Since its early days in the 19th century, medicinal chemistry has concentrated its efforts on the treatment of diseases, using tools from areas such as chemistry, pharmacology, and molecular biology. The understanding of biological mechanisms and signaling pathways is crucial information for the development of potential agents for the treatment of diseases mainly because they are such complex processes. Given the limitations that the experimental approach presents, computational chemistry is a valuable alternative for the study of these systems and their behavior. Thus, classical molecular dynamics, based on Newton's laws, is considered a technique of great accuracy, when appropriated force fields are used, and provides satisfactory contributions to the scientific community. However, as many configurations are generated in a large MD simulation, methods such as Statistical Inefficiency and Optimal Wavelet Signal Compression Algorithm are great tools that can reduce the number of subsequent QM calculations. Accordingly, this review aims to briefly discuss the importance and relevance of medicinal chemistry allied to computational chemistry as well as to present a case study where, through a molecular dynamics simulation of AMPK protein (50 ns) and explicit solvent (TIP3P model), a minimum number of snapshots necessary to describe the oscillation profile of the protein behavior was proposed. For this purpose, the RMSD calculation, together with the sophisticated OWSCA method was used to propose the minimum number of snapshots.

• MeSH
• algoritmy MeSH
• farmaceutická chemie MeSH
• kvantová teorie MeSH
• lidé MeSH
• proteinkinasy aktivované AMP metabolismus   chemie   MeSH
• simulace molekulární dynamiky * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Lens epithelium-derived growth factor p75 (LEDGF/p75), member of the hepatoma-derived growth-factor-related protein (HRP) family, is a transcriptional co-activator and involved in several pathologies including HIV infection and malignancies such as MLL-rearranged leukemia. LEDGF/p75 acts by tethering proteins to the chromatin through its integrase binding domain. This chromatin interaction occurs between the PWWP domain of LEDGF/p75 and nucleosomes carrying a di- or trimethylation mark on histone H3 Lys36 (H3K36me2/3). Our aim is to rationally devise small molecule drugs capable of inhibiting such interaction. To bootstrap this development, we resorted to X-ray crystallography-based fragment screening (FBS-X). Given that the LEDGF PWWP domain crystals were not suitable for FBS-X, we employed crystals of the closely related PWWP domain of paralog HRP-2. As a result, as many as 68 diverse fragment hits were identified, providing a detailed sampling of the H3K36me2/3 pocket pharmacophore. Subsequent structure-guided fragment expansion in three directions yielded multiple compound series binding to the pocket, as verified through X-ray crystallography, nuclear magnetic resonance and differential scanning fluorimetry. Our best compounds have double-digit micromolar affinity and optimally sample the interactions available in the pocket, judging by the Kd-based ligand efficiency exceeding 0.5 kcal/mol per non-hydrogen atom. Beyond π-stacking within the aromatic cage of the pocket and hydrogen bonding, the best compounds engage in a σ-hole interaction between a halogen atom and a conserved water buried deep in the pocket. Notably, the binding pocket in LEDGF PWWP is considerably smaller compared to the related PWWP1 domains of NSD2 and NSD3 which feature an additional subpocket and for which nanomolar affinity compounds have been developed recently. The absence of this subpocket in LEDGF PWWP limits the attainable affinity. Additionally, these structural differences in the H3K36me2/3 pocket across the PWWP domain family translate into a distinct selectivity of the compounds we developed. Our top-ranked compounds are interacting with both homologous LEDGF and HRP-2 PWWP domains, yet they showed no affinity for the NSD2 PWWP1 and BRPF2 PWWP domains which belong to other PWWP domain subfamilies. Nevertheless, our developed compound series provide a strong foundation for future drug discovery targeting the LEDGF PWWP domain as they can further be explored through combinatorial chemistry. Given that the affinity of H3K36me2/3 nucleosomes to LEDGF/p75 is driven by interactions within the pocket as well as with the DNA-binding residues, we suggest that future compound development should target the latter region as well. Beyond drug discovery, our compounds can be employed to devise tool compounds to investigate the mechanism of LEDGF/p75 in epigenetic regulation.

