tiago rodrigues - Academia.edu (original) (raw)

Papers by tiago rodrigues

Angewandte Chemie (International ed. in English), Jan 2, 2014

Flow systems have been successfully utilized for a wide variety of applications in chemical resea... more Flow systems have been successfully utilized for a wide variety of applications in chemical research and development, including the miniaturization of (bio)analytical methods and synthetic (bio)organic chemistry. Currently, we are witnessing the growing use of microfluidic technologies for the discovery of new chemical entities. As a consequence, chemical biology and molecular medicine research are being reshaped by this technique. In this Minireview we portray the state-of-the-art, including the most recent advances in the application of microchip reactors as well as the micro- and mesoscale coil reactor-assisted synthesis of bioactive small molecules, and forecast the potential future use of this promising technology.

TheScientificWorldJournal, 2013

In the face of a growing human population and increased urbanization, the demand for pesticides w... more In the face of a growing human population and increased urbanization, the demand for pesticides will simply rise. Farmers must escalate yields on increasingly fewer farm acres. However, the risks of pesticides, whether real or perceived, may force changes in the way these chemicals are used. Scientists are working toward pest control plans that are environmentally sound, effective, and profitable. In this context the development of new pesticide formulations which may improve application effectiveness, safety, handling, and storage can be pointed out as a solution. As a contribution to the area, the microencapsulation of the herbicide oxadiargyl (OXA) in (2-hydroxypropyl)--cyclodextrin (HP--CD) was performed. The study was conducted in different aqueous media (ultrapure water and in different pH buffer solutions). In all cases an increment of the oxadiargyl solubility as a function of the HP--CD concentration that has been related to the formation of an inclusion complex was verified. UV-Vis and NMR experiments allowed concluding that the stoichiometry of the OXA/HP--CD complex formed is 1 : 1. The gathered results can be regarded as an important step for its removal from industrial effluents and/or to increase the stabilizing action, encapsulation, and adsorption in water treatment plants.

Journal of neuroscience research

We report a novel ( 13 C, 2 H) nuclear magnetic resonance (NMR) procedure to investigate lactate ... more We report a novel ( 13 C, 2 H) nuclear magnetic resonance (NMR) procedure to investigate lactate recycling through the monocarboxylate transporter of the plasma membrane of cells in culture. C6 glioma cells were incubated with [3-13 C]lactate in Krebs-Henseleit Buffer containing 50% 2 H 2 O (vol/vol) for up to 30 hr. 13 C NMR analysis of aliquots progressively taken from the medium, showed:

Magnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine, 2005

A fast and sensitive procedure to determine the turnover of the H2 hydrogen of lactate and quanti... more A fast and sensitive procedure to determine the turnover of the H2 hydrogen of lactate and quantify its 2 H-enrichment by 1 H NMR is illustrated using C6 cells metabolizing (3-13 C) lactate in 50% 2 H 2 O (vol/vol). 2 H substitution of the lactate H2 hydrogen resulted in two easily detectable transformations of the vicinal H3 doublet resonance: 1) the formation of an H3 singlet due to the disappearance of the homonuclear coupling to H2 ( 3 J ␤H-␣H ‫؍‬ 7.0 Hz), and 2) an upfield isotopic shift derived from the vicinal 2 H2 substitution (⌬ 3 ‫؍‬ -0.007 ppm). Only those lactate molecules that have passed through the cell cytosol experience these effects, since H2 deuteration involves lactate dehydrogenase activity and NAD( 2 H). Thus, analysis of the observed shifted and unshifted H3 lactate resonances from the incubation medium allows the discrimination of the perprotonated (3-13 C) lactate added as substrate, and the (3-13 C, 2-2 H) lactate recycled to the incubation medium after passage through the cytosol. Magn Reson Med 54:1014 -1019, 2005.

