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 Receptors antagonists & inhibitors   chemistry   genetics   MeSH
• Protein Kinase Inhibitors pharmacology   MeSH
• Humans MeSH
• Ligands MeSH
• Mutation MeSH
• Drug Design methods   MeSH
• Decision Making MeSH
• Molecular Docking Simulation MeSH
• Binding Sites MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review 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
• Glutamate Carboxypeptidase II antagonists & inhibitors   chemistry   genetics   metabolism   MeSH
• Enzyme Inhibitors chemistry   pharmacology   MeSH
• Protein Conformation MeSH
• Crystallography, X-Ray MeSH
• Humans MeSH
• Models, Molecular MeSH
• Polymorphism, Genetic MeSH
• Drug Design MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Review MeSH

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
• Models, Chemical MeSH
• Drug Discovery methods   MeSH
• Computer Simulation MeSH
• Drug Design * MeSH
• Publication type
• Research Support, Non-U.S. Gov't 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 chemistry   enzymology   MeSH
• Deoxyribonucleotides chemistry   MeSH
• Escherichia coli genetics   metabolism   MeSH
• Eukaryotic Cells chemistry   enzymology   MeSH
• Phosphates chemistry   MeSH
• Enzyme Inhibitors chemistry   MeSH
• Isoenzymes antagonists & inhibitors   chemistry   genetics   MeSH
• Catalytic Domain MeSH
• Protein Conformation MeSH
• Crystallography, X-Ray MeSH
• Humans MeSH
• Mitochondria chemistry   enzymology   MeSH
• Models, Molecular MeSH
• Nucleotidases antagonists & inhibitors   chemistry   genetics   MeSH
• Organophosphonates chemistry   MeSH
• Organ Specificity MeSH
• Drug Design MeSH
• Recombinant Proteins chemistry   genetics   MeSH
• Molecular Docking Simulation MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't 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.

• Keywords
• hodnocení politiky, národní strategie a akční plán protidrogové politiky, aktéři protidrogové politiky, design evaluace, metody hodnocení politik,
• MeSH
• Evaluation Studies as Topic MeSH
• Humans MeSH
• Substance-Related Disorders prevention & control   MeSH
• Program Development MeSH
• Data Collection methods   MeSH
• Preventive Health Services trends   MeSH
• Government Programs utilization   MeSH
• Policy Making MeSH
• Health Policy trends   legislation & jurisprudence   MeSH
• Check Tag
• Humans 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
• Histone Deacetylases * metabolism   MeSH
• Histone Deacetylase Inhibitors * pharmacology   chemistry   chemical synthesis   MeSH
• Humans MeSH
• Molecular Structure MeSH
• Cell Line, Tumor MeSH
• Neuroblastoma * drug therapy   pathology   MeSH
• Antineoplastic Agents * pharmacology   chemistry   chemical synthesis   MeSH
• Drug Design * MeSH
• Molecular Dynamics Simulation MeSH
• Molecular Docking Simulation MeSH
• Artificial Intelligence MeSH
• Dose-Response Relationship, Drug MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article 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
• Biphenyl Compounds chemical synthesis   chemistry   pharmacology   MeSH
• Dimerization * MeSH
• HEK293 Cells MeSH
• Humans MeSH
• Ligands MeSH
• Lignans chemical synthesis   chemistry   pharmacology   MeSH
• Pioglitazone pharmacology   MeSH
• PPAR gamma agonists   chemistry   metabolism   MeSH
• Protein Domains MeSH
• Drug Design * MeSH
• Retinoid X Receptor alpha metabolism   MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Various design and fabrication strategies of carrier-based drug delivery systems have been quickly established and applied for cancer therapy in recent years. These systems contribute greatly to current cancer treatments but further development needs to be made to eliminate obstacles such as low drug loading capacity and severe side effects. To achieve better drug delivery, we propose an innovative strategy for the construction of easy manufactured drug self-delivery systems based on molecular structures, which can be used for the co-delivery of curcuminoids and all the nitrogen-containing derivatives of camptothecin for better targeted cancer therapy with minimized side effects. The formation mechanism investigation demonstrates that the rigid planar structures of camptothecin derivatives and curcuminoids with relevant leaving hydrogens make it possible for them to be assembled into nanoparticles under suitable conditions. These nanoparticles show stabilized particle sizes (100 nm) under various conditions and tunable surface charges which increase from around -10 mV in a normal physiological condition (pH 7.4) to +40 mV under acidic tumor environments. In addition, in vivo mice experiments have demonstrated that, compared to irinotecan (a derivative of camptothecin) itself, the co-delivered irinotecan curcumin nanoparticles exhibited significantly enhanced lung and gallbladder targeting, improved macrophage-clearance escape and ameliorated colorectal cancer treatment with an eradication of life-threatening diarrhea, bringing hope for better targeted chemotherapy and clinical translation. Lastly, the strategy of structure based design of drug self-delivery systems may inspire more research and discoveries of similar self-delivered nano systems for wider pharmaceutical applications.

• MeSH
• Camptothecin MeSH
• Pharmaceutical Preparations * MeSH
• Drug Delivery Systems * MeSH
• Mice MeSH
• Cell Line, Tumor MeSH
• Neoplasms * drug therapy   MeSH
• Nanoparticles * MeSH
• Antineoplastic Agents * therapeutic use   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't 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-Phosphatidylinositol 4-Kinase * chemistry   metabolism   MeSH
• Adenine MeSH
• Adenosine Triphosphate * metabolism   MeSH
• Ligands MeSH
• Drug Design MeSH
• Molecular Docking Simulation MeSH
• Structure-Activity Relationship MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Yohimbine, a natural indole alkaloid and a nonselective adrenoceptor antagonist, possesses potential benefits in treating inflammatory disorders and sepsis. Nevertheless, its broader clinical use faces challenges due to its low receptor selectivity. A structure-activity relationship study of novel yohimbine analogues identified amino esters of yohimbic acid as potent and selective ADRA2A antagonists. Specifically, amino ester 4n, in comparison to yohimbine, showed a 6-fold higher ADRA1A/ADRA2A selectivity index (SI > 556 for 4n) and a 25-fold higher ADRA2B/ADRA2A selectivity index. Compound 4n also demonstrated high plasma and microsomal stability, moderate-to-low membrane permeability determining its limited ability to cross the blood-brain barrier, and negligible toxicity on nontumor normal human dermal fibroblasts. Compound 4n represents an important complementary pharmacological tool to study the involvement of adrenoceptor subtypes in pathophysiologic conditions such as inflammation and sepsis and a novel candidate for further preclinical development to treat ADRA2A-mediated pathologies.

• MeSH
• Adrenergic alpha-2 Receptor Antagonists * pharmacology   chemistry   chemical synthesis   MeSH
• Receptors, Adrenergic, alpha-2 * metabolism   MeSH
• Humans MeSH
• Drug Design * MeSH
• Structure-Activity Relationship MeSH
• Yohimbine * pharmacology   chemistry   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH