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1.
J Cheminform ; 9(1): 43, 2017 Jul 04.
Article in English | MEDLINE | ID: mdl-29086093

ABSTRACT

Drug design of protein kinase inhibitors is now greatly enabled by thousands of publicly available X-ray structures, extensive ligand binding data, and optimized scaffolds coming off patent. The extensive data begin to enable design against a spectrum of targets (polypharmacology); however, the data also reveal heterogeneities of structure, subtleties of chemical interactions, and apparent inconsistencies between diverse data types. As a result, incorporation of all relevant data requires expert choices to combine computational and informatics methods, along with human insight. Here we consider polypharmacological targeting of protein kinases ALK, MET, and EGFR (and its drug resistant mutant T790M) in non small cell lung cancer as an example. Both EGFR and ALK represent sources of primary oncogenic lesions, while drug resistance arises from MET amplification and EGFR mutation. A drug which inhibits these targets will expand relevant patient populations and forestall drug resistance. Crizotinib co-targets ALK and MET. Analysis of the crystal structures reveals few shared interaction types, highlighting proton-arene and key CH-O hydrogen bonding interactions. These are not typically encoded into molecular mechanics force fields. Cheminformatics analyses of binding data show EGFR to be dissimilar to ALK and MET, but its structure shows how it may be co-targeted with the addition of a covalent trap. This suggests a strategy for the design of a focussed chemical library based on a pan-kinome scaffold. Tests of model compounds show these to be compatible with the goal of ALK, MET, and EGFR polypharmacology.

2.
Chem Biol Drug Des ; 82(5): 506-19, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23746052

ABSTRACT

Virtual screening methods are now widely used in early stages of drug discovery, aiming to rank potential inhibitors. However, any practical ligand set (of active or inactive compounds) chosen for deriving new virtual screening approaches cannot fully represent all relevant chemical space for potential new compounds. In this study, we have taken a retrospective approach to evaluate virtual screening methods for the leukemia target kinase ABL1 and its drug-resistant mutant ABL1-T315I. 'Dual active' inhibitors against both targets were grouped together with inactive ligands chosen from different decoy sets and tested with virtual screening approaches with and without explicit use of target structures (docking). We show how various scoring functions and choice of inactive ligand sets influence overall and early enrichment of the libraries. Although ligand-based methods, for example principal component analyses of chemical properties, can distinguish some decoy sets from active compounds, the addition of target structural information via docking improves enrichment, and explicit consideration of multiple target conformations (i.e. types I and II) achieves best enrichment of active versus inactive ligands, even without assuming knowledge of the binding mode. We believe that this study can be extended to other therapeutically important kinases in prospective virtual screening studies.


Subject(s)
Drug Evaluation, Preclinical/standards , Protein Kinase Inhibitors/chemistry , Proto-Oncogene Proteins c-abl/antagonists & inhibitors , Algorithms , Area Under Curve , Binding Sites , Drug Resistance, Neoplasm/drug effects , Enzyme Activation/drug effects , Humans , Ligands , Molecular Docking Simulation , Mutation , Principal Component Analysis , Protein Binding/drug effects , Protein Kinase Inhibitors/pharmacology , Protein Structure, Tertiary , Proto-Oncogene Proteins c-abl/genetics , Proto-Oncogene Proteins c-abl/metabolism , ROC Curve , Recombinant Proteins/biosynthesis , Recombinant Proteins/chemistry , Recombinant Proteins/genetics
3.
Biol Chem ; 393(10): 1121-9, 2012 Oct.
Article in English | MEDLINE | ID: mdl-23092797

ABSTRACT

The era of structure-based protein kinase inhibitor design began in the early 1990s with the determination of crystal structures of protein kinase A (PKA, or cyclic AMP-dependent kinase). Although many other protein kinases have since been extensively characterized, PKA remains a prototype for studies of protein kinase active conformations. It serves well as a model for the structural properties of AGC subfamily protein kinases, clarifying inhibitor selectivity profiles. Its reliable expression, constitutive activity, simple domain structure, and reproducible crystallizability have also made it a useful surrogate for the discovery of inhibitors of both established and emerging AGC kinase targets.


