Hans De Winter

University of Antwerp | UA · Department of Pharmaceutical sciences

Cosolvent molecular dynamics (MD) simulations are molecular dynamics simulations used to identify preferable locations of small organic fragments on a protein target. Most cosolvent molecular dynamics workflows make use of only water-soluble fragments, as hydrophobic fragments would cause lipophilic aggregation. To date the two approaches that allo...

The circumsporozoite protein (CSP) is the main surface antigen of the Plasmodium sporozoite (SPZ) and forms the basis of the currently only licensed anti‐malarial vaccine (RTS,S/AS01). CSP uniformly coats the SPZ and plays a pivotal role in its immunobiology, in both the insect and the vertebrate hosts. Although CSP's N‐terminal domain (CSP N ) has...

Receptor-Interacting serine/threonine-Protein Kinase 1 (RIPK1) emerged as an important driver of inflammation and, consequently, inflammatory pathologies. The enzymatic activity of RIPK1 is known to indirectly promote inflammation by triggering cell death, in the form of apoptosis, necroptosis and pyroptosis. Small molecule Receptor-Interacting ser...

Vildagliptin is a marketed DPP4 inhibitor, used in the management of type 2 diabetes. The molecule also has notable DPP8/9 affinity, with some preference for DPP9. Therefore, we aimed to use vildagliptin as a starting point for selective DPP8/9 inhibitors, and to engineer out the parent compound's DPP4‐affinity. In addition, we wanted to identify s...

The fragment docking program SEED (Solvation Energy for Exhaustive Docking) is evaluated on 15 different protein targets, with a focus on enrichment and hit rate. It is shown that SEED allows for consistent computational enrichment of fragment libraries, independent of the effective hit rate. Depending on the actual target protein, true positive ra...

Bacterial glycosyltransferases of the GT51 family are key enzymes in the bacterial cell wall synthesis. Inhibiting cell wall synthesis is a very effective approach for development of antibiotics, as this can lead to either bacteriostatic or bactericidal effects. Even though the existence of this family has been known for over 50 years, only one pot...

Fibroblast activation protein (FAP) is a proline-selective serine protease. It is hardly expressed in healthy adult tissue, but upregulated in tissue remodeling sites associated with several diseases including epithelial cancer types, atherosclerosis, arthritis and fibrosis. Ongoing research aims at clinical implementation of FAP as a biomarker for...

Target‐guided synthesis (TGS) has emerged as a promising strategy in drug discovery. Although reported examples of TGS generally involve two‐component reactions, there is a strong case for developing target‐guided versions of three‐component reactions (3CRs) because of their potential to deliver highly diversified druglike molecules. To this end, t...

The caseinolytic protease proteolytic subunit (ClpP) is a serine protease playing an important role in proteostasis of eukaryotic organelles and prokaryotic cells. Alteration of ClpP function has been proved to affect the virulence and infectivity of a number of pathogens. Increased bacterial resistance to antibiotics has become a global problem an...

Ferroptosis is an iron-catalysed, non-apoptotic form of regulated necrosis that results in oxidative lipid damage in cell membranes that can be inhibited by the radical-trapping antioxidant Ferrostatin-1 (Fer-1). Novel inhibitors derived from the Fer-1 scaffold inhibited ferroptosis potently but suffered from solubility issues. In this paper, we re...

In recent years, the pharmaceutical industry has been confronted with rising R&D costs paired with decreasing productivity. Attrition rates for new molecules are tremendous, with a substantial number of molecules failing in an advanced stage of development. Repositioning previously approved drugs for new indications can mitigate these issues by red...

In recent years, the pharmaceutical industry has been confronted with rising R&D costs paired with decreasing productivity. Attrition rates for new molecules are tremendous, with a substantial number of molecules failing in an advanced stage of development. Repositioning previously approved drugs for new indications can mitigate these issues by red...

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Spectrophores are novel descriptors that are calculated from the three-dimensional atomic properties of molecules. In our current implementation, the atomic properties that were used to calculate spectrophores include atomic partial charges, atomic lipophilicity indices, atomic shape deviations and atomic softness properties. This approach can easi...

Receptor interacting protein kinase 1 (RIPK1) plays a crucial role in tumor necrosis factor (TNF)-induced necroptosis, suggesting that this pathway might be druggable. Most inhibitors of RIPK1 are classified as either type II or type III kinase inhibitors. This opened up some interesting perspectives for the discovery of novel inhibitors that targe...

