Laura Luca - Academia.edu (original) (raw)
Papers by Laura Luca
Current Topics in Medicinal Chemistry, 2005
Over the last years α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors (AMP... more Over the last years α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors (AMPARs) have been intensively studied owing to their crucial role in physiological and pathological processes. Efforts targeting AMPAR have been focused on identification of ligands as potential therapeutic agents useful in the prevention and treatment of a variety of neurological and non-neurological diseases. In particular, extensive work was addressed to the discovery of selective antagonists some of which proved to be potent anticonvulsant agents.
Journal of Medicinal Chemistry, 2003
N- tetrahydroisoquinoline derivatives were designed and synthesized as potential noncompetitive A... more N- tetrahydroisoquinoline derivatives were designed and synthesized as potential noncompetitive AMPA receptor antagonists on the basis of molecular modeling studies. Sound-induced seizure testing showed that this class of compounds possessed anticonvulsant properties. In particular, 10c was more potent than talampanel (2), a noncompetitive AMPA receptor antagonist currently being investigated in phase III trials as an antiepileptic agent. Furthermore, electrophysiological studies indicated that 10c was a highly effective noncompetitive-type modulator of the AMPA receptor.
Biochemical and Biophysical Research Communications, 2007
The targeting of HIV-1 integrase (IN) for the design of novel antiviral compounds has until now p... more The targeting of HIV-1 integrase (IN) for the design of novel antiviral compounds has until now proceeded slowly, mainly due to the lack of three-dimensional structures reporting detail interactions between IN and its DNA substrates as well as the complete enzyme with its three domains. Recently, we have proposed that Tn5 transposase (Tnp) can be used as a useful surrogate model for IN in attempt to address the potential binding modes of Integrase Strand Transfer Inhibitors. In order to strengthen our hypothesis, molecular dynamics simulations of IN inhibitors bound to Tn5 Tnp active site are now reported. A comparison of the obtained results with well documented specific mutations associated with resistance to HIV-1 IN inhibitors confirmed that Tn5 Tnp can provide a valuable platform for the structure-based discovery of new ligands.
Farmaco, 2003
This paper reports our work in the field of nonnucleoside RT inhibitors (NNRTIs). On the basis of... more This paper reports our work in the field of nonnucleoside RT inhibitors (NNRTIs). On the basis of extensive studies on 1H ,3Hthiazolo[3,4-a ]benzimidazole derivatives (TBZs) followed by structure Á/activity relationship (SAR) considerations and molecular modeling, the design and synthesis of a series of 2,3-diaryl-1,3-thiazolidin-4-ones have been performed. Some derivatives proved to be highly effective in inhibiting human immunodeficiency virus type-1 (HIV-1) replication at nanomolar concentrations with minimal toxicity, acting as reverse transcriptase (RT) inhibitors. Computational studies were used in order to probe the binding of our ligands to HIV-1-RT.
Journal of Medicinal Chemistry, 2005
A three-dimensional common feature pharmacophore model was developed using the X-ray structure of... more A three-dimensional common feature pharmacophore model was developed using the X-ray structure of RT/non-nucleoside inhibitor (NNRTI) complexes. Starting from the pharmacophore hypothesis and the structure of the lead compound TBZ, new NNRTIs were designed and synthesized, having the benzimidazol-2-one system as a scaffold. Docking experiments showed that these molecules docked in a position and orientation similar to that of known inhibitors. Biological testing confirmed that our strategy was successful in searching for new leads as NNRTIs.
Journal of Medicinal Chemistry, 2006
The crystal structure of Tn5 transposase-DNA complex was used in docking experiments to predict b... more The crystal structure of Tn5 transposase-DNA complex was used in docking experiments to predict binding modes of HIV-1 integrase strand transfer inhibitors (INSTIs). In fact, the identification of HIV-1 integrase inhibitors from an in vitro screen using Tn5 transposase as the target has been recently reported. Our results suggest the utility of this protein as a useful surrogate model for IN and also for in silico screening, in the search for new potential INSTIs.