Journal of neuroscience research, Jan 15, 2007

Interactions between the dopaminergic and glutamatergic neurotransmission systems were investigat... more Interactions between the dopaminergic and glutamatergic neurotransmission systems were investigated in the adult brain of wild-type (WT) and transgenic mice lacking the dopamine D 1 or D 2 receptor subtypes. Activity of the glutamine cycle was evaluated by using 13 C NMR spectroscopy, and striatal activity was assessed by c-Fos expression and motor coordination. Brain extracts from (1,2-13 C 2 ) acetate-infused mice were prepared and analyzed by 13 C NMR to determine the incorporation of the label into the C4 and C5 carbons of glutamate and glutamine. D 1 R -/mice showed a significantly higher concentration of cerebral (4,5-13 C 2 ) glutamine, consistent with an increased activity of the glutamate-glutamine cycle and of glutamatergic neurotransmission. Conversely, D 2 R -/mice did not show any significant changes in (4,5-13 C 2 ) glutamate or (4,5-13 C 2 ) glutamine, suggesting that alterations in glutamine metabolism are mediated through D 1 receptors. This was confirmed with D 1 R -/and WT mice treated with reserpine, a dopamine-depleting drug, or with reserpine followed by L-DOPA, a dopamine precursor. Exposure to reserpine increased (4,5-13 C 2 ) glutamine in WT to levels similar to those found in untreated D 1 R -/mice. These values were the same as those reached in the reserpinetreated D 1 R -/mice. Treatment of WT animals with L-DOPA returned (4,5-13 C 2 ) glutamine levels to normal, but this was not verified in D 1 R -/animals. Reserpine impaired motor coordination and decreased c-Fos expression, whereas L-DOPA restored both variables to normal values in WT but not in D 1 R -/-. Together, our results reveal novel neurometabolic interactions between glutamatergic and dopaminergic systems that are mediated through the D 1 , but not the D 2 , dopamine receptor subtype. V V C 2007 Wiley-Liss, Inc.

Analytical biochemistry, Jan 15, 2007

Lactate plays pivotal roles in the metabolism of the brain, both as an intracellular energy subst... more Lactate plays pivotal roles in the metabolism of the brain, both as an intracellular energy substrate for oxidation in neural cells and as a shuttle intermediate for the transcellular metabolic coupling between neurons and astrocytes . In particular, the classical astrocyte to neuron lactate shuttle hypothesis proposed a flux of lactate from astrocytes to neurons to support the energy demands occurring during glutamatergic neurotransmission . However, the reversibility of the lactate dehydrogenase isozymes and the monocarboxylate transporters in the plasma membrane indicates that lactate can both leave and return to the intracellular space, in a recycling process driven by the concentration of lactate inside and outside the cell and the transmembrane pH gradient. The lactate recycling process may become particularly important during cerebral activation events or in tumoral tissues, where intracellular production of lactate is thought to play a central role in cell energetics as a switch between glycolysis and oxidation of extracellular monocarboxylates . However, despite its importance, lactate recycling through the plasma membrane remains a difficult process to investigate, given the identical nature of recycled and nonrecycled lactate molecules hindering their unambiguous identification.

Journal of Cheminformatics, 2014

The fast pace of drug discovery programs, aided by highthroughput screening campaigns, often reli... more The fast pace of drug discovery programs, aided by highthroughput screening campaigns, often relies on the generation of combinatorial libraries to identify new chemical entities. The Ugi 4-and 3-component reactions in particular , have proven to be robust in producing both tool compounds and drugs . Here we report a high-throughput entry into the imidazopyridine scaffold, using a microfluidic-assisted synthesis setup, coupled to a target prediction tool to de-orphan a focused compound library with high success rate, and identify an innovative GPCR-inhibiting chemotype. Combinatorial compounds were correctly identified as ligand-efficient adenosine A 1/2B , and adrenergic α 1A/B inhibitors with K i values in the low micromolar range.

