RESUMEN
Gram-negative antibiotic development has been hindered by a poor understanding of the types of compounds that can accumulate within these bacteria1,2. The presence of efflux pumps and substrate-specific outer-membrane porins in Pseudomonas aeruginosa renders this pathogen particularly challenging3. As a result, there are few antibiotic options for P. aeruginosa infections4 and its many porins have made the prospect of discovering general accumulation guidelines seem unlikely5. Here we assess the whole-cell accumulation of 345 diverse compounds in P. aeruginosa and Escherichia coli. Although certain positively charged compounds permeate both bacterial species, P. aeruginosa is more restrictive compared to E. coli. Computational analysis identified distinct physicochemical properties of small molecules that specifically correlate with P. aeruginosa accumulation, such as formal charge, positive polar surface area and hydrogen bond donor surface area. Mode of uptake studies revealed that most small molecules permeate P. aeruginosa using a porin-independent pathway, thus enabling discovery of general P. aeruginosa accumulation trends with important implications for future antibiotic development. Retrospective antibiotic examples confirmed these trends and these discoveries were then applied to expand the spectrum of activity of a gram-positive-only antibiotic, fusidic acid, into a version that demonstrates a dramatic improvement in antibacterial activity against P. aeruginosa. We anticipate that these discoveries will facilitate the design and development of high-permeating antipseudomonals.
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Antibacterianos , Diseño de Fármacos , Porinas , Pseudomonas aeruginosa , Antibacterianos/química , Antibacterianos/metabolismo , Antibacterianos/farmacología , Escherichia coli/metabolismo , Pruebas de Sensibilidad Microbiana , Pseudomonas aeruginosa/efectos de los fármacos , Pseudomonas aeruginosa/metabolismo , Estudios Retrospectivos , Electricidad Estática , Enlace de Hidrógeno , Ácido Fusídico/metabolismo , Diseño de Fármacos/métodosRESUMEN
Nonadditivity (NA) in Structure-Activity and Structure-Property Relationship (SAR) data is a rare but very information rich phenomenon. It can indicate conformational flexibility, structural rearrangements, and errors in assay results and structural assignment. While purely ligand-based conformational causes of NA are rather well understood and mundane, other factors are less so and cause surprising NA that has a huge influence on SAR analysis and ML model performance. We here report a systematic analysis across a wide range of properties (20 on-target biological activities and 4 physicochemical ADME-related properties) to understand the frequency of various different phenomena that may lead to NA. A set of novel descriptors were developed to characterize double transformation cycles and identify trends in NA. Double transformation cycles were classified into "surprising" and "mundane" categories, with the majority being classed as mundane. We also examined commonalities among surprising cycles, finding LogP differences to have the most significant impact on NA. A distinct behavior of NA for on-target sets compared to ADME sets was observed. Finally, we show that machine learning models struggle with highly nonadditive data, indicating that a better understanding of NA is an important future research direction.
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Aprendizaje Automático , Relación Estructura-Actividad , Humanos , Ligandos , Descubrimiento de Drogas/métodos , Conformación MolecularRESUMEN
DNA encoded library (DEL) synthesis represents a convenient means to produce, annotate and store large collections of compounds in a small volume. While DELs are well suited for drug discovery campaigns, the chemistry used in their production must be compatible with the DNA tag, which can limit compound class accessibility. As a result, most DELs are heavily populated with peptidomimetic and sp2 -rich molecules. Herein, we show that sp3 -rich mono- and bicyclic heterocycles can be made on DNA from ketochlorohydrin aldol products through a reductive amination and cyclization process. The resulting hydroxypyrrolidines possess structural features that are desirable for DELs and target a distinct region of pharmaceutically relevant chemical space.