Bioorganic & Medicinal Chemistry Letters, 2008
We report herein the development of a new three-dimensional pharmacophore model for HIV-1 integra... more We report herein the development of a new three-dimensional pharmacophore model for HIV-1 integrase inhibitors which led to the discovery of some 4-[1-(4-fluorobenzyl)-1H-indol-3-yl]-2-hydroxy-4-oxobut-2-enoic acids that are able to specifically inhibit the strand transfer step of integration at nanomolar concentration. The synthesis of the new designed molecules is also described.
Bioorganic & Medicinal Chemistry, 2008
Several N(1)-substituted 1,3-dihydro-2H-benzimidazol-2-ones were synthesized and evaluated as ant... more Several N(1)-substituted 1,3-dihydro-2H-benzimidazol-2-ones were synthesized and evaluated as anti-HIV agents. Some of them proved to be highly effective in inhibiting HIV-1 replication at nanomolar concentration as potent non-nucleoside HIV-1 RT inhibitors (NNRTIs) with low cytotoxicity. SAR studies highlighted that the nature of the substituents at N(1) and on the benzene ring of benzimidazolone moiety significantly influenced the anti-HIV activity of this class of potent antiretroviral agents.
Expert Opinion on Therapeutic Patents, 2004
The interest in AMPA glutamate receptors has grown enormously in recent years, due to their cruci... more The interest in AMPA glutamate receptors has grown enormously in recent years, due to their crucial role in physiological and pathological processes. This led to the development of AMPA ligands as research tools and potential therapeutic agents. In particular, extensive work ...
![Research paper thumbnail of New 4-[(1Benzyl1H-indol-3-yl)carbonyl]-3-hydroxyfuran-2(5H)-ones, β-Diketo Acid Analogs as HIV1 Integrase Inhibitors](https://attachments.academia-assets.com/48764981/thumbnails/1.jpg)
](Archiv Der Pharmazie, 2007
In addition to our recent report on a series of rationally designed benzylindolyldiketo acids act... more In addition to our recent report on a series of rationally designed benzylindolyldiketo acids acting as potent HIV-1 integrase strand transfer inhibitors, we disclose the results obtained with novel compounds chemically modified on the diketo acid moiety in order to investigate its influence on the biological activity and cytotoxicity. The activity of designed and synthesized 4-[(1-benzyl-1H-indol-3-yl)carbonyl]-3-hydroxyfuran-2(5H)-one derivatives lies in the micromolar range with regard to HIV IN enzymatic activity. The microwave-assisted synthesis was employed in some steps of the chemical procedures.
Bioorganic & Medicinal Chemistry Letters, 2001
Design, synthesis and anti-HIV activity of a series of 2,3-diaryl-1,3-thiazolidin-4-ones are repo... more Design, synthesis and anti-HIV activity of a series of 2,3-diaryl-1,3-thiazolidin-4-ones are reported. Some derivatives proved to be highly effective in inhibiting HIV-1 replication at nanomolar concentrations thereby acting as non-nucleoside HIV-1 RT inhibitors (NNRTIs). SAR studies evidenced that the nature of the substituents at the 2 and 3 positions of the thiazolidinone nucleus largely influenced the in vitro anti-HIV activity of this new class of potent antiviral agents. #
Journal of Medicinal Chemistry, 2006
This paper describes the synthesis of racemic 3,5-dihydro-5-methyl-7,8-methylenedioxy-4H-2,3-benz... more This paper describes the synthesis of racemic 3,5-dihydro-5-methyl-7,8-methylenedioxy-4H-2,3-benzodiazepin-4-one (()-5, attempted stereoselective synthesis of its enantiomers, chiral HPLC resolution of the racemate, and assignment of the absolute configuration. Enantiomer (5S)-(-)-5 is provided with an in vivo anticonvulsant activity 8 times higher than its enantiomer (5R)-(+)-5. This result is confirmed in the in vitro test by the ability to inhibit the kainate-induced increase of the [Ca 2+ ] i in a primary culture of rat cerebellar granule cells which express R-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. Binding affinity of compound (()-5 at the AMPA and N-methyl-D-aspartic acid (NMDA) receptors was also evaluated.