Synthetic glucocorticoids (GC) are the mainstay therapy for treatment of acute and chronic inflammatory disorders. Due to the high adverse effects associated with long-term use, GC pharmacology has focused since the nineties on more selective glucocorticoid ligand binding strategies, classified as selective glucocorticoid receptor agonists (SEGRAs)...

The pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP) plays a pivotal role in the pathophysiology of various allergy disorders that are mediated by type 2 helper T cell (Th2) responses, such as asthma and atopic dermatitis. TSLP forms a ternary complex with the TSLP receptor (TSLPR) and the interleukin-7-receptor subunit alpha (IL-7Rα),...

Synthetic glucocorticoids (GC) are the mainstay therapy for treatment of acute and chronic inflammatory disorders. Due to the high adverse effects associated with long-term use, GC pharmacology has focused since the nineties on more selective GC ligand-binding strategies, classified as selective glucocorticoid receptor (GR) agonists (SEGRAs) or sel...

Molecular 2D–3D modeling of selective glucocorticoid receptor agonist GSK866 (A) and synthetic analogs UAMC-1158 (B), UAMC-1159 (C), UAMC-1217 (D), UAMC-1218 (E) in the glucocorticoid receptor ligand-binding domain crystal structure 3E7C.

The Gram-negative anaerobe Porphyromonas gingivalis is associated with chronic periodontitis. Clinical isolates of P. gingivalis strains with high dipeptidyl peptidase 4 (DPP4) expression also had a high capacity for biofilm formation and were more infective. The X-ray crystal structure of P. gingivalis DPP4 was solved at 2.2 Å resolution. Despite...

The pro-inflammatory cytokine thymic stromal lymphopoietin (TSLP) is pivotal to the pathophysiology of widespread allergic diseases mediated by type 2 helper T cell (Th2) responses, including asthma and atopic dermatitis. The emergence of human TSLP as a clinical target against asthma calls for maximally harnessing its therapeutic potential via str...

A new metric for the evaluation of model performance in the field of virtual screening and quantitative structure–activity relationship applications is described. This metric has been termed the power metric and is defined as the fraction of the true positive rate divided by the sum of the true positive and false positive rates, for a given cutoff...

Objectives: The resistance development, cross-resistance to other NNRTIs and the impact of resistance on viral replicative fitness were studied for the new and potent NNRTI UAMC01398. Methods: Resistance was selected by dose escalation and by single high-dose selection against a comprehensive panel of NNRTIs used as therapeutics and NNRTIs under...

New non-nucleoside reverse transcriptase inhibitors (NNRTI), which are similar in structure to earlier described di(arylamino)pyrimidines but featuring a 2,6-di(arylamino)-3-fluoropyridine , 2,4-di(arylamino)-5-fluoropyrimidine or 1,3-di(arylamino)-4-fluorobenzene moiety instead of a 2,4-disubstituted pyrimidine moiety, are reported. The short and...

Selected pyrrolidines, 2-cyanopyrrolidines and heteroaromatic isoindoline analogues were evaluated as P1-residues in dipeptide-derived inhibitors of DPP8/9. Potency testing indicates that DPP8 or DPP9 specificity cannot be obtained with the selected set of P1- and P2-fragments. Nonetheless, the nanomolar DPP8/9 potencies and remarkable selectivitie...

Urokinase plasminogen activator (uPA) is a biomarker and therapeutic target for several cancer types. Its inhibition is regarded as a promising, non-cytotoxic approach in cancer therapy by blocking growth and/or metastasis of solid tumors. Earlier, we reported the Modified Substrate Activity Screening (MSAS) approach and applied it for the identifi...

The work of the molecular modeling can be divided in three equally important steps. The first one is the choice of the descriptors that must be able to describe accurately the properties studied. The second one is modeling method that must be planned carefully to produce the response we are looking for. Finally, the validation process that need to...

Fibroblast activation protein (FAP) is a serine protease that is selectively expressed in many diseases involving activated stroma, including cancer, arthritis and hepatic and pulmonary fibrosis. FAP is closely related to dipeptidyl peptidase IV (DPPIV), of which many inhibitors are known and several are marketed as drugs. One of these is the xanth...

A computer-based method of generating a descriptor of a three-dimensional object wherein the following steps are performed for each of a set of one or more cages and for each of one or more properties: (i) enclosing entirely the three-dimensional object in the cage, (ii) for each property, while keeping the three-dimensional object entirely enclos...

A Spectrophore™ is a one-dimensional descriptor that describes the three-dimensional molecular field surrounding a molecule generated by a given set of atomic properties. In a typical application, Spectrophores™ are calculated from the molecular shape in combination with the electrostatic, lipophilic, softness, and hardness potential surrounding th...

