Most of the available crystal structures of epidermal growth factor receptor (EGFR) kinase domain, bound to drug inhibitors, originated from ligand-based drug design studies. Here, we used variations in 110 crystal structures to assemble eight distinct families highlighting the C-helix orientation in the N-lobe of the EGFR kinase domain. The families shared similar mutational profiles and similarity in the ligand R-groups (chemical composition, geometry, and charge) facing the C-helix, mutation sites, and DFG domain. For structure-based drug design, we recommend a systematic decision-making process for choice of template, guided by appropriate pairwise fitting and clustering before the molecular docking step. Alternatively, the binding site shape/volume can be used to filter and select the compound libraries.

• MeSH
• erbB receptory antagonisté a inhibitory   chemie   genetika   MeSH
• inhibitory proteinkinas farmakologie   MeSH
• lidé MeSH
• ligandy MeSH
• mutace MeSH
• racionální návrh léčiv metody   MeSH
• rozhodování MeSH
• simulace molekulového dockingu MeSH
• vazebná místa MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

The human 5'(3')-deoxyribonucleotidases catalyze the dephosphorylation of deoxyribonucleoside monophosphates to the corresponding deoxyribonucleosides and thus help to maintain the balance between pools of nucleosides and nucleotides. Here, the structures of human cytosolic deoxyribonucleotidase (cdN) at atomic resolution (1.08 Å) and mitochondrial deoxyribonucleotidase (mdN) at near-atomic resolution (1.4 Å) are reported. The attainment of an atomic resolution structure allowed interatomic distances to be used to assess the probable protonation state of the phosphate anion and the side chains in the enzyme active site. A detailed comparison of the cdN and mdN active sites allowed the design of a cdN-specific inhibitor.

• MeSH
• cytosol chemie   enzymologie   MeSH
• deoxyribonukleotidy chemie   MeSH
• Escherichia coli genetika   metabolismus   MeSH
• eukaryotické buňky chemie   enzymologie   MeSH
• fosfáty chemie   MeSH
• inhibitory enzymů chemie   MeSH
• izoenzymy antagonisté a inhibitory   chemie   genetika   MeSH
• katalytická doména MeSH
• konformace proteinů MeSH
• krystalografie rentgenová MeSH
• lidé MeSH
• mitochondrie chemie   enzymologie   MeSH
• molekulární modely MeSH
• nukleotidasy antagonisté a inhibitory   chemie   genetika   MeSH
• organofosfonáty chemie   MeSH
• orgánová specificita MeSH
• racionální návrh léčiv MeSH
• rekombinantní proteiny chemie   genetika   MeSH
• simulace molekulového dockingu MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Recent years witnessed rapid expansion of our knowledge about structural features of human glutamate carboxypeptidase II (GCPII). There are over thirty X-ray structures of human GCPII (and of its close ortholog GCPIII) publicly available at present. They include structures of ligand-free wild-type enzymes, complexes of wild-type GCPII/GCPIII with structurally diversified inhibitors as well as complexes of the GCPII(E424A) inactive mutant with several substrates. Combined structural data were instrumental for elucidating the catalytic mechanism of the enzyme. Furthermore the detailed knowledge of the GCPII architecture and protein-inhibitor interactions offers mechanistic insight into structure-activity relationship studies and can be exploited for the rational design of novel GCPII-specific compounds. This review presents a summary of structural information that has been gleaned since 2005, when the first GCPII structures were solved.

• MeSH
• glutamátkarboxypeptidasa II antagonisté a inhibitory   chemie   genetika   metabolismus   MeSH
• inhibitory enzymů chemie   farmakologie   MeSH
• konformace proteinů MeSH
• krystalografie rentgenová MeSH
• lidé MeSH
• molekulární modely MeSH
• polymorfismus genetický MeSH
• racionální návrh léčiv MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

AlphaFold is an artificial intelligence approach for predicting the three-dimensional (3D) structures of proteins with atomic accuracy. One challenge that limits the use of AlphaFold models for drug discovery is the correct prediction of folding in the absence of ligands and cofactors, which compromises their direct use. We have previously described the optimization and use of the histone deacetylase 11 (HDAC11) AlphaFold model for the docking of selective inhibitors such as FT895 and SIS17. Based on the predicted binding mode of FT895 in the optimized HDAC11 AlphaFold model, a new scaffold for HDAC11 inhibitors was designed, and the resulting compounds were tested in vitro against various HDAC isoforms. Compound 5a proved to be the most active compound with an IC50 of 365 nM and was able to selectively inhibit HDAC11. Furthermore, docking of 5a showed a binding mode comparable to FT895 but could not adopt any reasonable poses in other HDAC isoforms. We further supported the docking results with molecular dynamics simulations that confirmed the predicted binding mode. 5a also showed promising activity with an EC50 of 3.6 μM on neuroblastoma cells.