Free Radical Biology and Medicine, 2010

Food and Chemical Toxicology, 2012

Baccharis dracunculifolia DC (Asteraceae) is the main botanical source used by honeybees to produ... more Baccharis dracunculifolia DC (Asteraceae) is the main botanical source used by honeybees to produce Brazilian green propolis whose hepatoprotective properties have been already described. In this work we investigated the protective effects of the glycolic extract of B. dracunculifolia (GEBd) against oxidative stress in isolated rat liver mitochondria (RLM). The GEBd was prepared by fractionated percolation using propylene glycol as solvent. The total phenols and flavonoids, which are substances with recognized antioxidant action, were quantified in GEBd and the phytochemical analysis was carried out by HPLC. GEBd exhibited significant scavenger activity towards DPPH radicals and superoxide anions in a concentrationdependent manner, and also a Fe 2+ chelating activity. GEBd decreased the basal H 2 O 2 generation and the Fe 2+ -or t-BuOOH-induced ROS production in isolated mitochondria. Lipid oxidation of mitochondrial membranes, protein thiol groups and GSH oxidation were also prevented by GEBd. This shows that B. dracunculifolia exhibit potent antioxidant activity protecting liver mitochondria against oxidative damage and such action probably contribute to the antioxidant and hepatoprotective effects of green propolis.

Angewandte Chemie (International ed. in English), Jan 16, 2013

Computer-aided approaches help to mitigate attrition rates of drug candidates and suggest new che... more Computer-aided approaches help to mitigate attrition rates of drug candidates and suggest new chemical entities for sustained drug discovery. In this study we followed a dual strategy of ligand-based de novo design and fragment grafting for generating innovative and readily synthesizable compounds, which we morphed into a highly potent and selective kinase inhibitor. We disclose the discovery of a ligand-efficient (ligand efficiency (LE) = 0.35) inhibitor presenting an IC 50 value of 64 nm against vascular endothelial growth factor receptor-2 (VEGFR-2) kinase. This lead compound exhibits the highest kinase selectivity profile known to date among VEGFR-2 kinase inhibitors (Gini index = 0.87), with the essential selectivity feature having been generated by de novo design. Further profiling fully corroborated VEGFR-2-selective effects on a cellular level. Our findings validate fragment-based de novo design as a premier method for rapid leadstructure prototyping, thereby offering a compelling solution to finding tailored bioactive compounds for chemical biology and drug discovery.

Nature chemistry, 2014

Natural products have long been a source of useful biological activity for the development of new... more Natural products have long been a source of useful biological activity for the development of new drugs. Their macromolecular targets are, however, largely unknown, which hampers rational drug design and optimization. Here we present the development and experimental validation of a computational method for the discovery of such targets. The technique does not require three-dimensional target models and may be applied to structurally complex natural products. The algorithm dissects the natural products into fragments and infers potential pharmacological targets by comparing the fragments to synthetic reference drugs with known targets. We demonstrate that this approach results in confident predictions. In a prospective validation, we show that fragments of the potent antitumour agent archazolid A, a macrolide from the myxobacterium Archangium gephyra, contain relevant information regarding its polypharmacology. Biochemical and biophysical evaluation confirmed the predictions. The results obtained corroborate the practical applicability of the computational approach to natural product 'de-orphaning'.

Chimia, 2014

Predicting the macromolecular targets of drug-like molecules has become everyday practice in medi... more Predicting the macromolecular targets of drug-like molecules has become everyday practice in medicinal chemistry. We present an overview of our recent research activities in the area of polypharmacology-guided drug design. A focus is put on the self-organizing map (SOM) as a tool for compound clustering and visualization. We show how the SOM can be efficiently used for target-panel prediction, drug re-purposing, and the design of focused compound libraries. We also present the concept of virtual organic synthesis in combination with quantitative estimates of ligand-receptor binding, which we used for de novo designing target-selective ligands. We expect these and related approaches to enable the future discovery of personalized medicines.