Subject(s)
Cyclic AMP-Dependent Protein Kinases/antagonists & inhibitors , Drug Discovery/methods , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Adenosine Triphosphate/metabolism , Amino Acid Sequence , Cyclic AMP-Dependent Protein Kinases/chemistry , Cyclic AMP-Dependent Protein Kinases/metabolism , Humans , Molecular Sequence Data , Protein Kinase Inhibitors/metabolism , Substrate Specificity
4.
J Eur Acad Dermatol Venereol ; 25(10): 1160-7, 2011 Oct.
Article in English | MEDLINE | ID: mdl-21198951

ABSTRACT

BACKGROUND: Pemphigus vegetans (P Veg) is a rare clinical form of pemphigus. Studies on P Veg are rare in the literature and none has so far evaluated the prognostic parameters. OBJECTIVE: In this retrospective study of P Veg, we aimed to analyse epidemiological, clinical, immunopathological and therapeutic data. Study of prognostic factors with accuracy of patient survival was also carried out. METHODS: This is a retrospective study (1981-2009) including 17 cases of P Veg. Statistical analysis was performed with chi-square and Fisher tests looking for a possible relationship between clinical data and prognostic factors. Follow-up time and disease-free survival time were estimated using Kaplan-Meier methods. Clinical data were evaluated in univariate analysis looking for a significant association with survival. Equality of survival distribution was studied using log rank test. RESULTS: The hospital prevalence of P Veg was 0.084‰ with a frequency of 9.1% among pemphigus. The mean age at onset was 47.6 years, with a sex-ratio (F/M) about 4.66. Neumann P Veg was the predominant clinical form (11/17). Clinically, the lesions were multifocal (16/17), prevailed on folds and mucous membranes. Under corticosteroids the mean period for healing was 24 ± 9 days. During the follow-up time, three patients died and 11 patients relapsed. Median of overall relapse-free survival was 13 ± 1.7 months. No significant association between clinical data and prognostic factors was found. LIMITATIONS: This study was a retrospective chart analysis and the number of patients was small. CONCLUSION: The P Veg seems to be more frequent in Tunisia with high rate of mortality.


Subject(s)
Pemphigus/immunology , Pemphigus/pathology , Adrenal Cortex Hormones/therapeutic use , Adult , Aged , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Pemphigus/drug therapy , Prevalence , Prognosis , Retrospective Studies , Tunisia
5.
Pathol Biol (Paris) ; 59(6): 334-5, 2011 Dec.
Article in French | MEDLINE | ID: mdl-19942369

ABSTRACT

Since the advent of the first glycopeptide intermediately susceptible Staphylococcus aureus (GISA) and its heterogeneous variant hGISA in 1997, debate still ensues as their clinical significance. We report here the first case of GISA in Rabta hospital of Tunisia. Antimicrobial resistance was determined by the disk diffusion method in accordance with CA-SFM (Comity of Antibiogramm of French society of Microbiology). The MIC of vancomycin and teicoplanin was determined by E-test. The detection of mec A gene, virulence factors genes and agr groups (1-4) was performed by multiplex PCR. spa types were determined with the assistance of Ridom of Staph Type software (Ridom GmbH, Wurburg, Germany). The allelic profiles of MRSA were assigned on the basis of their MLST type using the eBURST program. A MRSA bacteraemia patient was treated with teicoplanin for 14 days. S. aureus isolated from patient's blood culture was identified as MRSA and GISA with teicoplanin MIC of 16 mg/l. The molecular study of this strain showed that it belongs to the clonal complex CC8 and is attached to the iberian clone (agr1, enterotoxin A, ST 247, spa type t052). Clinicians and laboratories alike are increasingly aware that patients on long-term vancomycin therapy may signal the presence and potential spread of hGISA/GISA strains. hGISA/GISA strains emerged from lineages with agr types I and II. The multiresitance of the Iberian clone ST247 could be explained by the presence of several resistance genes.