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

2′-Deoxy-5-(isothiazol-5-yl)uridine (12) was synthesized starting from 2′-deoxy-5-iodouridine using a Pd-catalysed cross-coupling reaction with propiolaldehyde diethyl acetal followed by deprotection and ring closure using thiosulfate. 2′-Deoxyuridine 12 has a particular place among the 5-heteroaryl-substituted 2′-deoxyuridines in that it has a hig...

While improved alkylation procedures have been worked out for the coupling of purine bases to the anhydrohexitol ring using sulphonate activating groups on the anhydrohexitol ring, the Mitsunobu reaction seems to be the method of choice for synthesis of the pyrimidine analogues. In a mixed sequence context, the anhydrohexitol oligonucleotides still...

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Recently great interest has arisen in the synthesis of combinatorial libraries, and this technology provides a significant partner to contemporary strategies in rational design and lead discovery. By simple combination of a given set of building blocks, high numbers of different molecules are produced simultaneously, increasing the possibility of d...

Within the context of early drug discovery, a new pharmacophore-based tool to score and align small molecules (Pharao) is described. The tool is built on the idea to model pharmacophoric features by Gaussian 3D volumes instead of the more common point or sphere representations. The smooth nature of these continuous functions has a beneficent effect...

A new aspartic protease inhibitory chemotype bearing a 2-amino-3,4-dihydroquinazoline ring was identified by high-throughput screening for the inhibition of BACE-1. X-ray crystallography revealed that the exocyclic amino group participated in a hydrogen bonding array with the two catalytic aspartic acids of BACE-1 (Asp(32), Asp(228)). BACE-1 inhibi...

Peptide ligands are known to often bind in an extended conformation to maximize the contact surface with the receptor. The complementarity of shape and surface is a very important factor contributing to the stability of a ligand receptor complex. In this communication we try to answer the following questions: What is the influence of conformation o...

Though various attempts have been made in literature to model the particle size distribution of an active pharmaceutical ingredient (API) in function of the required release profile of the pharmaceutical product, so far one has not succeeded to develop a universal approach in the correlation of particle size distribution and in vitro dissolution da...

A series of pyrimidyl-5-hydroxamic acids was prepared for evaluation as inhibitors of histone deacetylase (HDAC). Amino-2-pyrimidinyl can be used as a linker to provide HDAC inhibitors of good enzymatic potency.

Immediate release direct compression tablet formulations require a strict control of the particle characteristics (i.e. particle size (distribution) and shape) of both the active pharmaceutical ingredient (API) and the excipients. In this publication, the development of a dry dispersion laser diffraction (LD) method has been outlined. With this met...

A homology model of the active site region of tripeptidyl peptidase II (TPP II) was constructed based on the crystal structures of four subtilisin-like templates. The resulting model was subsequently validated by judging expectations of the model versus observed activities for a broad set of prepared TPP II inhibitors. The structure-activity relati...

2′-Deoxy-5-(isothiazol-5-yl)uridine (12) was synthesized starting from 2′-deoxy-5-iodouridine using a Pd-catalysed cross-coupling reaction with propiolaldehyde diethyl acetal followed by deprotection and ring closure using thiosulfate. 2′-Deoxyuridine 12 has a particular place among the 5-heteroaryl-substituted 2′-deoxyuridines in that it has a hig...

We have systematically explored the structure-activity relationship (SAR) for a series of compounds 2 as inhibitors of tripeptidyl-peptidase II (TPP II), a serine protease responsible for the degradation of cholecystokinin-8 (CCK-8). This SAR evaluation of the core structure 2 suggest a fairly restrictive pharmacophore for such related structures,...

For Abstract see ChemInform Abstract in Full Text.

Butabindide, 1, was previously reported as a potent inhibitor (IC50 = 7 nM) of the serine protease enzyme tripeptidyl peptidase II (TPPII), an endogenous protease that degrades cholecystokinin-8 (CCK-8). We found that 1 has some inherent chemical instability, yielding diketopiperazine 2 fairly readily under mimicked physiological conditions. We the...

The quality of various quantum similarity descriptors is studied systematically for a series of peptide isosteres important in pharmacology. To cope with the drawbacks of the Carb6 and Hodgkin-Richards type indices, those being the time-consuming three-dimensional integration and the importance of the relative orientation, position, and conformatio...

