Showing papers by "Vincent Zoete published in 2017"
TL;DR: The new SwissADME web tool is presented that gives free access to a pool of fast yet robust predictive models for physicochemical properties, pharmacokinetics, drug-likeness and medicinal chemistry friendliness, among which in-house proficient methods such as the BOILED-Egg, iLOGP and Bioavailability Radar are presented.
Abstract: To be effective as a drug, a potent molecule must reach its target in the body in sufficient concentration, and stay there in a bioactive form long enough for the expected biologic events to occur. Drug development involves assessment of absorption, distribution, metabolism and excretion (ADME) increasingly earlier in the discovery process, at a stage when considered compounds are numerous but access to the physical samples is limited. In that context, computer models constitute valid alternatives to experiments. Here, we present the new SwissADME web tool that gives free access to a pool of fast yet robust predictive models for physicochemical properties, pharmacokinetics, drug-likeness and medicinal chemistry friendliness, among which in-house proficient methods such as the BOILED-Egg, iLOGP and Bioavailability Radar. Easy efficient input and interpretation are ensured thanks to a user-friendly interface through the login-free website http://www.swissadme.ch. Specialists, but also nonexpert in cheminformatics or computational chemistry can predict rapidly key parameters for a collection of molecules to support their drug discovery endeavours.
6,135 citations
TL;DR: A new freely available integrated web-based educational tool, Drug Design Workshop, is introduced, which presents the basics of drug design and provides anyone with access to computational methods and resources to conceive and evaluate molecules for their potential to become actual drugs.
Abstract: Due to its impact on society, the design of new drugs has the potential to interest a wide audience, and provides a rare opportunity to introduce several concepts in chemistry and biochemistry. Drug design can be seen as a multiobjective cyclic optimization process. Indeed, it is important to develop the understanding not only that a drug is generally an effective ligand for a protein of therapeutic interest, but also that these molecules need to have drug-like properties. Computer-aided drug design and bioinformatics approaches play a fundamental role in addressing these different challenges. Here we introduce a new freely available integrated web-based educational tool, Drug Design Workshop, which presents the basics of drug design and provides anyone with access to computational methods and resources to conceive and evaluate molecules for their potential to become actual drugs. We provide 3 examples of drug design targets for the discovery of common or state-of-the-art drugs, which can be used by educa...
40 citations
TL;DR: The results demonstrate that the QM/MM code preserves the high accuracy of most classical scores on the Astex Diverse set, while it yields significant improvements on both sets of metalloproteins at moderate computational cost.
Abstract: We developed a hybrid quantum mechanical/molecular mechanical (QM/MM) on-the-fly docking algorithm to address the challenges of treating polarization and selected metal interactions in docking. The algorithm is based on our classical docking algorithm Attracting Cavities and relies on the semiempirical self-consistent charge density functional tight-binding (SCC-DFTB) method and the CHARMM force field. We benchmarked the performance of this approach on three very diverse data sets: (1) the Astex Diverse set of 85 common noncovalent drug/target complexes formed both by hydrophobic and electrostatic interactions; (2) a zinc metalloprotein data set of 281 complexes, where polarization is strong and ligand/protein interactions are dominated by electrostatic interactions; and (3) a heme protein data set of 72 complexes, where ligand/protein interactions are dominated by covalent ligand/iron binding. Redocking performance of the on-the-fly QM/MM docking algorithm was compared to the performance of classical Att...
38 citations
TL;DR: A new, metabolic classification of human hepatoblastoma is revealed, with potential future implications for patients’ diagnosis and treatment.
Abstract: Hepatoblastoma is the most common malignant pediatric liver cancer. Histological evaluation of tumor biopsies is used to distinguish among the different subtypes of hepatoblastoma, with fetal and embryonal representing the two main epithelial components. With frequent CTNNB1 mutations, hepatoblastoma is a Wnt/β‐catenin‐driven malignancy. Considering that Wnt activation has been associated with tumor metabolic reprogramming, we characterized the metabolic profile of cells from hepatoblastoma and compared it to cells from hepatocellular carcinoma. First, we demonstrated that glucose transporter GLUT3 is a direct TCF4/β‐catenin target gene. RNA sequencing enabled to identify molecular and metabolic features specific to hepatoblastoma and revealed that several glycolytic enzymes are overexpressed in embryonal‐like compared to fetal‐like tumor cells. This led us to implement successfully three biomarkers to distinguish embryonal from fetal components by immunohistochemistry from a large panel of human hepatoblastoma samples. Functional analyses demonstrated that embryonal‐like hepatoblastoma cells are highly glycolytic and sensitive to hexokinase‐1 silencing. Altogether, our findings reveal a new, metabolic classification of human hepatoblastoma, with potential future implications for patients’ diagnosis and treatment.