Angewandte Chemie (International ed. in English), Jan 26, 2015

We report a multi-objective de novo design study driven by synthetic tractability and aimed at th... more We report a multi-objective de novo design study driven by synthetic tractability and aimed at the prioritization of computer-generated 5-HT 2B receptor ligands with accurately predicted target-binding affinities. Relying on quantitative bioactivity models we designed and synthesized structurally novel, selective, nanomolar, and ligand-efficient 5-HT 2B modulators with sustained cell-based effects. Our results suggest that seamless amalgamation of computational activity prediction and molecular design with microfluidics-assisted synthesis enables the swift generation of small molecules with the desired polypharmacology.

PloS one, 2013

Mutations of the monocarboxylate transporter 8 (MCT8) cause a severe X-linked intellectual defici... more Mutations of the monocarboxylate transporter 8 (MCT8) cause a severe X-linked intellectual deficit and neurological impairment. MCT8 is a specific thyroid hormone (T 4 and T 3 ) transporter and the patients also present unusual abnormalities in the serum profile of thyroid hormone concentrations due to altered secretion and metabolism of T 4 and T 3 . Given the role of thyroid hormones in brain development, it is thought that the neurological impairment is due to restricted transport of thyroid hormones to the target neurons. In this work we have investigated cerebral metabolism in mice with Mct8 deficiency. Adult male mice were infused for 30 minutes with (1-13 C) glucose and brain extracts prepared and analyzed by 13 C nuclear magnetic resonance spectroscopy. Genetic inactivation of Mct8 resulted in increased oxidative metabolism as reflected by increased glutamate C4 enrichment, and of glutamatergic and GABAergic neurotransmissions as observed by the increases in glutamine C4 and GABA C2 enrichments, respectively. These changes were distinct to those produced by hypothyroidism or hyperthyroidism. Similar increments in glutamate C4 enrichment and GABAergic neurotransmission were observed in the combined inactivation of Mct8 and D2, indicating that the increased neurotransmission and metabolic activity were not due to increased production of cerebral T 3 by the D2-encoded type 2 deiodinase. In conclusion, Mct8 deficiency has important metabolic consequences in the brain that could not be correlated with deficiency or excess of thyroid hormone supply to the brain during adulthood.

Bioorganic & medicinal chemistry letters, 2009

(1H-Pyridin-4-ylidene)amines containing lipophilic side chains at the imine nitrogen atom were pr... more (1H-Pyridin-4-ylidene)amines containing lipophilic side chains at the imine nitrogen atom were prepared as potential clopidol isosteres in the development of antimalarials. Their antiplasmodial activity was evaluated in vitro against the Plasmodium falciparum W2 (chloroquine-resistant) and FCR3 (atovaquone-resistant) strains. The most active of these derivatives, 4m, had an IC(50) of 1microM against W2 and 3microM against FCR3. Molecular modeling studies suggest that (1H-pyridin-4-ylidene)amines may bind to the ubiquinol oxidation Q(o) site of cytochrome bc(1).

Chemical Science, 2013

Drug discovery programs urgently seek new chemical entities that meet the needs of a demanding ph... more Drug discovery programs urgently seek new chemical entities that meet the needs of a demanding pharmaceutical industry. Consequently, de novo ligand design is currently re-emerging as a noveltygenerating approach. Using ligand-based de novo design software, we computationally generated, chemically synthesized and biochemically tested a new arylsulfonamide against Aurora A kinase, a validated drug target in several types of cancer. The designed compound exhibited desired direct inhibitory activity against Aurora A kinase. By chemical optimization we obtained a lead structure exhibiting sustained activity in phenotypic assays. These results emphasize the potential of ligand-based de novo design to consistently deliver functional new chemotypes within short timeframes and limited effort.