Subject(s)
Drug Resistance, Bacterial , Glycopeptides/therapeutic use , Staphylococcal Infections/drug therapy , Staphylococcal Infections/microbiology , Staphylococcus aureus/isolation & purification , Aged , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/therapeutic use , Drug Resistance, Bacterial/physiology , Female , Glycopeptides/administration & dosage , Hospitals , Humans , Microbial Sensitivity Tests , Staphylococcal Infections/diagnosis , Staphylococcal Infections/epidemiology , Staphylococcus aureus/drug effects , Staphylococcus aureus/physiology , Tunisia
6.
Bioorg Med Chem ; 18(18): 6874-85, 2010 Sep 15.
Article in English | MEDLINE | ID: mdl-20708408

ABSTRACT

A series of cis-restricted 1,4- and 1,5-disubstituted 1,2,3-triazole analogs of combretastatin A-4 (1) have been prepared. Cytotoxicity and tubulin inhibition studies showed that 2-methoxy-5-((5-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-1-yl)methyl)aniline (5e) and 2-methoxy-5-(1-(3,4,5-trimethoxybenzyl)-1H-1,2,3-triazol-5-yl)aniline (6e) were two of the most active compounds. Molecular modeling studies revealed that the N-2 and N-3 atoms in the triazole rings in 5e and 6e did not form hydrogen bonds with the amino acids in the anticipated pharmacophore.


Subject(s)
Aniline Compounds/chemistry , Microtubules/chemistry , Stilbenes/chemistry , Triazoles/chemistry , Tubulin Modulators/chemistry , Aniline Compounds/chemical synthesis , Aniline Compounds/toxicity , Binding Sites , Cell Line, Tumor , Computer Simulation , Humans , Microtubules/metabolism , Protein Structure, Tertiary , Stilbenes/chemical synthesis , Stilbenes/toxicity , Triazoles/chemical synthesis , Triazoles/toxicity , Tubulin Modulators/chemical synthesis , Tubulin Modulators/toxicity
7.
Nat Prod Rep ; 27(4): 489-98, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20336234

ABSTRACT

The isolation in 1977 of the microbial alkaloid staurosporine inaugurated research into several distinct series of related natural and synthetic compounds. This has especially included research into applications as anticancer drugs, beginning with the observation of low nanomolar inhibition of protein kinases. At present, several staurosporine cognates are in advanced clinical trials as anticancer agents, with the potential to join the 10 other protein kinase inhibitors now approved for clinical use. Staurosporine is a broadly selective and potent protein kinase inhibitor, with submicromolar binding to the vast majority of the protein kinases tested, and binding most of them more tightly than 100 nM. Crystal structures have shown the extended buried surface area interactions between the protein kinase adenine binding site and the extended aromatic plane of the inhibitor, together with protein-saccharide interactions in the ribose binding site. Together with structures of closely related analogues, there are now some 70 X-ray crystal structures in the Protein Data Bank that enable analysis of target binding properties of the clinical compounds. In this manuscript we review the discovery of these compounds, revisit crystal structures and review the observed interactions. These support the interpretation of kinase selectivity profiles of staurosporine and its analogues, including midostaurin (PKC412), for which a co-crystal structure is not yet available. Further, the mix of purely natural, biosynthetically and chemically modified compounds described here offer insights into prospects and strategies for drug discovery via bioprospecting.


Subject(s)
Alkaloids/chemistry , Alkaloids/pharmacology , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Staurosporine/chemistry , Staurosporine/pharmacology , Alkaloids/isolation & purification , Databases, Factual , Molecular Sequence Data , Molecular Structure , Protein Kinase Inhibitors/isolation & purification , Sequence Homology, Amino Acid , Staurosporine/isolation & purification , Streptomyces/chemistry
8.
J Mol Graph Model ; 27(2): 217-24, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18547851