Biochemical and Biophysical Research Communications, 2003
A model of the full-length HIV-1 integrase dimer was constructed assembling the experimentally de... more A model of the full-length HIV-1 integrase dimer was constructed assembling the experimentally determined structures of the single domains. Subsequently, the three-domain protein-viral DNA complex was generated for the first time through an automated docking algorithm, obtained modifying the ESCHER program, a well-known method for protein-protein docking. A detailed study of the contacts established with DNA by the enzyme revealed that the predicted model reproduced the results of mutagenesis and cross-linking experiments, confirming the validity of our docking approach in predicting the base specificity in the DNA-protein interaction.
Biochemical and Biophysical Research Communications, 2005
We have carried out a molecular dynamics (MD) simulation of full-length HIV-1 integrase (IN) dime... more We have carried out a molecular dynamics (MD) simulation of full-length HIV-1 integrase (IN) dimer complexed with viral DNA with the aim of gaining information about the enzyme motion and investigating the movement of the catalytic flexible loop (residues 140-149) thought to be essential in the catalytic mechanism of IN. During the simulation, we observed quite a different behavior of this region in the presence or absence of the viral DNA. In particular, the MD results underline the crucial role of the residue Tyr143 in the mechanism of integration of viral DNA into the host chromosome. The present findings confirm the experimental data (e.g., site-directed mutagenesis experiments) showing that the loop is involved in the integration reactions and its mobility is correlated with the catalytic activity of HIV-1 integrase.
Retrovirology, 2007
Background: Treatment of feline immunodeficiency virus (FIV) infection has been hampered by the a... more Background: Treatment of feline immunodeficiency virus (FIV) infection has been hampered by the absence of a specific combination antiretroviral treatment (ART). Integrase strand transfer inhibitors (INSTIs) are emerging as a promising new drug class for HIV-1 treatment, and we evaluated the possibility of inhibiting FIV replication using INSTIs.
Journal of Medicinal Chemistry, 2005
Using a training set of diketo-like acid HIV-1 integrase (IN) strand-transfer inhibitors, a 3D ph... more Using a training set of diketo-like acid HIV-1 integrase (IN) strand-transfer inhibitors, a 3D pharmacophore model was derived having quantitative predictive ability in terms of activity. The best statistical hypothesis consisted of four features (one hydrophobic aromatic region, two hydrogen-bond acceptors, and one hydrogen-bond donor) with r of 0.96. The resulting pharmacophore model guided the rational design of benzylindoles as new potent IN inhibitors, whose microwave-assisted synthesis and biological evaluation are reported.
Journal of Chemical Information and Modeling, 2003
A three-dimensional pharmacophore model for the binding of noncompetitive AMPA receptor antagonis... more A three-dimensional pharmacophore model for the binding of noncompetitive AMPA receptor antagonists was developed in order to map common structural features of highly active compounds. This hypothesis, which consists of two hydrophobic regions, one hydrogen bond acceptor and one aromatic region, was successfully used as framework for the design of a new class of allosteric modulators containing a tetrahydroisoquinoline skeleton and for in silico screening. The promising biological results suggested that the identified molecules might be useful "lead compounds" for future drug development.
Journal of Chemical Information and Modeling, 2007
A structure-based molecular modeling approach was performed to identify novel structural characte... more A structure-based molecular modeling approach was performed to identify novel structural characteristics and scaffolds that might represent new classes of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). The software LigandScout was used for identification and visualization of protein-ligand interaction sites and pharmacophore model generation. In the next step virtual screening of 3D multiconformational databases together with docking experiments allowed the identification of promising candidates for biological testing. The positive biological results obtained confirm the validity of our work strategy.
Journal of Medicinal Chemistry, 2002
Journal of Medicinal Chemistry, 2009
A new model of HIV-1 integrase-Mg-DNA complex that is useful for docking experiments has been bui... more A new model of HIV-1 integrase-Mg-DNA complex that is useful for docking experiments has been built. It was used to study the binding mode of integrase strand transfer inhibitor 1 (CHI-1043) and other fluorine analogues. Molecular modeling results prompted us to synthesize the designed derivatives which showed potent enzymatic inhibition at nanomolar concentration, high antiviral activity, and low toxicity. Microwave assisted organic synthesis (MAOS) was employed in several steps of the synthetic pathway, thus reducing reaction times and improving yields.
