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ABSTRACT: Bacillus anthracis has been employed as an agent of bioterrorism, with high mortality, despite anti-microbial treatment, which strongly indicates
the need of new drugs to treat anthrax. Shikimate pathway is a seven step biosynthetic route which generates chorismic acid
from phosphoenol pyruvate and erythrose-4-phosphate. Chorismic acid is the major branch point in the synthesis of aromatic
amino acids, ubiquinone, and secondary metabolites. The shikimate pathway is essential for many pathological organisms, whereas
it is absent in mammals. Therefore, these enzymes are potential targets for the development of nontoxic antimicrobial agents
and herbicides and have been submitted to intensive structural studies. The forth enzyme of this pathway is responsible for
the conversion of dehydroshikimate to shikimate in the presence of NADP. In order to pave the way for structural and functional
efforts toward development of new antimicrobials we describe the molecular modeling of shikimate dehydrogenase from Bacillus anthracis complexed with the cofactor NADP. This study was able to identify the main residues of the NADP binding site responsible
for ligand affinities. This structural study can be used in the design of more specific drugs against infectious diseases.
Journal of Molecular Modeling 04/2012; 15(2):147-155. · 1.80 Impact Factor
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ABSTRACT: Purine nucleoside phosphorylase (PNP) (EC.2.4.2.1) is an enzyme that catalyzes the cleavage of N-ribosidic bonds of the purine
ribonucleosides and 2-deoxyribonucleosides in the presence of inorganic orthophosphate as a second substrate. This enzyme
is involved in purine-salvage pathway and has been proposed as a promising target for design and development of antimalarial
and antibacterial drugs. Recent elucidation of the three-dimensional structure of PNP by X-ray protein crystallography left
open the possibility of structure-based virtual screening initiatives in combination with molecular dynamics simulations focused
on identification of potential new antimalarial drugs. Most of the previously published molecular dynamics simulations of
PNP were carried out on human PNP, a trimeric PNP. The present article describes for the first time molecular dynamics simulations
of hexameric PNP from Plasmodium falciparum (PfPNP). Two systems were simulated in the present work, PfPNP in ligand free form, and in complex with immucillin and sulfate.
Based on the dynamical behavior of both systems the main results related to structural stability and protein-drug interactions
are discussed.
Purine nucleoside phosphorylase is a potential target for the development of antibacterial and antimalarial drugs. Molecular
dynamics simulations have been performed to evaluate the structural and dynamical properties of PfPNP. Two systems were simulated,
the protein in the apo form and a second system for the ternary complex involving PfPNP, SO4, and an inhibitor.
Journal of Molecular Modeling 04/2012; 16(3):543-550. · 1.80 Impact Factor
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ABSTRACT: Cytidine Deaminase (CD) is an evolutionarily conserved enzyme that participates in the pyrimidine salvage pathway recycling cytidine and deoxycytidine into uridine and deoxyuridine, respectively. Here, our goal is to apply computational techniques in the pursuit of potential inhibitors of Mycobacterium tuberculosis CD (MtCDA) enzyme activity. Molecular docking simulation was applied to find the possible hit compounds. Molecular dynamics simulations were also carried out to investigate the physically relevant motions involved in the protein-ligand recognition process, aiming at providing estimates for free energy of binding. The proposed approach was capable of identifying a potential inhibitor, which was experimentally confirmed by IC(50) evaluation. Our findings open up the possibility to extend this protocol to different databases in order to find new potential inhibitors for promising targets based on a rational drug design process.
Journal of Molecular Modeling 05/2011; 18(2):467-79. · 1.80 Impact Factor
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Walter Filgueira de Azevedo
Current Medicinal Chemistry 03/2011; 18(9):1255-7. · 4.86 Impact Factor
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Walter Filgueira De Azevedo
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ABSTRACT: Molecular docking is a simulation process where the binding of a small molecule is identified in the structure of a protein target. There are several different computational approaches to solve this problem. Here it will be described recent developments in application of evolutionary algorithms to molecular docking simulations. Evolutionary algorithms are classified as a group of computational techniques based on the concepts of Darwin's theory of evolution that are designed to the best possible find solution to optimisation problems. A successfully implementation of this algorithm can be found in the program MolDock. The main features of MolDock are reviewed here we also describe application of MolDock to purine nucleoside phosphorylase, shikimate kinase and cyclin-dependent kinase 2.
Current drug targets 03/2010; 11(3):327-34. · 3.93 Impact Factor
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ABSTRACT: Drug development has become the Holy Grail of many structural bioinformatics groups. The explosion of information about protein structures, ligand-binding affinity, parasite genome projects, and biological activity of millions of molecules opened the possibility to correlate this scattered information in order to generate reliable computational models to predict the likelihood of being able to modulate a target with a small-molecule drug. Computational methods have shown their potential in drug discovery and development allied with in vitro and in vivo methodologies. The present review discusses the main bioinformatics tools available for drug discovery and development.