• MeSH
• knihovny malých molekul chemie   farmakologie   chemická syntéza   MeSH
• krystalografie rentgenová MeSH
• lidé MeSH
• mezibuněčné signální peptidy a proteiny metabolismus   chemie   MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• proteinové domény MeSH
• racionální návrh léčiv * MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Hledání optimálního nastavení podmínek chemické analýzy je zpravidla zdlouhavý proces. Tento článek k tomuto účelu navrhuje využití neuronových sítí, zejména ve vztahu k určení optimální podmínek pro analýzu zkoumaných látek s využitím technologie LC/MS/MS a ESI ionizací, a to na základě znalosti jejich základních vlastností, označených jako univerzální deskriptory. Práce se soustředí na nalezení takových podmínek analýzy, kdy dochází k maximalizaci signálu iontu prekurzoru. Práce se zabývá zejména otázkou, zda lze výsledky zjištěné na jednom typu analytu použít k neurální interpolační predikci optimálních podmínek analytů podobných.

The search for the optimal instrumental settings of conditions in chemical analysis is typically a lengthy process. This article proposes the use of neural networks for this purpose, particularly in relation to determining the optimal conditions for the analysis of substances under study using LC/MS/MS and ESI technologies, based on the knowledge of their fundamental properties, referred to as universal descriptors. The work focuses on finding such analysis conditions that maximize the precursor ion signal. The paper specifically addresses the question of whether the results obtained from one type of analyte can be used for neural-interpolated prediction of optimal conditions for similar analytes.

• MeSH
• chemické bojové látky chemie   MeSH
• chemické techniky analytické metody   MeSH
• chromatografie kapalinová metody   MeSH
• hmotnostní spektrometrie s elektrosprejovou ionizací metody   MeSH
• hmotnostní spektrometrie metody   MeSH
• lidé MeSH
• neuronové sítě MeSH
• organofosfáty * chemie   analýza   MeSH
• Check Tag
• lidé MeSH

The search for the optimal instrumental settings of conditions in chemical analysis is typically a lengthy process. This article proposes the use of neural networks for this purpose, particularly in relation to determining the optimal conditions for the analysis of substances under study using LC/MS/MS and ESI technologies, based on the knowledge of their fundamental properties, referred to as universal descriptors. The work focuses on finding such analysis conditions that maximize the precursor ion signal. The paper specifically addresses the question of whether the results obtained from one type of analyte can be used for neural-interpolated prediction of optimal conditions for similar analytes.

• MeSH
• chemické bojové látky analýza   chemie   MeSH
• chemické techniky analytické metody   MeSH
• chromatografie kapalinová metody   MeSH
• hmotnostní spektrometrie s elektrosprejovou ionizací metody   MeSH
• hmotnostní spektrometrie metody   MeSH
• lidé MeSH
• neuronové sítě MeSH
• organofosfáty * analýza   chemie   MeSH
• Check Tag
• lidé MeSH

In this work, the solid-liquid equilibrium (SLE) curve for ten active pharmaceutical ingredients (APIs) with the polymer polyvinylpyrrolidone (PVP) K12 was purely predicted using the Conductor-like Screening Model for Real Solvents (COSMO-RS). In particular, two COSMO-RS-based strategies were followed (i.e., a traditional approach and an expedited approach), and their performances were compared. The veracity of the predicted SLE curves was assessed via a comparison with their respective SLE dataset that was obtained using the step-wise dissolution (S-WD) method. Overall, the COSMO-RS-based API-PVP K12 SLE curves were in satisfactory agreement with the S-WD-based data points. Of the twenty predicted SLE curves, only two were found to be in strong disagreement with the corresponding experimental values (both modeled using the expedited approach). Hence, it was recommended to use the traditional approach when predicting the API-polymer SLE curve. At the present moment, COSMO-RS may be an effective computational tool for the expeditious screening of API-polymer compatibility, particularly in the case of promising novel APIs, for which experimental datasets are likely limited or non-existent.