Current Topics in Medicinal Chemistry, 2005
Over the last years α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors (AMP... more Over the last years α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid glutamate receptors (AMPARs) have been intensively studied owing to their crucial role in physiological and pathological processes. Efforts targeting AMPAR have been focused on identification of ligands as potential therapeutic agents useful in the prevention and treatment of a variety of neurological and non-neurological diseases. In particular, extensive work was addressed to the discovery of selective antagonists some of which proved to be potent anticonvulsant agents.
Journal of Medicinal Chemistry, 2003
N- tetrahydroisoquinoline derivatives were designed and synthesized as potential noncompetitive A... more N- tetrahydroisoquinoline derivatives were designed and synthesized as potential noncompetitive AMPA receptor antagonists on the basis of molecular modeling studies. Sound-induced seizure testing showed that this class of compounds possessed anticonvulsant properties. In particular, 10c was more potent than talampanel (2), a noncompetitive AMPA receptor antagonist currently being investigated in phase III trials as an antiepileptic agent. Furthermore, electrophysiological studies indicated that 10c was a highly effective noncompetitive-type modulator of the AMPA receptor.
Biochemical and Biophysical Research Communications, 2007
The targeting of HIV-1 integrase (IN) for the design of novel antiviral compounds has until now p... more The targeting of HIV-1 integrase (IN) for the design of novel antiviral compounds has until now proceeded slowly, mainly due to the lack of three-dimensional structures reporting detail interactions between IN and its DNA substrates as well as the complete enzyme with its three domains. Recently, we have proposed that Tn5 transposase (Tnp) can be used as a useful surrogate model for IN in attempt to address the potential binding modes of Integrase Strand Transfer Inhibitors. In order to strengthen our hypothesis, molecular dynamics simulations of IN inhibitors bound to Tn5 Tnp active site are now reported. A comparison of the obtained results with well documented specific mutations associated with resistance to HIV-1 IN inhibitors confirmed that Tn5 Tnp can provide a valuable platform for the structure-based discovery of new ligands.
Farmaco, 2003
This paper reports our work in the field of nonnucleoside RT inhibitors (NNRTIs). On the basis of... more This paper reports our work in the field of nonnucleoside RT inhibitors (NNRTIs). On the basis of extensive studies on 1H ,3Hthiazolo[3,4-a ]benzimidazole derivatives (TBZs) followed by structure Á/activity relationship (SAR) considerations and molecular modeling, the design and synthesis of a series of 2,3-diaryl-1,3-thiazolidin-4-ones have been performed. Some derivatives proved to be highly effective in inhibiting human immunodeficiency virus type-1 (HIV-1) replication at nanomolar concentrations with minimal toxicity, acting as reverse transcriptase (RT) inhibitors. Computational studies were used in order to probe the binding of our ligands to HIV-1-RT.
Journal of Medicinal Chemistry, 2005
A three-dimensional common feature pharmacophore model was developed using the X-ray structure of... more A three-dimensional common feature pharmacophore model was developed using the X-ray structure of RT/non-nucleoside inhibitor (NNRTI) complexes. Starting from the pharmacophore hypothesis and the structure of the lead compound TBZ, new NNRTIs were designed and synthesized, having the benzimidazol-2-one system as a scaffold. Docking experiments showed that these molecules docked in a position and orientation similar to that of known inhibitors. Biological testing confirmed that our strategy was successful in searching for new leads as NNRTIs.
Journal of Medicinal Chemistry, 2006
The crystal structure of Tn5 transposase-DNA complex was used in docking experiments to predict b... more The crystal structure of Tn5 transposase-DNA complex was used in docking experiments to predict binding modes of HIV-1 integrase strand transfer inhibitors (INSTIs). In fact, the identification of HIV-1 integrase inhibitors from an in vitro screen using Tn5 transposase as the target has been recently reported. Our results suggest the utility of this protein as a useful surrogate model for IN and also for in silico screening, in the search for new potential INSTIs.