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ADN , Bibliotecas de Moléculas Pequeñas , Bibliotecas de Moléculas Pequeñas/química , ADN/química , Biblioteca de Genes , Descubrimiento de Drogas/métodos , AminaciónRESUMEN
Large databases of biologically relevant molecules, such as ChEMBL, SureChEMBL, or compound collections of pharmaceutical or agrochemical companies, are invaluable sources of medicinal chemistry information, albeit implicit. We developed a modified matched molecular pair approach to systematically and exhaustively extract the transformations in these databases and distill them into snippets of explicit design knowledge that are easily interpretable and directly applicable. The resulting "playbooks of medicinal chemistry design moves" capture the collective pharmaceutical and agrochemical research expertise across multiple chemists, companies, targets, and projects. They can be queried in an automated fashion for systematic prospective design and compound generation. The ChEMBL playbook and an application to exploit it are available at https://github.com/mahendra-awale/medchem_moves.
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Química Farmacéutica , Bases de Datos Factuales , Estudios ProspectivosRESUMEN
We report a database of tautomeric structures that contains 2819 tautomeric tuples extracted from 171 publications. Each tautomeric entry has been annotated with experimental conditions reported in the respective publication, plus bibliographic details, structural identifiers (e.g., NCI/CADD identifiers FICTS, FICuS, uuuuu, and Standard InChI), and chemical information (e.g., SMILES, molecular weight). The majority of tautomeric tuples found were pairs; the remaining 10% were triples, quadruples, or quintuples, amounting to a total number of structures of 5977. The types of tautomerism were mainly prototropic tautomerism (79%), followed by ring-chain (13%) and valence tautomerism (8%). The experimental conditions reported in the publications included about 50 pure solvents and 9 solvent mixtures with 26 unique spectroscopic or nonspectroscopic methods. 1H and 13C NMR were the most frequently used methods. A total of 77 different tautomeric transform rules (SMIRKS) are covered by at least one example tuple in the database. This database is freely available as a spreadsheet at https://cactus.nci.nih.gov/download/tautomer/.
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Isomerismo , Bases de Datos Factuales , Espectroscopía de Resonancia MagnéticaRESUMEN
We investigated how many cases of the same chemical sold as different products (at possibly different prices) occurred in a prototypical large aggregated database and simultaneously tested the tautomerism definitions in the chemoinformatics toolkit CACTVS. We applied the standard CACTVS tautomeric transforms plus a set of recently developed ring-chain transforms to the Aldrich Market Select (AMS) database of 6 million screening samples and building blocks. In 30â¯000 cases, two or more AMS products were found to be just different tautomeric forms of the same compound. We purchased and analyzed 166 such tautomer pairs and triplets by 1H and 13C NMR to determine whether the CACTVS transforms accurately predicted what is the same "stuff in the bottle". Essentially all prototropic transforms with examples in the AMS were confirmed. Some of the ring-chain transforms were found to be too "aggressive", i.e. to equate structures with one another that were different compounds.
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Bases de Datos Factuales , Informática/métodos , Compuestos Orgánicos/química , Bases de Datos Factuales/economía , IsomerismoRESUMEN
Warfarin, an important anticoagulant drug, can exist in solution in 40 distinct tautomeric forms through both prototropic tautomerism and ring-chain tautomerism. We have investigated all warfarin tautomers with computational and NMR approaches. Relative energies calculated at the B3LYP/6-311G++(d,p) level of theory indicate that the 4-hydroxycoumarin cyclic hemiketal tautomer is the most stable tautomer in aqueous solution, followed by the 4-hydroxycoumarin open-chain tautomer. This is in agreement with our NMR experiments where the spectral assignments indicate that warfarin exists mainly as a mixture of cyclic hemiketal diastereomers, with an open-chain tautomer as a minor component. We present a diagram of the interconversion of warfarin created taking into account the calculated equilibrium constants (pK(T)) for all tautomeric reactions. These findings help with gaining further understanding of proton transfer and ring closure tautomerization processes. We also discuss the results in the context of chemoinformatics rules for handling tautomerism.