• MeSH
• histondeacetylasy * metabolismus   MeSH
• inhibitory histondeacetylas * farmakologie   chemie   chemická syntéza   MeSH
• lidé MeSH
• molekulární struktura MeSH
• nádorové buněčné linie MeSH
• neuroblastom * farmakoterapie   patologie   MeSH
• protinádorové látky * farmakologie   chemie   chemická syntéza   MeSH
• racionální návrh léčiv * MeSH
• simulace molekulární dynamiky MeSH
• simulace molekulového dockingu MeSH
• umělá inteligence MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

The nuclear receptors peroxisome proliferator-activated receptor γ (PPARγ) and its hetero-dimerization partner retinoid X receptor α (RXRα) are considered as drug targets in the treatment of diseases like the metabolic syndrome and diabetes mellitus type 2. Effort has been made to develop new agonists for PPARγ to obtain ligands with more favorable properties than currently used drugs. Magnolol was previously described as dual agonist of PPARγ and RXRα. Here we show the structure-based rational design of a linked magnolol dimer within the ligand binding domain of PPARγ and its synthesis. Furthermore, we evaluated its binding properties and functionality as a PPARγ agonist in vitro with the purified PPARγ ligand binding domain (LBD) and in a cell-based nuclear receptor transactivation model in HEK293 cells. We determined the synthesized magnolol dimer to bind with much higher affinity to the purified PPARγ ligand binding domain than magnolol (K i values of 5.03 and 64.42 nM, respectively). Regarding their potency to transactivate a PPARγ-dependent luciferase gene both compounds were equally effective. This is likely due to the PPARγ specificity of the newly designed magnolol dimer and lack of RXRα-driven transactivation activity by this dimeric compound.

• MeSH
• bifenylové sloučeniny chemická syntéza   chemie   farmakologie   MeSH
• dimerizace * MeSH
• HEK293 buňky MeSH
• lidé MeSH
• ligandy MeSH
• lignany chemická syntéza   chemie   farmakologie   MeSH
• pioglitazon farmakologie   MeSH
• PPAR gama agonisté   chemie   metabolismus   MeSH
• proteinové domény MeSH
• racionální návrh léčiv * MeSH
• retinoidní X receptor alfa metabolismus   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Novel 4-aminoquinazoline-6-carboxamide derivatives bearing differently substituted aryl or heteroaryl groups at position 7 in the core were rationally designed, synthesized and evaluated for biological activity in vitro as phosphatidylinositol 4-kinase IIα (PI4K2A) inhibitors. The straightforward approach described here enabled the sequential, modular synthesis and broad functionalization of the scaffold in a mere six steps. The SAR investigation reported here is based on detailed structural analysis of the conserved binding mode of ATP and other adenine derivatives to the catalytic site of type II PI4Ks, combined with extensive docking studies. Several compounds exhibited significant activity against PI4K2A. Moreover, we solved a crystal structure of PI4K2B in complex with one of our lead ligand candidates, which validated the ligand binding site and pose predicted by our docking-based ligand model. These discoveries suggest that our structure-based approach may be further developed and employed to synthesize new inhibitors with optimized potency and selectivity for this class of PI4Ks.

• MeSH
• 1-fosfatidylinositol-4-kinasa * chemie   metabolismus   MeSH
• adenin MeSH
• adenosintrifosfát * metabolismus   MeSH
• ligandy MeSH
• racionální návrh léčiv MeSH
• simulace molekulového dockingu MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

HIV protease is a primary target for the design of virostatics. Screening of libraries of non-peptide low molecular weight compounds led to the identification of several new compounds that inhibit HIV PR in the low micromolar range. X-ray structure of the complex of one of them, a dibenzo[b,e][1,4]diazepinone derivative, showed that two molecules of the inhibitor bind to the PR active site. Covalent linkage of two molecules of such a compound by a two-carbon linker led to a decrease of the inhibition constant of the resulting compound by 3 orders of magnitude. Molecular modeling shows that these dimeric inhibitors form two crucial hydrogen bonds to the catalytic aspartates that are responsible for their improved activity compared to the monomeric parental building blocks. Dibenzo[b,e][1,4]diazepinone analogues might represent a potential new class of HIV PIs.

• MeSH
• benzodiazepiny chemie   MeSH
• HIV infekce farmakoterapie   enzymologie   virologie   MeSH
• HIV-1 účinky léků   MeSH
• HIV-proteasa chemie   metabolismus   MeSH
• inhibitory HIV-proteasy chemická syntéza   farmakologie   MeSH
• katalytická doména MeSH
• katalýza MeSH
• konformace proteinů MeSH
• krystalografie rentgenová MeSH
• lidé MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• peptidové fragmenty farmakologie   MeSH
• racionální návrh léčiv * MeSH
• vodíková vazba MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• Konspekt
• Biochemie. Molekulární biologie. Biofyzika
• NLK Obory
• biochemie

New and modern techniques of drug design are extensively used in parallel or instead of the classic ones. Applicability of virtual screening (VS) is growing with the computational performance. This article includes list and short description of most frequent used methods in VS. These methods are divided into two groups – ligand-based VS and structure-based VS. Ligand based methods include chemical similarity, pharmacophore and quantitative structure-activity relationship. Molecular docking and scoring are methods of the structure-based VS.