ABSTRACT

The family of peroxisome proliferator-activated receptors (PPARs) is the molecular target of synthetic antidiabetic and hypolipidemic drugs. The side effects of these drugs are limiting their use in patients with high lipid levels. Natural compounds, like Docosahexaenoic acid (DHA) from fish oil, have beneficial effects in the treatment of metabolic diseases, and several DHA derivatives are known to activate PPAR genes. Experimental studies on affinities of DHA and its derivatives for PPARs are not available. In the present study we are therefore using computational docking, molecular dynamics simulation, and several scoring programs to predict affinities and binding modes of DHA for PPARs and retinoid-X receptor alpha, which is the DNA binding partner of PPARs. The calculations indicated that DHA binds to PPARs and the retinoid-X receptor alpha with high affinity, and that different PPARs exhibited different structural effects on the first four carbons atoms of DHA. Our data indicate that the beneficial health effects of DHA may be obtained by high affinity binding to the PPARs.


Subject(s)
Docosahexaenoic Acids/chemistry , Peroxisome Proliferator-Activated Receptors/chemistry , Retinoid X Receptor alpha/chemistry , Computer Simulation , Docosahexaenoic Acids/metabolism , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/metabolism , Ligands , Models, Molecular , Peroxisome Proliferator-Activated Receptors/agonists , Peroxisome Proliferator-Activated Receptors/metabolism , Pioglitazone , Protein Binding , Retinoid X Receptor alpha/metabolism , Rosiglitazone , Thermodynamics , Thiazolidinediones/chemistry , Thiazolidinediones/metabolism
9.
Chem Biol Drug Des ; 72(1): 50-7, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18554251

ABSTRACT

Peroxisome proliferator-activated receptor gamma belongs to the nuclear receptor superfamily and is activated by the antidiabetic drugs rosiglitazone and pioglitazone. Ligand-independent constitutive activity of peroxisome proliferator-activated receptor gamma is also demonstrated. X-ray crystallographic structures show that the active or inactive conformations of the receptor are determined by the position of helix 12 in the C-terminal end. In this study, molecular dynamics simulations were used to gain molecular insight into the activation process and the structural stability of inactive and active peroxisome proliferator-activated receptor gamma receptor structure. The simulations showed: (i) during molecular dynamics simulations without agonist at the active site, the receptor structure with helix 12 in a position corresponding to activated receptor structure was structurally more stable than with helix 12 in a position corresponding to inactive receptor structure, which may contribute to the constitutive activity of the receptor; (ii) docosahexenoic acid stabilized the active receptor conformation more efficiently than the glitazones; (iii) docosahexenoic acid, but not glitazones, induced structural changes into the inactive receptor structure such that helix 12 was shifted into a position more similar to that of an active receptor structure, which indicate that docosahexenoic acid is a more effective peroxisome proliferator-activated receptor gamma agonist than the glitazones.


Subject(s)
Computer Simulation , PPAR gamma/chemistry , Binding Sites , Docosahexaenoic Acids/chemistry , Docosahexaenoic Acids/pharmacology , Enzyme Activation , Enzyme Stability , Hypoglycemic Agents/chemistry , Ligands , Models, Molecular , PPAR gamma/agonists , Protein Conformation , Thiazolidinediones/chemistry
10.
Bioorg Med Chem ; 16(9): 4829-38, 2008 May 01.
Article in English | MEDLINE | ID: mdl-18396050

ABSTRACT

A series of cis-restricted 1,5-disubstituted 1,2,3-triazole analogues of combretastatin A-4 (1) have been prepared. The triazole 12f, 2-methoxy-5-(1-(3,4,5-trimethoxyphenyl)-1H-1,2,3-triazol-5-yl)aniline, displayed potent cytotoxic activity against several cancer cell lines with IC(50) values in the nanomolar range. The ability of triazoles to inhibit tubulin polymerization has been evaluated, and 12f inhibited tubulin polymerization with IC(50)=4.8microM. Molecular modeling experiments involving 12f and the colchicine binding site of alpha,beta-tubulin showed that the triazole moiety interacts with beta-tubulin via hydrogen bonding with several amino acids.