Current drug targets 04/2009; 10(3):232-9. · 3.93 Impact Factor
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ABSTRACT: Sequencing of parasite genomes opened the possibility to identify potential protein targets for drug development. Several protein targets have been found in the genome of Plasmodium falciparum, Trypanosoma cruzi, Trypanosoma brucei and Leishmania major. Bioinformatics analysis is an important tool for the identification of protein targets for drug development against parasitic diseases. In this review we comment about three protein targets, identified in parasite genomes, and discuss the main features that may guide future efforts for virtual screening initiatives.
Current drug targets 04/2009; 10(3):193-201. · 3.93 Impact Factor
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ABSTRACT: The development of databases devoted to biological information opened the possibility to integrate, query and analyze biological data obtained from several sources that otherwise would be scattered through the web. Several issues arise in the handling of biological information, mainly due to the diversity of biological subject matter and the complexity of biological approaches towards phenomena of the living world. The integration of genomic data, three-dimensional structures of proteins, biological activity, and drugs availability allows a system approach to the study of the biology. Here we review the current status of these research efforts to develop genomic databases for protozoan parasites, such as the apicomplexan parasites, Trypanosoma cruzi and Leishmania spp. These databases may help in the discovery and development of new drugs against parasite-mediated diseases.
Current drug targets 04/2009; 10(3):240-5. · 3.93 Impact Factor
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ABSTRACT: The study of protein-drug interaction is of pivotal importance to understand the structural features essential for ligand affinity. The explosion of information about protein structures has paved the way to develop structure-based virtual screening approaches. Parasitic protein kinases have been pointed out as potential targets for antiparasitic development. The identification of protein kinases in the Plasmodium falciparum genome has opened the possibility to test new families of inhibitors as potential antimalarial drugs. In addition, other key enzymes which play roles in biosynthetic pathways, such as enoyl reductase and chorismate synthase, can be valuable targets for drug development. This review is focused on these protein targets that may help to materialize new generations of antimalarial drugs.
Current drug targets 04/2009; 10(3):271-8. · 3.93 Impact Factor
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ABSTRACT: Purine Nucleoside Phosphorylase (PNP) catalyzes the reversible phosphorolysis of N-glycosidic bonds of purine nucleosides and deoxynucleosides, except for adenosine, to generate ribose 1-phosphate and the purine base. PNP has been submitted to intensive structural studies. This work describes for the first time a structural model of PNP from Streptococcus pyogenes (SpPNP). We modeled the complexes of SpPNP with six different ligands in order to determine the structural basis for specificity of these ligands against SpPNP. Molecular dynamics (MD) simulations were performed in order to evaluate the overall stability of SpPNP model. The analysis of the MD simulation was assessed mainly by principal component analysis (PCA) to explore the trimeric structure behavior. Structural comparison, between SpPNP and human PNP, was able to identify the main features responsible for differences in ligand-binding affinities, such as mutation in the purine-binding site and in the second phosphate-binding site. The PCA analysis suggests a different behavior for each subunit in the trimer structure.
Biophysical chemistry 03/2009; 142(1-3):7-16. · 2.28 Impact Factor
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ABSTRACT: The complex CDK3-cyclin is involved in the control of the progression of G0. While the mechanisms governing early and late G1 progression are well understood, very little is known about the G0-G1 transition. Human CDK3 is closely related to cyclin-dependent kinase 2 (CDK2). Since there is no crystallographic structure of human CDK3, this work describes for the first time a molecular model of human CDK3 complexed with several inhibitors. Comparison of the binary complexes with different inhibitors strongly indicates that those inhibitors should inhibit CDK3 as well as CDK2.
Computers in biology and medicine 02/2009; 39(2):130-40. · 1.27 Impact Factor
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ABSTRACT: Precise computational methods to determine ligand-binding affinity are needed to accelerate the discovery of new drugs. Assessing protein-ligand interaction is of great importance for virtual screening initiatives. The affinity may be computational evaluated using scoring functions involving terms for intermolecular hydrogen bonds, contact surface, hydrophobic contacts, electrostatic interactions and others. Empirical scoring functions have been developed to evaluate ligand-binding affinity very rapidly. In addition to predict affinity, these scoring functions have been employed to identify the best results obtained from docking simulations. This review describes several computational methods, employed to estimate ligand-binding affinity and discuss their development and main applications.
Current drug targets 01/2009; 9(12):1031-9. · 3.93 Impact Factor
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ABSTRACT: By means of virtual screening of small molecules databases it is possible to identify new potential inhibitors against a target of interest. Molecular docking is a computer simulation procedure to predict the conformation of a receptor-ligand complex. Each docking program makes use of one or more specific search algorithms, which are the methods used to predict the possible conformations of a binary complex. In the present review we describe several molecular-docking search algorithms, and the programs which apply such methodologies. We also discuss how virtual screening can be optimized, describing methods that may increase accuracy of the simulation process, with relatively fast docking algorithms.
Current drug targets 01/2009; 9(12):1040-7. · 3.93 Impact Factor
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ABSTRACT: Protein crystallography is the main technique used to obtain three-dimensional information for binary complexes involving protein and drugs. Once a protein target has its three-dimensional structure elucidated, the next natural step is the solving of the structure complexed either with its natural substrate, or any ligand or even an inhibitor. Such information is of pivotal importance to understand the structural basis for inhibition of an enzyme. The relevant features, for application of protein crystallography to drug discovery, are discussed in this review.