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Anticoagulantes/química , Simulación de Dinámica Molecular , Teoría Cuántica , Warfarina/química , Espectroscopía de Resonancia Magnética , Estructura Molecular , EstereoisomerismoRESUMEN
A compound exhibits (prototropic) tautomerism if it can be represented by two or more structures that are related by a formal intramolecular movement of a hydrogen atom from one heavy atom position to another. When the movement of the proton is accompanied by the opening or closing of a ring it is called ring-chain tautomerism. This type of tautomerism is well observed in carbohydrates, but it also occurs in other molecules such as warfarin. In this work, we present an approach that allows for the generation of all ring-chain tautomers of a given chemical structure. Based on Baldwin's Rules estimating the likelihood of ring closure reactions to occur, we have defined a set of transform rules covering the majority of ring-chain tautomerism cases. The rules automatically detect substructures in a given compound that can undergo a ring-chain tautomeric transformation. Each transformation is encoded in SMIRKS line notation. All work was implemented in the chemoinformatics toolkit CACTVS. We report on the application of our ring-chain tautomerism rules to a large database of commercially available screening samples in order to identify ring-chain tautomers.
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Conformación Molecular , Ciclización , Bases de Datos de Compuestos QuímicosRESUMEN
UNLABELLED: Decoys are molecules that are presumed to be inactive against a target (i.e. will not likely bind to the target) and are used to validate the performance of molecular docking or a virtual screening workflow. The Directory of Useful Decoys database (http://dud.docking.org/) provides a free directory of decoys for use in virtual screening, though it only contains a limited set of decoys for 40 targets.To overcome this limitation, we have developed an application called DecoyFinder that selects, for a given collection of active ligands of a target, a set of decoys from a database of compounds. Decoys are selected if they are similar to active ligands according to five physical descriptors (molecular weight, number of rotational bonds, total hydrogen bond donors, total hydrogen bond acceptors and the octanol-water partition coefficient) without being chemically similar to any of the active ligands used as an input (according to the Tanimoto coefficient between MACCS fingerprints). To the best of our knowledge, DecoyFinder is the first application designed to build target-specific decoy sets. AVAILABILITY: A complete description of the software is included on the application home page. A validation of DecoyFinder on 10 DUD targets is provided as Supplementary Table S1. DecoyFinder is freely available at http://URVnutrigenomica-CTNS.github.com/DecoyFinder.
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Bases de Datos Factuales , Modelos Moleculares , Proteínas/análisis , Programas Informáticos , Algoritmos , Biología Computacional/métodos , Gráficos por Computador , Enlace de Hidrógeno , Ligandos , Peso Molecular , Interfaz Usuario-ComputadorRESUMEN
We have undertaken theoretical investigations of the asymmetric hydroformylation of styrene by the [Rh{(R,S)-BINAPHOS}(CO)(2)H] catalyst, focusing on the origin of the ligand coordination preferences and stereoinduction. We evaluated the different factors governing the preference of the BINAPHOS ligand to coordinate with the phosphane moiety at the equatorial site and the phosphite moiety at the apical site. The donor-acceptor interactions, obtained using a modified version of energy decomposition analysis (EDA) based on orbital deletion, favour the phosphite moiety at the equatorial site. However, the electronic distortion and the steric effects inverse this tendency. Calculations also suggest that the coordination preference was transferred to the selectivity-determining transition state. We propose a stereochemical model based on quantitative quadrant maps obtained from a new molecular descriptor, the distance-weighted volume (V(W)), which is easily computed from ground-state structures. Repulsive interactions between the substrate and the apical phosphite were responsible for the enantiodifferentiation. The axial chirality of the phosphite discriminated one of the competitive equatorial-apical paths, whereas the axial chirality of the backbone discriminated one of the two enantiomers. Transition-state calculations revealed that the placement of phosphane at the apical site would lower enantioselectivity, explaining the poor performance of other phosphane-phosphite ligands. Finally, comparison with previous studies allowed the definition of several prerequisites for diphosphane ligands for high stereoselectivity: 1)â specific equatorial-apical coordination bringing chirality to the apical site, 2)â combination of two stereogenic centres and 3)â rigid structures.