Advances in Neurobiology, 2011

Future Medicinal Chemistry, 2011

Angewandte Chemie (International ed. in English), Jan 2, 2014

Flow systems have been successfully utilized for a wide variety of applications in chemical resea... more Flow systems have been successfully utilized for a wide variety of applications in chemical research and development, including the miniaturization of (bio)analytical methods and synthetic (bio)organic chemistry. Currently, we are witnessing the growing use of microfluidic technologies for the discovery of new chemical entities. As a consequence, chemical biology and molecular medicine research are being reshaped by this technique. In this Minireview we portray the state-of-the-art, including the most recent advances in the application of microchip reactors as well as the micro- and mesoscale coil reactor-assisted synthesis of bioactive small molecules, and forecast the potential future use of this promising technology.

TheScientificWorldJournal, 2013

In the face of a growing human population and increased urbanization, the demand for pesticides w... more In the face of a growing human population and increased urbanization, the demand for pesticides will simply rise. Farmers must escalate yields on increasingly fewer farm acres. However, the risks of pesticides, whether real or perceived, may force changes in the way these chemicals are used. Scientists are working toward pest control plans that are environmentally sound, effective, and profitable. In this context the development of new pesticide formulations which may improve application effectiveness, safety, handling, and storage can be pointed out as a solution. As a contribution to the area, the microencapsulation of the herbicide oxadiargyl (OXA) in (2-hydroxypropyl)--cyclodextrin (HP--CD) was performed. The study was conducted in different aqueous media (ultrapure water and in different pH buffer solutions). In all cases an increment of the oxadiargyl solubility as a function of the HP--CD concentration that has been related to the formation of an inclusion complex was verified. UV-Vis and NMR experiments allowed concluding that the stoichiometry of the OXA/HP--CD complex formed is 1 : 1. The gathered results can be regarded as an important step for its removal from industrial effluents and/or to increase the stabilizing action, encapsulation, and adsorption in water treatment plants.

Journal of neuroscience research

We report a novel ( 13 C, 2 H) nuclear magnetic resonance (NMR) procedure to investigate lactate ... more We report a novel ( 13 C, 2 H) nuclear magnetic resonance (NMR) procedure to investigate lactate recycling through the monocarboxylate transporter of the plasma membrane of cells in culture. C6 glioma cells were incubated with [3-13 C]lactate in Krebs-Henseleit Buffer containing 50% 2 H 2 O (vol/vol) for up to 30 hr. 13 C NMR analysis of aliquots progressively taken from the medium, showed:

Magnetic resonance in medicine : official journal of the Society of Magnetic Resonance in Medicine / Society of Magnetic Resonance in Medicine, 2005

A fast and sensitive procedure to determine the turnover of the H2 hydrogen of lactate and quanti... more A fast and sensitive procedure to determine the turnover of the H2 hydrogen of lactate and quantify its 2 H-enrichment by 1 H NMR is illustrated using C6 cells metabolizing (3-13 C) lactate in 50% 2 H 2 O (vol/vol). 2 H substitution of the lactate H2 hydrogen resulted in two easily detectable transformations of the vicinal H3 doublet resonance: 1) the formation of an H3 singlet due to the disappearance of the homonuclear coupling to H2 ( 3 J ␤H-␣H ‫؍‬ 7.0 Hz), and 2) an upfield isotopic shift derived from the vicinal 2 H2 substitution (⌬ 3 ‫؍‬ -0.007 ppm). Only those lactate molecules that have passed through the cell cytosol experience these effects, since H2 deuteration involves lactate dehydrogenase activity and NAD( 2 H). Thus, analysis of the observed shifted and unshifted H3 lactate resonances from the incubation medium allows the discrimination of the perprotonated (3-13 C) lactate added as substrate, and the (3-13 C, 2-2 H) lactate recycled to the incubation medium after passage through the cytosol. Magn Reson Med 54:1014 -1019, 2005.