Bioorganic & Medicinal Chemistry Letters, 2008
We report herein the development of a new three-dimensional pharmacophore model for HIV-1 integra... more We report herein the development of a new three-dimensional pharmacophore model for HIV-1 integrase inhibitors which led to the discovery of some 4-[1-(4-fluorobenzyl)-1H-indol-3-yl]-2-hydroxy-4-oxobut-2-enoic acids that are able to specifically inhibit the strand transfer step of integration at nanomolar concentration. The synthesis of the new designed molecules is also described.
Bioorganic & Medicinal Chemistry, 2008
Several N(1)-substituted 1,3-dihydro-2H-benzimidazol-2-ones were synthesized and evaluated as ant... more Several N(1)-substituted 1,3-dihydro-2H-benzimidazol-2-ones were synthesized and evaluated as anti-HIV agents. Some of them proved to be highly effective in inhibiting HIV-1 replication at nanomolar concentration as potent non-nucleoside HIV-1 RT inhibitors (NNRTIs) with low cytotoxicity. SAR studies highlighted that the nature of the substituents at N(1) and on the benzene ring of benzimidazolone moiety significantly influenced the anti-HIV activity of this class of potent antiretroviral agents.
Expert Opinion on Therapeutic Patents, 2004
The interest in AMPA glutamate receptors has grown enormously in recent years, due to their cruci... more The interest in AMPA glutamate receptors has grown enormously in recent years, due to their crucial role in physiological and pathological processes. This led to the development of AMPA ligands as research tools and potential therapeutic agents. In particular, extensive work ...
Archiv Der Pharmazie, 2007
In addition to our recent report on a series of rationally designed benzylindolyldiketo acids act... more In addition to our recent report on a series of rationally designed benzylindolyldiketo acids acting as potent HIV-1 integrase strand transfer inhibitors, we disclose the results obtained with novel compounds chemically modified on the diketo acid moiety in order to investigate its influence on the biological activity and cytotoxicity. The activity of designed and synthesized 4-[(1-benzyl-1H-indol-3-yl)carbonyl]-3-hydroxyfuran-2(5H)-one derivatives lies in the micromolar range with regard to HIV IN enzymatic activity. The microwave-assisted synthesis was employed in some steps of the chemical procedures.
Bioorganic & Medicinal Chemistry Letters, 2001
Design, synthesis and anti-HIV activity of a series of 2,3-diaryl-1,3-thiazolidin-4-ones are repo... more Design, synthesis and anti-HIV activity of a series of 2,3-diaryl-1,3-thiazolidin-4-ones are reported. Some derivatives proved to be highly effective in inhibiting HIV-1 replication at nanomolar concentrations thereby acting as non-nucleoside HIV-1 RT inhibitors (NNRTIs). SAR studies evidenced that the nature of the substituents at the 2 and 3 positions of the thiazolidinone nucleus largely influenced the in vitro anti-HIV activity of this new class of potent antiviral agents. #
Journal of Medicinal Chemistry, 2006
This paper describes the synthesis of racemic 3,5-dihydro-5-methyl-7,8-methylenedioxy-4H-2,3-benz... more This paper describes the synthesis of racemic 3,5-dihydro-5-methyl-7,8-methylenedioxy-4H-2,3-benzodiazepin-4-one (()-5, attempted stereoselective synthesis of its enantiomers, chiral HPLC resolution of the racemate, and assignment of the absolute configuration. Enantiomer (5S)-(-)-5 is provided with an in vivo anticonvulsant activity 8 times higher than its enantiomer (5R)-(+)-5. This result is confirmed in the in vitro test by the ability to inhibit the kainate-induced increase of the [Ca 2+ ] i in a primary culture of rat cerebellar granule cells which express R-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. Binding affinity of compound (()-5 at the AMPA and N-methyl-D-aspartic acid (NMDA) receptors was also evaluated.