Subject(s)
Antineoplastic Agents , Stilbenes , Triazoles , Tubulin/drug effects , Amino Acids/chemistry , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Binding Sites , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Dose-Response Relationship, Drug , Drug Screening Assays, Antitumor , Humans , Hydrogen Bonding , Inhibitory Concentration 50 , K562 Cells , Models, Molecular , Molecular Structure , Stereoisomerism , Stilbenes/chemical synthesis , Stilbenes/chemistry , Stilbenes/pharmacology , Structure-Activity Relationship , Triazoles/chemical synthesis , Triazoles/chemistry , Triazoles/pharmacology
11.
Cardiovasc Diabetol ; 7: 6, 2008 Mar 20.
Article in English | MEDLINE | ID: mdl-18355413

ABSTRACT

BACKGROUND: Peroxisome proliferator-activated receptors (PPARalpha, PPARgamma, and PPARdelta) are physiological sensors for glucose and lipid homeostasis. They are also the targets of synthetic drugs; such as fibrates as PPARalpha agonists which lower lipid level, and glitazones as PPARgamma agonists which lower glucose level. As diabetes and metabolic diseases are often associated with high blood glucose and lipid levels, drugs that activate both PPARalpha/gamma would be a logical approach. But synthetically developed PPARalpha/gamma dual agonists and glitazones are showing side effects such as weight gain and edema. Therefore, natural compounds and their close derivatives are focused as future drugs against metabolic diseases. PRESENTATION OF HYPOTHESIS: Docosahexaenoic acid and eicosapentaenoic acid, which are the fatty acids abundant in fish oil, are traditionally used against metabolic diseases. These fatty acids act as PPAR agonists that transcript the genes involved in glucose and lipid homeostasis. Present hypothesis suggests that the derivatives of these fatty acids are stronger PPAR agonists than the parent compounds. X-ray structures of PPARs indicate that alpha or beta derivatives of fatty acids would fit into PPARalpha/gamma binding cavity. Therefore, the derivatives will exhibit stronger affinities and activities than the parent compounds. TESTING OF THE HYPOTHESIS: Ligand binding assays and gene transactivation assays should be performed to test the hypothesis. Fluorescence-based methods are advantageous in binding assays, because they were found more suitable for fatty acid binding assays. In transactivation assays, care should be taken to remove contaminants from recombinant proteins. IMPLICATIONS OF THE HYPOTHESIS: Present hypothesis is framed on the basis of molecular structure of natural PPAR agonists. Small structural changes in the molecular structure of fatty acids have a great influence on activating different PPARs. Therefore, this hypothesis bridges the concept of natural PPAR agonists and the use of structural information in designing new drugs against diabetes and metabolic syndrome. The derivatives may also be used as anti-inflammatory and anticancer agents.


Subject(s)
Docosahexaenoic Acids/pharmacology , Drug Design , Eicosapentaenoic Acid/pharmacology , PPAR alpha/agonists , PPAR gamma/agonists , Animals , Anti-Inflammatory Agents/pharmacology , Antineoplastic Agents/pharmacology , Binding Sites , Crystallography, X-Ray , Docosahexaenoic Acids/chemistry , Docosahexaenoic Acids/metabolism , Eicosapentaenoic Acid/analogs & derivatives , Eicosapentaenoic Acid/chemistry , Eicosapentaenoic Acid/metabolism , Humans , Hypoglycemic Agents/pharmacology , Ligands , Models, Molecular , Molecular Structure , PPAR alpha/chemistry , PPAR alpha/metabolism , PPAR gamma/chemistry , PPAR gamma/metabolism , Protein Binding , Protein Conformation , Structure-Activity Relationship , Transcriptional Activation/drug effects
12.
Biophys J ; 94(4): 1412-27, 2008 Feb 15.
Article in English | MEDLINE | ID: mdl-17981907

