, Toxicologicas e Bromatologicas, Faculdade de Ciencias Farmaceuticas de Ribeirao Preto, Universidade de Sao Paulo, Ribeirao Preto, SP, Brazil.

The effects on mitochondrial respiration and complex I NADH oxidase activity of cubebin and derivatives were evaluated. The compounds inhibited the state 3 glutamate/malate-supported respiration of hamster liver mitochondria with IC(50) values ranging from 12.16 to 83.96 microM. NADH oxidase reaction was evaluated in submitochondrial particles. The compounds also inhibited this activity, showing the same order of potency observed for effects on state 3 respiration, as well as a tendency towards a non-competitive type of inhibition (K(I) values ranging from 0.62 to 16.1 microM). A potential binding mode of these compounds with complex I subunit B8, assessed by docking calculations, is proposed.
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http://dx.doi.org/10.1080/14756360802318845DOI Listing
April 2009

Molecular dynamics, density functional, ADMET predictions, virtual screening, and molecular interaction field studies for identification and evaluation of novel potential CDK2 inhibitors in cancer therapy.

J Phys Chem A 2008 Sep 13;112(38):8902-10. Epub 2008 Aug 13.

Departamento de Ciencias Farmaceuticas, Faculdade de Ciencias Farmaceuticas de Ribeirao Preto, Universidade de Sao Paulo, Av. do Cafe, s/n, Monte Alegre 14040-903, Ribeirao Preto-SP, Brazil.

In this work, we have used molecular dynamics, density functional theory, virtual screening, ADMET predictions, and molecular interaction field studies to design and propose eight novel potential inhibitors of CDK2. The eight molecules proposed showed interesting structural characteristics that are required for inhibiting the CDK2 activity and show potential as drug candidates for the treatment of cancer. The parameters related to the Rule of Five were calculated, and only one of the molecules violated more than one parameter. One of the proposals and one of the drug-like compounds selected by virtual screening indicated to be promising candidates for CDK2-based cancer therapy.
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http://dx.doi.org/10.1021/jp8011969DOI Listing
September 2008

Current topics in computer-aided drug design.

J Pharm Sci 2008 Mar;97(3):1089-98

Centro Brasileiro de Pesquisas Físicas, Rua Dr. Xavier Sigaud, 150, Urca, 22290-180 Rio de Janeiro, Brazil.

The addition of computer-aided drug design (CADD) technologies to the research and drug discovery approaches could lead to a reduction of up to 50% in the cost of drug design. Designing a drug is the process of finding or creating a molecule which has a specific activity on a biological organism. Development and drug discovery is a time-consuming, expensive, and interdisciplinary process whereas scientific advancements during the past two decades have altered the way pharmaceutical research produces new bioactive molecules. Advances in computational techniques and hardware solutions have enabled in silico methods to speed up lead optimization and identification. We will review current topics in computer-aided molecular design underscoring some of the most recent approaches and interdisciplinary processes. We will discuss some of the most efficient pathways and design.
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http://dx.doi.org/10.1002/jps.21293DOI Listing
March 2008

Transdermal delivery of ketoprofen: the influence of drug-dioleylphosphatidylcholine interactions.

Pharm Res 2006 Aug;23(8):1776-85

Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo, Av. do Café s/n, 14040-903, Ribeirão Preto, São Paulo, Brazil.

Purpose: Considering that most inflammatory diseases occur locally and near the body surface, transdermal delivery of non-steroidal anti-inflammatory drugs (NSAIDs) may be an interesting strategy for delivering these drugs directly to the diseased site. To optimize ketoprofen (KP) transdermal delivery we investigated the influence of dioleylphosphatidylcholine (DOPC) on skin permeation.

Materials And Methods: The formulations studied were: i) a physical mixture of KP and DOPC and ii) DOPC and KP complex, in a molar ratio of 1:3, obtained by dissolution of the components in chloroform followed by drying under a N2 atmosphere. Both systems were dispersed in mineral oil and the in vitro percutaneous was assayed by absorption using a flow through diffusion cell. Differential Scanning Calorimetry (DSC) and 1H NMR studies were carried out to characterize KP and DOPC interactions. Geometry optimizations using Density Functional Theory and semiempirical methods, as well as a flexible docking procedure were carried out to obtain a binding model for KP with DOPC. KP solubility and partition studies in the formulations, as well as skin irritation and hypersensitivity assays were also carried out.

Results: DSC determinations in the complex showed enthalpy and temperature depressions, indicating KP and DOPC interaction. In addition, dipole-dipole interactions between the KP carboxylic acid and OH groups in phospholipids were shown by 1H NMR studies. Based on the NMR studies, a KP-DOPC binding model is proposed, in which KP is involved by the two long aliphatic chains of the phospholipid. Solubility studies indicated that DOPC improved drug solubility. KP permeation was enhanced by both formulations tested, but the complex also increased its skin uptake. Such behavior could be attributed to the solubilizing, melting and enhancing effects of DOPC. Skin irritation and hypersensitivity were not significantly changed compared to control, suggesting that the formulation may be therapeutically explored for KP transdermal delivery.
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http://dx.doi.org/10.1007/s11095-006-9040-3DOI Listing
August 2006