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Modelos Teóricos , Compuestos Organofosforados/química , Catálisis , Modelos Moleculares , Conformación Molecular , Estructura Molecular , EstereoisomerismoRESUMEN
The in vivo half-life is a key property of every drug molecule, as it determines dosing regimens, peak-to-trough ratios and often dose. However, half-life optimization can be challenging due to its multifactorial nature, with in vitro metabolic turnover, plasma protein binding and volume of distribution all impacting half-life. We here propose that the medicinal chemistry design parameter Lipophilic Metabolism Efficiency (LipMetE) can greatly simplify half-life optimization of neutral and basic compounds. Using mathematical transformations, examples from preclinical GABAA projects and clinical compounds with human pharmacokinetic data, we show that LipMetE is directly proportional to the logarithm of half-life. As the design parameter LipMetE can be swiftly calculated using the readily available parameters LogD, intrinsic clearance and fraction unbound in human liver microsomes or hepatocytes, this approach enables rational half-life optimization from the early stages of drug discovery projects.
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Peroxisome Proliferator-Activated Receptor γ (PPARγ) full agonists are molecules with powerful insulin-sensitizing action that are used as antidiabetic drugs. Unfortunately, these compounds also present various side effects. Recent results suggest that effective PPARγ agonists should show a low transactivation activity but a high binding affinity to inhibit phosphorylation at Ser273. We use several structure activity relationship studies of synthetic PPARγ agonists to explore the different binding features of full and partial PPARγ agonists with the aim of differentiating the features needed for binding and those needed for the transactivation activity of PPARγ. Our results suggest that effective partial agonists should have a hydrophobic moiety and an acceptor site with an appropriate conformation to interact with arm II and establish a hydrogen bond with Ser342 or an equivalent residue at arm III. Despite the fact that interactions with arm I increase the binding affinity, this region should be avoided in order to not increase the transactivation activity of potential PPARγ partial agonists.
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Análisis por Conglomerados , Diseño de Fármacos , Hipoglucemiantes/química , Modelos Moleculares , PPAR gamma/agonistas , PPAR gamma/química , Relación Estructura-Actividad Cuantitativa , Sitios de Unión , Simulación por Computador , Hipoglucemiantes/agonistas , Hipoglucemiantes/metabolismo , Ligandos , Conformación Molecular , PPAR gamma/metabolismo , Tiazolidinedionas/químicaRESUMEN
The C-terminal binding protein (CtBP) is an NADH-dependent dimeric family of nuclear proteins that scaffold interactions between transcriptional regulators and chromatin-modifying complexes. Its association with poor survival in several cancers implicates CtBP as a promising target for pharmacological intervention. We employed computer-assisted drug design to search for CtBP inhibitors, using quantitative structure-activity relationship (QSAR) modeling and docking. Functional screening of these drugs identified 4 compounds with low toxicity and high water solubility. Micro molar concentrations of these CtBP inhibitors produces significant de-repression of epigenetically silenced pro-epithelial genes, preferentially in the triple-negative breast cancer cell line MDA-MB-231. This epigenetic reprogramming occurs through eviction of CtBP from gene promoters; disrupted recruitment of chromatin-modifying protein complexes containing LSD1, and HDAC1; and re-wiring of activating histone marks at targeted genes. In functional assays, CtBP inhibition disrupts CtBP dimerization, decreases cell migration, abolishes cellular invasion, and improves DNA repair. Combinatorial use of CtBP inhibitors with the LSD1 inhibitor pargyline has synergistic influence. Finally, integrated correlation of gene expression in breast cancer patients with nuclear levels of CtBP1 and LSD1, reveals new potential therapeutic vulnerabilities. These findings implicate a broad role for this class of compounds in strategies for epigenetically targeted therapeutic intervention.