34 citations
TL;DR: It is found that the HVEM(23–39) peptide can block BTLA/HVEM ligation, however, the blocking ability was due to the Cys encompassed in this peptide and that even free cysteine targeted the BTLA protein and blocked its interaction with HV EM.
Abstract: Antibody based immune-checkpoint blockade therapy is a major breakthrough in oncology, leading to clinical benefit for cancer patients. Among the growing family of inhibitory receptors, the B and T lymphocyte attenuator (BTLA), which interacts with herpes virus entry mediator (HVEM), is a promising target for immunotherapy. Indeed, BTLA inhibits T-cell proliferation and cytokine production. The crystal structure of the BTLA/HVEM complex has shown that the HVEM(26–38) fragment is directly involved in protein binding. We designed and analyzed the capacity of several analogs of this fragment to block the ligation between BTLA and HVEM, using competitive ELISA and cellular assay. We found that the HVEM(23–39) peptide can block BTLA/HVEM ligation. However, the blocking ability was due to the Cys encompassed in this peptide and that even free cysteine targeted the BTLA protein and blocked its interaction with HVEM. These data highlight a Cys-related artefact in vitro, which should be taken in consideration for future development of BTLA/HVEM blocking compounds.
29 citations
TL;DR: In this paper, the authors used quantum chemical calculations, docking, and quantum mechanics/molecular mechanics calculations based on available X-ray data to resolve this issue and to propose a physically meaningful binding mode.
Abstract: Indoleamine 2,3-dioxygenase 1 (IDO1) is an important target in cancer immunotherapy. The most advanced clinical compound, epacadostat (INCB024360), binds to the heme cofactor of IDO1 through an N-hydroxyamidine function. Conflicting binding modes have recently been proposed, reporting iron binding either through the hydroxyamidine oxygen or through the hydroxyamidine nitrogen atom. Here, we use quantum chemical calculations, docking, and quantum mechanics/molecular mechanics calculations based on available X-ray data to resolve this issue and to propose a physically meaningful binding mode. Our findings will aid the design of novel IDO1 ligands based on this pharmacophore.
15 citations
TL;DR: Overall, it is shown that binding of β2m to the TCR occurs in vitro and, as such, not only should be considered in structure-function studies of the T CR-pMHC complex but also could play a hitherto unidentified role in T-cell function in vivo.
Abstract: T-Cell receptor (TCR)-mediated recognition of the peptide-bound major histocompatibility complex (pMHC) initiates an adaptive immune response against antigen-presenting target cells. The recognition events take place at the TCR–pMHC interface, and their effects on TCR conformation and dynamics are controversial. Here, we have measured the time-resolved hydrogen/deuterium exchange (HDX) of a soluble TCR in the presence and absence of its cognate pMHC by mass spectrometry to delineate the impact of pMHC binding on solution-phase structural dynamics in the TCR. Our results demonstrate that while TCR–pMHC complex formation significantly stabilizes distinct CDR loops of the TCR, it does not trigger structural changes in receptor segments remote from the binding interface. Intriguingly, our HDX measurements reveal that the TCR α-constant domain (C- and F-strand) directly interacts with the unbound MHC light chain, β2-microglobulin (β2m). Surface plasmon resonance measurements corroborated a binding event betwee...
8 citations
01 Jan 2017
TL;DR: The most significant compounds in the field are reviewed and potential issues in the development of kynurenine pathway inhibitors for cancer therapy are discussed.
Abstract: A central role in the immune escape of tumors has been attributed to the kynurenine pathway of tryptophan metabolism, leading to the depletion of tryptophan and the production of different bioactive metabolites. The first and rate-limiting step in this pathway is catalyzed by the phylogenetically unrelated enzymes indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO), which have both been shown to be expressed in different cancers. Intense efforts in academia and in pharmaceutical companies to develop novel inhibitor scaffolds yielded a few compounds currently undergoing clinical trials. Here, we review the most significant compounds in the field and discuss potential issues in the development of kynurenine pathway inhibitors for cancer therapy.
3 citations
Patent•
24 May 2017
TL;DR: In this article, the present invention relates to methods of designing kinase mutants for reprogramming the sensitivity of a target kinase to some specific inhibitors, wherein those kinase inhibitors have little or no affinity for the wild-type target Kinase, vectors or cells expressing said mutated kinases, composition and uses thereof for the prevention and/or treatment of a disease or disorder, in particular cancer.
Abstract: The present invention relates to methods of designing kinase mutants for reprogramming the sensitivity of a target kinase to some specific inhibitors, methods of reprogramming the sensitivity of a target kinase to some specific inhibitors, wherein those kinase inhibitors have little or no affinity for the wild-type target kinase, vectors or cells expressing said mutated kinases, composition and uses thereof for the prevention and/or treatment of a disease or disorder, in particular cancer.