ABSTRACT

Three highly conserved active site residues (Ser, Tyr, and Lys) of the family of short-chain alcohol dehydrogenases/reductases (SDRs) were demonstrated to be essential for catalytic activity and have been denoted the catalytic triad of SDRs. In this study computational methods were adopted to study the ionization properties of these amino acids in SDRs from Drosophila melanogaster and Drosophila lebanonensis. Three enzyme models, with different ionization scenarios of the catalytic triad that might be possible when inhibitors bind to the enzyme cofactor complex, were constructed. The binding of the two alcohol competitive inhibitors were studied using automatic docking by the Internal Coordinate Mechanics program, molecular dynamic (MD) simulations with the AMBER program package, calculation of the free energy of ligand binding by the linear interaction energy method, and the hydropathic interactions force field. The calculations indicated that deprotonated Tyr acts as a strong base in the binary enzyme-NAD(+) complex. Molecular dynamic simulations for 5 ns confirmed that deprotonated Tyr is essential for anchoring and orientating the inhibitors at the active site, which might be a general trend for the family of SDRs. The findings here have implications for the development of therapeutically important SDR inhibitors.


Subject(s)
Alcohol Dehydrogenase/chemistry , Alcohol Dehydrogenase/ultrastructure , Alcohol Oxidoreductases/chemistry , Alcohol Oxidoreductases/ultrastructure , Models, Chemical , Models, Molecular , Binding Sites , Catalysis , Computer Simulation , Protein Binding , Protein Conformation , Protein Structure, Tertiary
13.
Chem Biol Drug Des ; 70(4): 360-5, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17937781

ABSTRACT

Docking and scoring tools are often used in the early stages of drug discovery projects today. Because the language of this field of drug design often includes intermingled terms of physics, chemistry, biology, and medicine, the significant developments of docking and scoring are challenging to follow for non-experts. In this Science Philosophy article, I attempt to clarify the concepts used in docking and scoring to help articulate the successes and limitations of this multidisciplinary field in more comprehensible manner.


Subject(s)
Algorithms , Drug Design , Software , Models, Molecular , Protein Conformation
14.
Genes Immun ; 3(6): 378-9, 2002 Sep.
Article in English | MEDLINE | ID: mdl-12209366

ABSTRACT

Desmoglein 1 is the target antigen and probably the initiating immunogen of the autoantibody response in pemphigus foliaceus (PF), a blistering autoimmune skin disease. We previously showed that the desmoglein 1 gene (DSG1) is polymorphic and that one of its variants is associated with the sporadic form of PF observed in France. Herewith, we report, based on a case-control analysis, that the same DSG1 polymorphism participates in susceptibility to the endemic form of PF seen in Tunisia and, thus, show that common genetic factors govern the breakage of tolerance to desmoglein 1 in different epidemiological and environmental situations.


Subject(s)
Cadherins/genetics , Pemphigus/genetics , Adolescent , Adult , Aged , Cadherins/immunology , Desmoglein 1 , Endemic Diseases , Female , Humans , Male , Middle Aged , Pemphigus/immunology , Polymorphism, Genetic , Tunisia
15.
FEBS Lett ; 456(3): 379-83, 1999 Aug 13.
Article in English | MEDLINE | ID: mdl-10462048

ABSTRACT

Goniothalamin, a plant styrylpyrone derivative isolated from Goniothalamus andersonii, induced apoptosis in Jurkat T-cells as assessed by the externalisation of phosphatidylserine. Immunoblotting showed processing of caspases-3 and -7 with the appearance of their catalytically active large subunits of 17 and 19 kDa, respectively. Activation of these caspases was further evidenced by detection of poly(ADP-ribose) polymerase cleavage (PARP). Pre-treatment with the caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp fluoromethyl ketone (Z-VAD.FMK) blocked apoptosis and the resultant cleavage of these caspases and PARP. Our results demonstrate that activation of at least two effector caspases is a key feature of goniothalamin-induced apoptosis in Jurkat T-cells.


Subject(s)
Apoptosis/drug effects , Caspases/metabolism , Jurkat Cells/drug effects , Pyrones/pharmacology , Amino Acid Chloromethyl Ketones/pharmacology , Annexin A5/analysis , Annexin A5/metabolism , Caspase 3 , Caspase 7 , Caspase Inhibitors , Cysteine Proteinase Inhibitors/pharmacology , Enzyme Activation/drug effects , Humans , Jurkat Cells/enzymology , Jurkat Cells/pathology , Poly(ADP-ribose) Polymerases/metabolism , Pyrones/metabolism
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