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Oxidorreductasas de Alcohol/genética , Neoplasias de la Mama/genética , Proteínas de Unión al ADN/genética , Epigénesis Genética/genética , Femenino , HumanosRESUMEN
C646 inhibits the lysine acetyltransferases (KATs) p300 and CBP and represents the most potent and selective small molecule KAT inhibitor identified to date. To gain insights into the cellular activity of this epigenetic probe, we applied chemoproteomics to identify covalent targets of the C646 chemotype. Modeling and synthetic derivatization was used to develop a clickable analogue (C646-yne) that inhibits p300 similarly to the parent compound and enables enrichment of bound proteins. LC-MS/MS identified the major covalent targets of C646-yne as highly abundant cysteine-containing proteins, and follow-up studies found that C646 can inhibit tubulin polymerization in vitro. Finally, we provide evidence that thiol reactivity of C646 may limit its ability to antagonize acetylation in cells. These findings should enable a more precise interpretation of studies utilizing C646 as a chemical probe of KAT activity and suggest that an underappreciated liability of electrophile-containing inhibitors is a reduction in their cellular potency due to consumption by abundant protein and metabolite thiol sinks.
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HIV-1 integrase (IN) plays an important role in the life cycle of HIV and is responsible for integration of the virus into the human genome. We present computational approaches used to design novel HIV-1 IN inhibitors. We created an IN inhibitor database by collecting experimental data from the literature. We developed quantitative structure-activity relationship (QSAR) models of HIV-1 IN strand transfer (ST) inhibitors using this database. The prediction accuracy of these models was estimated by external 5-fold cross-validation as well as with an additional validation set of 308 structurally distinct compounds from the publicly accessible BindingDB database. The validated models were used to screen a small combinatorial library of potential synthetic candidates to identify hits, with a subsequent docking approach applied to further filter out compounds to arrive at a small set of potential HIV-1 IN inhibitors. As result, 236 compounds with good druglikeness properties and with correct docking poses were identified as potential candidates for synthesis. One of the six compounds finally chosen for synthesis was experimentally confirmed to inhibit the ST reaction with an IC50(ST) of 37 µM. The IN inhibitor database is available for download from http://cactus.nci.nih.gov/download/iidb/.
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Inhibidores de Integrasa VIH/farmacología , Integrasa de VIH/metabolismo , VIH-1/enzimología , Relación Estructura-Actividad Cuantitativa , Evaluación Preclínica de Medicamentos , Inhibidores de Integrasa VIH/química , VIH-1/efectos de los fármacos , Humanos , Modelos Moleculares , Estructura MolecularRESUMEN
The finding that chromatin modifications are sensitive to changes in cellular cofactor levels potentially links altered tumor cell metabolism and gene expression. However, the specific enzymes and metabolites that connect these two processes remain obscure. Characterizing these metabolic-epigenetic axes is critical to understanding how metabolism supports signaling in cancer, and developing therapeutic strategies to disrupt this process. Here, we describe a chemical approach to define the metabolic regulation of lysine acetyltransferase (KAT) enzymes. Using a novel chemoproteomic probe, we identify a previously unreported interaction between palmitoyl coenzyme A (palmitoyl-CoA) and KAT enzymes. Further analysis reveals that palmitoyl-CoA is a potent inhibitor of KAT activity and that fatty acyl-CoA precursors reduce cellular histone acetylation levels. These studies implicate fatty acyl-CoAs as endogenous regulators of histone acetylation, and suggest novel strategies for the investigation and metabolic modulation of epigenetic signaling.