Current drug targets 01/2009; 9(12):1048-53. · 3.93 Impact Factor
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ABSTRACT: Precise experimental methods to determine ligand-binding affinity are needed to accelerate the discovery of new drugs. Assessing protein-ligand interaction is of great importance for drug development. One of the techniques that may be used to evaluate ligand-binding affinitty is isothermal titration calorimetry (ITC). This experimental methodology may be used to measure the heat of binding of a ligand to a protein. Furthermore, the development of new empirical scoring functions to assess evaluation protein-ligand interaction lack abundance of experimental information to be used to generate reliable scores. ITC technique may be used to fill this gap. Here we describe the application of this technique to ligand-binding affinity determination, and discuss the synergetic relationship between ITC data and the development of a new generation of empirical scoring functions.
Current drug targets 01/2009; 9(12):1071-6. · 3.93 Impact Factor
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ABSTRACT: Drug development is a high cost and laborious process, requiring a number of tests until a drug is made available in the market. Therefore, the use of methods to screen large number of molecules with less cost is crucial for faster identification of hits and leads. One strategy to identify drug-like molecules is the search for molecules able to interfere with a protein function, since protein interactions control most biological processes. Ideally the use of in silico screenings would make drug development faster and less expensive. Currently, however, the confirmation of biological activity is still needed. Due to the complexity of the task of drug discovery, an integrated and multi-disciplinary approach is ultimately required. Here we discuss examples of drugs developed through a combination of in silico and in vitro strategies. The potential use of these methodologies for the identification of active compounds as well as for early toxicity and bioavailability is also reviewed.
Current drug targets 01/2009; 9(12):1054-61. · 3.93 Impact Factor
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ABSTRACT: Molecular docking simulations are of pivotal importance for analysis of protein-ligand interactions and also an essential resource for virtual-screening initiatives. In molecular docking simulations several possible docked structures are generated, which create an ensemble of structures representing binary complexes. Therefore, it is crucial to find the best solution for the simulation. One approach to this problem is to employ empirical scoring function to identify the best docked structure. It is expected that scoring functions show a descriptive funnel-shaped energy surface without many false minima to impair the efficiency of conformational sampling. We employed this methodology against a test set with 300 docked structures. Docking simulations of these ligands against enzyme binding pocket indicated a funnel-shaped behavior of the complexation for this system. This review compares a set of recently proposed polynomial empirical scoring functions, implemented in a program called POLSCORE, with two popular scoring function programs (XSCORE and DrugScore). Overall comparison indicated that POLSCORE works better to predict the correct docked position, for the ensemble of docked structures analyzed in the present work.
Current drug targets 01/2009; 9(12):1062-70. · 3.93 Impact Factor
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ABSTRACT: With the progression of structural genomics projects, comparative modeling remains an increasingly important method of choice to obtain 3D structure of proteins. It helps to bridge the gap between the available sequence and structure information by providing reliable and accurate protein models. Comparative modeling based on more than 30% sequence identity is now approaching its natural template-based limits and further improvements require the development of effective refinement techniques capable of driving models toward native structure. For difficult targets, for which the most significant progress in recent years has been observed, optimal template selection and alignment accuracy are still the major problems. The past year has seen a maturation of molecular modeling, with an increasing number of comparative studies between established methods becoming possible, together with an explosion of new works especially in the areas of combinatorial chemistry and molecular diversity. To achieve this, knowledge about three-dimensional protein structures is crucial for the understanding of their functional mechanisms, and for a rational drug design. This review described recent progress in molecular modeling methodology.
Current drug targets 01/2009; 9(12):1084-91. · 3.93 Impact Factor
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ABSTRACT: Recent developments in computer power and chemoinformatics methodology make possible that a huge amount of data become available through internet. These databases are devoted to a wide spectrum of scientific fields. Here we are concerned with databases related to protein-drug interactions. More specifically, databases where potential new molecules could be accessed to be used in virtual screening initiatives. In the past decade several databases have been developed where molecules to be used in the virtual screening could be easily identified, downloaded and even purchased. This review describes and summarizes the recent advances in the development of these databases, and also the main applications related to virtual screening projects.
Current drug targets 01/2009; 9(12):1092-9. · 3.93 Impact Factor
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ABSTRACT: Molecular recognition process describes the interaction involving two molecules. In the case of biomolecules, these pairs of molecules could be protein-protein, protein-ligand or protein-nucleic acid. The first model to capture the essential features, behind the molecular recognition problem, was the lock-and-key paradigm. The overall analysis protein-protein, protein-nucleic acid and protein-ligand interaction based on the three-dimensional structures and physicochemical parameters, such as binding affinity, opened the possibility to provide further insights in this basic phenomenon. The main ideas behind the molecular recognition are discussed in the present review.
Current drug targets 01/2009; 9(12):1077-83. · 3.93 Impact Factor