Journal of neuroscience research, Jan 15, 2007

Interactions between the dopaminergic and glutamatergic neurotransmission systems were investigat... more Interactions between the dopaminergic and glutamatergic neurotransmission systems were investigated in the adult brain of wild-type (WT) and transgenic mice lacking the dopamine D 1 or D 2 receptor subtypes. Activity of the glutamine cycle was evaluated by using 13 C NMR spectroscopy, and striatal activity was assessed by c-Fos expression and motor coordination. Brain extracts from (1,2-13 C 2 ) acetate-infused mice were prepared and analyzed by 13 C NMR to determine the incorporation of the label into the C4 and C5 carbons of glutamate and glutamine. D 1 R -/mice showed a significantly higher concentration of cerebral (4,5-13 C 2 ) glutamine, consistent with an increased activity of the glutamate-glutamine cycle and of glutamatergic neurotransmission. Conversely, D 2 R -/mice did not show any significant changes in (4,5-13 C 2 ) glutamate or (4,5-13 C 2 ) glutamine, suggesting that alterations in glutamine metabolism are mediated through D 1 receptors. This was confirmed with D 1 R -/and WT mice treated with reserpine, a dopamine-depleting drug, or with reserpine followed by L-DOPA, a dopamine precursor. Exposure to reserpine increased (4,5-13 C 2 ) glutamine in WT to levels similar to those found in untreated D 1 R -/mice. These values were the same as those reached in the reserpinetreated D 1 R -/mice. Treatment of WT animals with L-DOPA returned (4,5-13 C 2 ) glutamine levels to normal, but this was not verified in D 1 R -/animals. Reserpine impaired motor coordination and decreased c-Fos expression, whereas L-DOPA restored both variables to normal values in WT but not in D 1 R -/-. Together, our results reveal novel neurometabolic interactions between glutamatergic and dopaminergic systems that are mediated through the D 1 , but not the D 2 , dopamine receptor subtype. V V C 2007 Wiley-Liss, Inc.

Analytical biochemistry, Jan 15, 2007

Lactate plays pivotal roles in the metabolism of the brain, both as an intracellular energy subst... more Lactate plays pivotal roles in the metabolism of the brain, both as an intracellular energy substrate for oxidation in neural cells and as a shuttle intermediate for the transcellular metabolic coupling between neurons and astrocytes . In particular, the classical astrocyte to neuron lactate shuttle hypothesis proposed a flux of lactate from astrocytes to neurons to support the energy demands occurring during glutamatergic neurotransmission . However, the reversibility of the lactate dehydrogenase isozymes and the monocarboxylate transporters in the plasma membrane indicates that lactate can both leave and return to the intracellular space, in a recycling process driven by the concentration of lactate inside and outside the cell and the transmembrane pH gradient. The lactate recycling process may become particularly important during cerebral activation events or in tumoral tissues, where intracellular production of lactate is thought to play a central role in cell energetics as a switch between glycolysis and oxidation of extracellular monocarboxylates . However, despite its importance, lactate recycling through the plasma membrane remains a difficult process to investigate, given the identical nature of recycled and nonrecycled lactate molecules hindering their unambiguous identification.

Journal of Cheminformatics, 2014

The fast pace of drug discovery programs, aided by highthroughput screening campaigns, often reli... more The fast pace of drug discovery programs, aided by highthroughput screening campaigns, often relies on the generation of combinatorial libraries to identify new chemical entities. The Ugi 4-and 3-component reactions in particular , have proven to be robust in producing both tool compounds and drugs . Here we report a high-throughput entry into the imidazopyridine scaffold, using a microfluidic-assisted synthesis setup, coupled to a target prediction tool to de-orphan a focused compound library with high success rate, and identify an innovative GPCR-inhibiting chemotype. Combinatorial compounds were correctly identified as ligand-efficient adenosine A 1/2B , and adrenergic α 1A/B inhibitors with K i values in the low micromolar range.