• MeSH
• chemické modely MeSH
• objevování léků metody   MeSH
• počítačová simulace MeSH
• racionální návrh léčiv * MeSH
• Publikační typ
• práce podpořená grantem MeSH

VÝCHODISKA: Požadavek hodnotit účinnost a úspěšnost realizovaných drogových politik se stává běžnou součástí schvalovaných protidrogových strategii v EU. Jednotlivé země stojí před otázkou vhodného způsobu evaluace svých národních strategii a/nebo akčních plánů a otázka evaluační metodiky se tak stává diskutovaným tématem v odborných kruzích. Také Česká republika evaluovala na přelomu let 2009 a 2010 Národní strategii protidrogové politiky na období 2005–2009. CÍLE: Článek popisuje výzkumný design, metody a shrnuje hlavní výsledky projektu, jehož cílem bylo vyhodnotit českou protidrogovou politiku v uplynulém období pěti let. METODIKA: Evaluace české protidrogové politiky vycházela z teoretického modelu zjednodušeného politického cyklu. Zaměřila se na fáze formulování, implementování a pak hodnotila výsledky protidrogové politiky. Při hodnocení byla použita kombinace různých kvalitativních a kvantitativních metod sběru a analýzy dat od analýzy dokumentů a semistrukturovaného rozhovoru přes dotazníkové šetření po SWOT analýzu v pracovních skupinách a analýzu epidemiologických dat. VÝSLEDKY: Podařilo se popsat úroveň a stav dosažení jednotlivých strategických cílů v širších souvislostech – evaluace identifikovala možné faktory, které mohly dosažení strategických cílů ovlivnit, a to ve fázi formulování i ve fázi implementace protidrogové politiky. Ukázalo se, že charakter a potenciál aktivit, které byly obsaženy v akčním plánu, a rovněž úspěšnost implementace těchto aktivit koresponduje s úrovní dosažení strategických cílů, k jejichž dosažení dané aktivity přispívaly. ZÁVĚRY: Získané zkušenosti a výsledky evaluace jsou příspěvkem k odborné diskusi na téma zkoumání a hodnocení protidrogové politiky. Evaluace poskytla zpětnou vazbu k jednotlivým fázím tvorby a realizace protidrogové politiky, k vývoji a výsledkům české protidrogové politiky v letech 2005–2009. Přinesla také nové podněty k uvažování o protidrogové politice a k přípravě strategických dokumentů v budoucnu.

BACKGROUND: The recognition of the need to evaluate the efficacy and efficiency of national drug policies has become an integrated part of approved drug policy documents. Countries face the issue of adequate evaluations of their national drug strategies/programmes and/or action plans; the issue of appropriate design and methodology is a topic for discussion among researchers and policy analysts. The Czech Republic was also confronted with this issue when evaluating its National Drug Policy Strategy for the Period 2005–2009 at the turn of 2010. AIMS: This article describes the research design, methods, and main findings of the evaluation of the Czech drug policy in the last five years. METHODOLOGY: The Czech drug policy evaluation was based on a (simplified) policy cycle model. It focused on the phase of the formulation of drug policy documents, their implementation and subsequently on the outcomes of the drug policy. Different methods of data collection and analysis were used with respect to the focus (of the individual segments) of evaluation: document analysis, semi-structured interviews, questionnaire surveys, SWOT analysis in working groups and analysis of epidemiological data sets. FINDINGS : The evaluation succeeded in describing the level and status of the accomplishment of the strategic goals in broader terms: the evaluation identified factors which may have had an influence on the achievement of the strategic goals during both the formulation and implemen- tation of the drug policy. The results indicate that the nature and potential of the activities incorporated in the action plan and their successful implementation correspond with the level of fulfilment of the strategic goals, the achievement of which they were intended to contribute to. CONCLUSIONS : The lessons learned during the evaluation process, together with the evaluation findings, contribute to the debate on research into the drug policy and its evaluation. The evaluation provided qualitative feedback on the formulation phase of the drug policy and its implementation, development and outcomes in the period 2005–2009. It also provided input facilitating reflection on the drug policy and the development of drug policy documents in the future.

• Klíčová slova
• hodnocení politiky, národní strategie a akční plán protidrogové politiky, aktéři protidrogové politiky, design evaluace, metody hodnocení politik,
• MeSH
• hodnotící studie jako téma MeSH
• lidé MeSH
• poruchy spojené s užíváním psychoaktivních látek prevence a kontrola   MeSH
• rozvoj plánování MeSH
• sběr dat metody   MeSH
• služby preventivní péče trendy   MeSH
• vládní programy využití   MeSH
• vytváření politiky MeSH
• zdravotní politika trendy   zákonodárství a právo   MeSH
• Check Tag
• lidé MeSH