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The influence of the orientation of a 3′-OH group on the conformation and stability of hexitol oligonucleotides in complexes with RNA and as single strands in aqueous solution was investigated by molecular-dynamics (MD) simulations with AMBER 4.1. The particle mesh Ewald (PME) method was used for the treatment of long-range electrostatic interactio...

High-throughput screening (HTS) of large libraries of compounds is applied by drug companies to pick up active molecules. Besides this “fishing” part, HTS can also play an important role as a source for structure-activity analysis, which relates physicochemical or structural features to biological activity. The latter aspect, although of great impo...

The properties of oligonucleotides with a six-membered carbohydrate mimic in the backbone structure and a 1,4-relationship between the base moiety and the hydroxymethyl group are summarized. The different six-membered rings that were studied are: 1,5-anhydro-2,3-dideoxy-D-arabino-hexitol, 1,5-anhydro-2-deoxy-D-mannitol, 1,5-anhydro-2-deoxy-D-altrit...

The title compound, C19H21BrN2O, is a central active serotonin 5-HT2c antagonist with some HI affinity. The (6,7,6)-tricyclic moiety is asymmetrically folded with a dihedral angle of 124.3(1)° between the aromatic planes. The fused tetrahydroisoxazole ring adopts a conformation halfway between that of a twist and an envelope.

Hexitol nucleic acids (HNA) are oligonucleotides built up from natural nucleobases and a phosphorylated 1,5-anhydrohexitol backbone. Molecular associations between HNA and RNA are more stable than between HNA and DNA and between natural nucleic acids (dsDNA, dsRNA, DNA/RNA). 1H NMR analysis of a HNA dimer confirms the axial orientation of the base...

While improved alkylation procedures have been worked out for the coupling of purine bases to the anhydrohexitol ring using sulphonate activating groups on the anhydrohexitol ring, the Mitsunobu reaction seems to be the method of choice for synthesis of the pyrimidine analogues. In a mixed sequence context, the anhydrohexitol oligonucleotides still...

The cyclohexane nucleosides with a 1,4-relationship between nucleoside base and hydroxymethyl moiety were synthesized using a conjugated addition reaction of the nucleobases to ethyl 1,3-cyclohexadiene-1-carboxylate and hydroboration of the cyclohexenyl precursor. The lack of antiviral activity of the compounds was correlated with the conformation...

Recently great interest has arisen in the synthesis of combinatorial libraries, and this technology provides a significant partner to contemporary strategies in rational design and lead discovery. By simple combination of a given set of building blocks, high numbers of different molecules are produced simultaneously, increasing the possibility of d...

Thymidine kinase from HSV-1 (HSV-1 TK) is a key enzyme in the metabolic activation of antiviral nucleosides. High affinity of such compounds for the enzyme is required for efficient phosphorylation. In this study, affinity data from a series of 5-substituted 2'-deoxyuridine substrates in combination with the crystal structure of the viral enzyme we...

The synthesis of 3′-deoxy-3′-C-hydroxymethyl-aldopentopyranosyl nucleosides using an intramolecular radical C-C bond formation reaction is described. This method gives good results for the synthesis of thymine and adenine nucleosides, but not for cytosine and guanine nucleosides. Dependent on the configuration (β-d-erythro or α-l-threo), the confor...

In an attempt to obtain a picture of the binding conformation of aldehyde substrates to human aldose reductase (hAR), modeling calculations have been performed on the binding of three substrates, D-xylose, L-xylose, and D-lyxose, to wild-type human aldose reductase and two of its site-directed mutants. It was found that the average geometry of D-xy...

The syntheses of 3’-deoxy-3’-C-hydroxymethyl-aldopentopyranosyl nucleosides usmg an intramolecular radical C-C bond formation reactton is described. This method gives good results for the synthesis of thymme and adenine nucleosides, but not for cytosme and guanine nucleosides Dependent on the configuration (f%D-tXythrO or a-L-three), the conformano...

Human aldose reductase (hAR), an NADPH-dependent enzyme, catalyzes the reversible reduction of a wide variety of carbonyl-containing compounds to their respective alcohol counterparts (Flynn and Green, 1993). Although a physiological role for this enzyme has not yet been established, inhibitors of hAR appear to be effective in the treatment of diab...

C24H25FN4O2, M(r) = 420.5, monoclinic, P2(1)/n, a = 19.95 (1), b = 9.782 (5), c = 22.07 (1) angstrom, beta = 102.82 (3)-degrees, V = 4201 (3) angstrom3, Z = 8, D(m) = 1.32, D(x) = 1.329 Mg M-3 graphite-monochromated Mo Kalpha radiation, lambda = 0.71069 angstrom, mu = 0.087 mm-1, F(000) = 1776, T = 293 K, final R = 0.071 for 7404 unique observed re...