Free Radical Biology and Medicine, 2010

Food and Chemical Toxicology, 2012

Baccharis dracunculifolia DC (Asteraceae) is the main botanical source used by honeybees to produ... more Baccharis dracunculifolia DC (Asteraceae) is the main botanical source used by honeybees to produce Brazilian green propolis whose hepatoprotective properties have been already described. In this work we investigated the protective effects of the glycolic extract of B. dracunculifolia (GEBd) against oxidative stress in isolated rat liver mitochondria (RLM). The GEBd was prepared by fractionated percolation using propylene glycol as solvent. The total phenols and flavonoids, which are substances with recognized antioxidant action, were quantified in GEBd and the phytochemical analysis was carried out by HPLC. GEBd exhibited significant scavenger activity towards DPPH radicals and superoxide anions in a concentrationdependent manner, and also a Fe 2+ chelating activity. GEBd decreased the basal H 2 O 2 generation and the Fe 2+ -or t-BuOOH-induced ROS production in isolated mitochondria. Lipid oxidation of mitochondrial membranes, protein thiol groups and GSH oxidation were also prevented by GEBd. This shows that B. dracunculifolia exhibit potent antioxidant activity protecting liver mitochondria against oxidative damage and such action probably contribute to the antioxidant and hepatoprotective effects of green propolis.

Angewandte Chemie (International ed. in English), Jan 16, 2013

Computer-aided approaches help to mitigate attrition rates of drug candidates and suggest new che... more Computer-aided approaches help to mitigate attrition rates of drug candidates and suggest new chemical entities for sustained drug discovery. In this study we followed a dual strategy of ligand-based de novo design and fragment grafting for generating innovative and readily synthesizable compounds, which we morphed into a highly potent and selective kinase inhibitor. We disclose the discovery of a ligand-efficient (ligand efficiency (LE) = 0.35) inhibitor presenting an IC 50 value of 64 nm against vascular endothelial growth factor receptor-2 (VEGFR-2) kinase. This lead compound exhibits the highest kinase selectivity profile known to date among VEGFR-2 kinase inhibitors (Gini index = 0.87), with the essential selectivity feature having been generated by de novo design. Further profiling fully corroborated VEGFR-2-selective effects on a cellular level. Our findings validate fragment-based de novo design as a premier method for rapid leadstructure prototyping, thereby offering a compelling solution to finding tailored bioactive compounds for chemical biology and drug discovery.

Nature chemistry, 2014

Natural products have long been a source of useful biological activity for the development of new... more Natural products have long been a source of useful biological activity for the development of new drugs. Their macromolecular targets are, however, largely unknown, which hampers rational drug design and optimization. Here we present the development and experimental validation of a computational method for the discovery of such targets. The technique does not require three-dimensional target models and may be applied to structurally complex natural products. The algorithm dissects the natural products into fragments and infers potential pharmacological targets by comparing the fragments to synthetic reference drugs with known targets. We demonstrate that this approach results in confident predictions. In a prospective validation, we show that fragments of the potent antitumour agent archazolid A, a macrolide from the myxobacterium Archangium gephyra, contain relevant information regarding its polypharmacology. Biochemical and biophysical evaluation confirmed the predictions. The results obtained corroborate the practical applicability of the computational approach to natural product 'de-orphaning'.

Chimia, 2014

Predicting the macromolecular targets of drug-like molecules has become everyday practice in medi... more Predicting the macromolecular targets of drug-like molecules has become everyday practice in medicinal chemistry. We present an overview of our recent research activities in the area of polypharmacology-guided drug design. A focus is put on the self-organizing map (SOM) as a tool for compound clustering and visualization. We show how the SOM can be efficiently used for target-panel prediction, drug re-purposing, and the design of focused compound libraries. We also present the concept of virtual organic synthesis in combination with quantitative estimates of ligand-receptor binding, which we used for de novo designing target-selective ligands. We expect these and related approaches to enable the future discovery of personalized medicines.