Biochemical and Biophysical Research Communications, 2003
A model of the full-length HIV-1 integrase dimer was constructed assembling the experimentally de... more A model of the full-length HIV-1 integrase dimer was constructed assembling the experimentally determined structures of the single domains. Subsequently, the three-domain protein-viral DNA complex was generated for the first time through an automated docking algorithm, obtained modifying the ESCHER program, a well-known method for protein-protein docking. A detailed study of the contacts established with DNA by the enzyme revealed that the predicted model reproduced the results of mutagenesis and cross-linking experiments, confirming the validity of our docking approach in predicting the base specificity in the DNA-protein interaction.
Biochemical and Biophysical Research Communications, 2005
We have carried out a molecular dynamics (MD) simulation of full-length HIV-1 integrase (IN) dime... more We have carried out a molecular dynamics (MD) simulation of full-length HIV-1 integrase (IN) dimer complexed with viral DNA with the aim of gaining information about the enzyme motion and investigating the movement of the catalytic flexible loop (residues 140-149) thought to be essential in the catalytic mechanism of IN. During the simulation, we observed quite a different behavior of this region in the presence or absence of the viral DNA. In particular, the MD results underline the crucial role of the residue Tyr143 in the mechanism of integration of viral DNA into the host chromosome. The present findings confirm the experimental data (e.g., site-directed mutagenesis experiments) showing that the loop is involved in the integration reactions and its mobility is correlated with the catalytic activity of HIV-1 integrase.
Retrovirology, 2007
Background: Treatment of feline immunodeficiency virus (FIV) infection has been hampered by the a... more Background: Treatment of feline immunodeficiency virus (FIV) infection has been hampered by the absence of a specific combination antiretroviral treatment (ART). Integrase strand transfer inhibitors (INSTIs) are emerging as a promising new drug class for HIV-1 treatment, and we evaluated the possibility of inhibiting FIV replication using INSTIs.
Journal of Medicinal Chemistry, 2005
Using a training set of diketo-like acid HIV-1 integrase (IN) strand-transfer inhibitors, a 3D ph... more Using a training set of diketo-like acid HIV-1 integrase (IN) strand-transfer inhibitors, a 3D pharmacophore model was derived having quantitative predictive ability in terms of activity. The best statistical hypothesis consisted of four features (one hydrophobic aromatic region, two hydrogen-bond acceptors, and one hydrogen-bond donor) with r of 0.96. The resulting pharmacophore model guided the rational design of benzylindoles as new potent IN inhibitors, whose microwave-assisted synthesis and biological evaluation are reported.
Journal of Chemical Information and Modeling, 2003
A three-dimensional pharmacophore model for the binding of noncompetitive AMPA receptor antagonis... more A three-dimensional pharmacophore model for the binding of noncompetitive AMPA receptor antagonists was developed in order to map common structural features of highly active compounds. This hypothesis, which consists of two hydrophobic regions, one hydrogen bond acceptor and one aromatic region, was successfully used as framework for the design of a new class of allosteric modulators containing a tetrahydroisoquinoline skeleton and for in silico screening. The promising biological results suggested that the identified molecules might be useful "lead compounds" for future drug development.
Journal of Chemical Information and Modeling, 2007
A structure-based molecular modeling approach was performed to identify novel structural characte... more A structure-based molecular modeling approach was performed to identify novel structural characteristics and scaffolds that might represent new classes of HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs). The software LigandScout was used for identification and visualization of protein-ligand interaction sites and pharmacophore model generation. In the next step virtual screening of 3D multiconformational databases together with docking experiments allowed the identification of promising candidates for biological testing. The positive biological results obtained confirm the validity of our work strategy.
Journal of Medicinal Chemistry, 2002
Journal of Medicinal Chemistry, 2009
A new model of HIV-1 integrase-Mg-DNA complex that is useful for docking experiments has been bui... more A new model of HIV-1 integrase-Mg-DNA complex that is useful for docking experiments has been built. It was used to study the binding mode of integrase strand transfer inhibitor 1 (CHI-1043) and other fluorine analogues. Molecular modeling results prompted us to synthesize the designed derivatives which showed potent enzymatic inhibition at nanomolar concentration, high antiviral activity, and low toxicity. Microwave assisted organic synthesis (MAOS) was employed in several steps of the synthetic pathway, thus reducing reaction times and improving yields.