C10H15N3O4, M(r) = 241.25, orthorhombic, P2(1)2(1)2(1), a = 7.4013 (4), b = 8.7563 (5), c = 17.392 (1) angstrom, V = 1127.1 (1) angstrom 3, Z = 4, D(m) = 1.42, D(x) = 1.422 Mg m-3, Ni-filtered Cu K-alpha radiation, lambda = 1.54178 angstrom, mu = 0.895 mm-1, F(000) = 512, T = 293 K, final R = 0.044 for 1024 unique observed [F greater-than-or-equal-...

(I) 1-[(2R,6R)-6-Hydroxymethyl-1,4-dioxan-2-yl]uracil, C9H12N2O5, M(r) = 228.20, trigonal, P3(1)21, a = 9.438 (5), c = 19.77 (2) angstrom, V = 1522 (2) angstrom 3, Z = 6, D(m) = 1.49, D(x) = 1.494 Mg m-3, lambda(Mo K-alpha) = 0.71069 angstrom, mu = 0.115 mm-1, F(000) = 720, T = 293 K, final R = 0.036 for 1541 unique observed [F greater-than-or-equa...

(I) 1-(2-Deoxy-2-fluoro-beta-D-arabinopyranosyl)thymine-water complex, C10H13FN2O5.H2O, M(r) = 278.24, monoclinic, P2(1), a = 8.669 (4), b = 6.395 (3), c = 10.713 (7) angstrom, beta = 103.73 (5)-degrees, V = 576.9 (6) angstrom 3, Z = 2, D(m) = 1.60, D(x) = 1.602 Mg m-3, graphite-monochromated Mo K-alpha radiation, lambda = 0.71069 angstrom, mu = 0....

C21H27N3O3, M(r) = 369.5, triclinic, P1BAR, a = 6.801 (7), b = 11.08 (1), c = 26.82 (4) angstrom, alpha = 79.2 (1), beta = 86.5 (1), gamma = 82.52 (9)-degrees, V = 1967 (4) angstrom 3, Z = 4, D(m) = 1.25, D(x) = 1.247 Mg m-3, graphite-monochromated Mo K-alpha radiation, lambda = 0.71069 angstrom, mu = 0.079 mm-1, F(000) = 792, T = 293 K, final R =...

C 9 H 11 IN 2 O 5 cristalline dans P2 1 avec a=5,458, b=8,237, c=12,812 A, β=98,42°, Z=2; affinement jusqu'a R=0,039. Le cycle du sucre adopte une conformation chaise legerement aplatie. La base heterocyclique est placee dans une orientation -ap (antiperiplane) par rapport au sucre (χ=196,4°). L'empilement du cristal est determinee par trois liaiso...

(1) 1-(2,3-Dideoxy-erythro-alpha-D-hexopyranosyl)thymine, C11H16N2O5, M(r) = 256.26, orthorhombic, P2(1)2(1)2(1), a = 4.871 (2), b = 13.182 (7), c = 18.678 (9) angstrom, V = 1199 (1) angstrom3, Z = 4, D(m) = 1.43, D(x) = 1.419 Mg m-3, lambda-(Mo K-alpha) = 0.71069 angstrom, mu = 0.106 mm-1, F(000) = 544, room temperature, final R = 0.032 for 1197 u...

1-(2,3-Dideoxy-3-fluoro-beta-D-erythro-pento-furanosyl)cytosine, C9H12FN3O3, M(r) = 229.21, triclinic, P1, a = 6.997 (4), b = 7.396 (4), c = 10.639 (5) angstrom, alpha = 94.48 (4), beta = 107.74 (4), gamma = 104.40 (4)-degrees, V = 500.8 (5) angstrom3, Z = 2, D(m) = 1.52, D(x) = 1.520 Mg m-3, lambda-(Mo K-alpha) = 0.71069 angstrom, mu = 0.1198 mm-1...

C17H27N3O4S, Mr = 369.48, monoclinic, P2(1)/c, a = 13.333 (7), b = 7.946 (4), c = 17.550 (10) A, beta = 96.99 (4) degrees, V = 1845 (2) A3, Z = 4, Dm = 1.33, Dx = 1.330 Mg m-3, graphite-monochromated Cu K alpha radiation, lambda = 1.54178 A, mu = 1.744 mm-1, F(000) = 792, T = 293 K. Final R = 0.038 for 2405 unique observed reflections. The folded c...