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Acilcoenzima A/metabolismo , N-Acetiltransferasa de Aminoácidos/metabolismo , Histona Acetiltransferasas/metabolismo , Lisina/metabolismo , Acetilación , Acilcoenzima A/biosíntesis , Acilcoenzima A/química , N-Acetiltransferasa de Aminoácidos/química , Células HEK293 , Histona Acetiltransferasas/química , Humanos , Cinética , Lisina/química , Modelos Químicos , Palmitoil Coenzima A/química , Palmitoil Coenzima A/metabolismo , ProteómicaRESUMEN
Thiazolidinediones (TZDs), such as rosiglitazone and pioglitazone, are peroxisome proliferator-activated receptor γ (PPARγ) full agonists that have been widely used in the treatment of type 2 diabetes mellitus. Despite the demonstrated beneficial effect of reducing glucose levels in the plasma, TZDs also induce several adverse effects. Consequently, the search for new compounds with potent antidiabetic effects but fewer undesired effects is an active field of research. Interestingly, the novel proposed mechanisms for the antidiabetic activity of PPARγ agonists, consisting of PPARγ Ser273 phosphorylation inhibition, ligand and receptor mutual dynamics, and the presence of an alternate binding site, have recently changed the view regarding the optimal characteristics for the screening of novel PPARγ ligands. Furthermore, transcriptional genomics could bring essential information about the genome-wide effects of PPARγ ligands. Consequently, facing the new mechanistic scenario proposed for these compounds is essential for resolving the paradoxes among their agonistic function, antidiabetic activities, and side effects and should allow the rational development of better and safer PPARγ-mediated antidiabetic drugs.
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PPAR gamma/metabolismo , Animales , Descubrimiento de Drogas , Humanos , Hipoglucemiantes/farmacología , Hipoglucemiantes/uso terapéutico , Ligandos , PPAR gamma/agonistas , PPAR gamma/antagonistas & inhibidores , PPAR gamma/química , Fosforilación/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
BACKGROUND: Natural extracts have played an important role in the prevention and treatment of diseases and are important sources for drug discovery. However, to be effectively used in these processes, natural extracts must be characterized through the identification of their active compounds and their modes of action. METHODOLOGY/PRINCIPAL FINDINGS: From an initial set of 29,779 natural products that are annotated with their natural source and using a previously developed virtual screening procedure (carefully validated experimentally), we have predicted as potential peroxisome proliferators-activated receptor gamma (PPARγ) partial agonists 12 molecules from 11 extracts known to have antidiabetic activity. Six of these molecules are similar to molecules with described antidiabetic activity but whose mechanism of action is unknown. Therefore, it is plausible that these 12 molecules could be the bioactive molecules responsible, at least in part, for the antidiabetic activity of the extracts containing them. In addition, we have also identified as potential PPARγ partial agonists 10 molecules from 16 plants with undescribed antidiabetic activity but that are related (i.e., they are from the same genus) to plants with known antidiabetic properties. None of the 22 molecules that we predict as PPARγ partial agonists show chemical similarity with a group of 211 known PPARγ partial agonists obtained from the literature. CONCLUSIONS/SIGNIFICANCE: Our results provide a new hypothesis about the active molecules of natural extracts with antidiabetic properties and their mode of action. We also suggest plants with undescribed antidiabetic activity that may contain PPARγ partial agonists. These plants represent a new source of potential antidiabetic extracts. Consequently, our work opens the door to the discovery of new antidiabetic extracts and molecules that can be of use, for instance, in the design of new antidiabetic drugs or functional foods focused towards the prevention/treatment of type 2 Diabetes Mellitus.
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Productos Biológicos/farmacología , Simulación por Computador , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/farmacología , PPAR gamma/agonistas , Extractos Vegetales/farmacología , Descubrimiento de Drogas , Humanos , Estructura Molecular , Relación Estructura-ActividadRESUMEN
Peroxisome proliferator-activated receptor gamma (PPARγ) has become an attractive molecular target for drugs that aim to treat diabetes mellitus type II, and its therapeutic potency against skin cancer and other skin diseases is also currently being explored. To study the relationship between the structure of several PPARγ full agonists and the trans-activation activity of PPARγ, we have performed a three-dimensional quantitative structure-activity relationship (3D-QSAR) study of tyrosine-based derivatives, based on the 3D alignment of conformations obtained by docking. Highly predictive 3D-QSAR models, with Pearson-R values of 0.86 and 0.90, were obtained for the transactivation activity and binding affinity of PPARγ, respectively. These models are in good agreement with the structural characteristics of the binding pocket of PPARγ and provide some structural insights for the improvement of PPARγ full agonist bioactivities.