Angewandte Chemie (International ed. in English), Jan 26, 2015

We report a multi-objective de novo design study driven by synthetic tractability and aimed at th... more We report a multi-objective de novo design study driven by synthetic tractability and aimed at the prioritization of computer-generated 5-HT 2B receptor ligands with accurately predicted target-binding affinities. Relying on quantitative bioactivity models we designed and synthesized structurally novel, selective, nanomolar, and ligand-efficient 5-HT 2B modulators with sustained cell-based effects. Our results suggest that seamless amalgamation of computational activity prediction and molecular design with microfluidics-assisted synthesis enables the swift generation of small molecules with the desired polypharmacology.

PloS one, 2013

Mutations of the monocarboxylate transporter 8 (MCT8) cause a severe X-linked intellectual defici... more Mutations of the monocarboxylate transporter 8 (MCT8) cause a severe X-linked intellectual deficit and neurological impairment. MCT8 is a specific thyroid hormone (T 4 and T 3 ) transporter and the patients also present unusual abnormalities in the serum profile of thyroid hormone concentrations due to altered secretion and metabolism of T 4 and T 3 . Given the role of thyroid hormones in brain development, it is thought that the neurological impairment is due to restricted transport of thyroid hormones to the target neurons. In this work we have investigated cerebral metabolism in mice with Mct8 deficiency. Adult male mice were infused for 30 minutes with (1-13 C) glucose and brain extracts prepared and analyzed by 13 C nuclear magnetic resonance spectroscopy. Genetic inactivation of Mct8 resulted in increased oxidative metabolism as reflected by increased glutamate C4 enrichment, and of glutamatergic and GABAergic neurotransmissions as observed by the increases in glutamine C4 and GABA C2 enrichments, respectively. These changes were distinct to those produced by hypothyroidism or hyperthyroidism. Similar increments in glutamate C4 enrichment and GABAergic neurotransmission were observed in the combined inactivation of Mct8 and D2, indicating that the increased neurotransmission and metabolic activity were not due to increased production of cerebral T 3 by the D2-encoded type 2 deiodinase. In conclusion, Mct8 deficiency has important metabolic consequences in the brain that could not be correlated with deficiency or excess of thyroid hormone supply to the brain during adulthood.

Bioorganic & medicinal chemistry letters, 2009

(1H-Pyridin-4-ylidene)amines containing lipophilic side chains at the imine nitrogen atom were pr... more (1H-Pyridin-4-ylidene)amines containing lipophilic side chains at the imine nitrogen atom were prepared as potential clopidol isosteres in the development of antimalarials. Their antiplasmodial activity was evaluated in vitro against the Plasmodium falciparum W2 (chloroquine-resistant) and FCR3 (atovaquone-resistant) strains. The most active of these derivatives, 4m, had an IC(50) of 1microM against W2 and 3microM against FCR3. Molecular modeling studies suggest that (1H-pyridin-4-ylidene)amines may bind to the ubiquinol oxidation Q(o) site of cytochrome bc(1).

Chemical Science, 2013

Drug discovery programs urgently seek new chemical entities that meet the needs of a demanding ph... more Drug discovery programs urgently seek new chemical entities that meet the needs of a demanding pharmaceutical industry. Consequently, de novo ligand design is currently re-emerging as a noveltygenerating approach. Using ligand-based de novo design software, we computationally generated, chemically synthesized and biochemically tested a new arylsulfonamide against Aurora A kinase, a validated drug target in several types of cancer. The designed compound exhibited desired direct inhibitory activity against Aurora A kinase. By chemical optimization we obtained a lead structure exhibiting sustained activity in phenotypic assays. These results emphasize the potential of ligand-based de novo design to consistently deliver functional new chemotypes within short timeframes and limited effort.

Advances in Neurobiology, 2011

Future Medicinal Chemistry, 2011