• MeSH
• farmaceutická chemie metody   MeSH
• léčivé přípravky chemie   MeSH
• polymery chemie   MeSH
• povidon * chemie   MeSH
• rozpouštědla chemie   MeSH
• rozpustnost MeSH
• uvolňování léčiv MeSH
• Publikační typ
• časopisecké články MeSH

INTRODUCTION: The widespread importance of the synthesis and modification of anticancer agents has given rise to many numbers of medicinal chemistry programs. In this regard, triazine derivatives have attracted attention due to their remarkable activity against a wide range of cancer cells. This evaluation covers work reports to define the anticancer activity, the most active synthesized compound for the target, the SAR and, when described, the probable MOA besides similarly considered to deliver complete and target-pointed data for the development of types of anti-tumour medicines of triazine derivatives. Triazine scaffold for the development of anticancer analogues. Triazine can also relate to numerous beneficial targets, and their analogues have auspicious in-vitro and in-vivo anti-tumour activity. Fused molecules can improve efficacy, and drug resistance and diminish side effects, and numerous hybrid molecules are beneath diverse stages of clinical trials, so hybrid derivatives of triazine may offer valuable therapeutic involvement for the dealing of tumours. OBJECTIVE: The objective of the recent review was to summarize the recent reports on triazine as well as its analogues with respect to its anticancer therapeutic potential. CONCLUSION: The content of the review would be helpful to update the researchers working towards the synthesis and designing of new molecules for the treatment of various types of cancer disease with the recent molecules that have been produced from the triazine scaffold. Triazine scaffolds based on 1,3,5-triazine considerably boost molecular diversity levels and enable covering chemical space in key medicinal chemistry fields.

• MeSH
• lidé MeSH
• nádory farmakoterapie   MeSH
• protinádorové látky * farmakologie   chemie   terapeutické užití   MeSH
• screeningové testy protinádorových léčiv MeSH
• triaziny * farmakologie   chemie   terapeutické užití   MeSH
• vyvíjení léků metody   MeSH
• vztahy mezi strukturou a aktivitou MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

• MeSH
• interpretace obrazu počítačem metody   přístrojové vybavení   MeSH
• laboratorní automatizace metody   přístrojové vybavení   MeSH
• mikroskopie klasifikace   metody   MeSH
• objevování léků * metody   MeSH
• rychlé screeningové testy metody   MeSH
• techniky kombinatorické chemie metody   MeSH
• vyvíjení léků metody   přístrojové vybavení   MeSH
• Publikační typ
• přehledy MeSH

Electrochemical methods can be used not only for the sensitive analysis of proteins but also for deeper research into their structure, transport functions (transfer of electrons and protons), and sensing their interactions with soft and solid surfaces. Last but not least, electrochemical tools are useful for investigating the effect of an electric field on protein structure, the direct application of electrochemical methods for controlling protein function, or the micromanipulation of supramolecular protein structures. There are many experimental arrangements (modalities), from the classic configuration that works with an electrochemical cell to miniaturized electrochemical sensors and microchip platforms. The support of computational chemistry methods which appropriately complement the interpretation framework of experimental results is also important. This text describes recent directions in electrochemical methods for the determination of proteins and briefly summarizes available methodologies for the selective labeling of proteins using redox-active probes. Attention is also paid to the theoretical aspects of electron transport and the effect of an external electric field on the structure of selected proteins. Instead of providing a comprehensive overview, we aim to highlight areas of interest that have not been summarized recently, but, at the same time, represent current trends in the field.

• MeSH
• elektrochemické techniky * metody   MeSH
• elektrochemie MeSH
• oxidace-redukce MeSH
• proteiny * MeSH
• transport elektronů MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

• MeSH
• AIDS * farmakoterapie   prevence a kontrola   MeSH
• antivirové látky dějiny   MeSH
• cidofovir MeSH
• dějiny 20. století MeSH
• dějiny 21. století MeSH
• kombinace léků emtricitabin a tenofovir MeSH
• organická chemie MeSH
• schvalování léčiv dějiny   MeSH
• tenofovir MeSH
• vyvíjení léků dějiny   MeSH
• Check Tag
• dějiny 20. století MeSH
• dějiny 21. století MeSH
• Publikační typ
• historické články MeSH

• O autorovi
• Holý, Antonín, 1936-2012 Autorita

Publikace obsahuje příběhy o dějinách lékárnictví a vývoji nových léčiv. Určeno odborné i široké veřejnosti.; Objevy medikamentů často zahrnovaly prvky náhody i osobního angažování vědců. Publikace přináší vyvážený poměr mezi fakty a samotným příběhem popisujícím různá úskalí i nečekané zvraty, které se při vývoji léčiv mohou stát.

• MeSH
• dějiny 20. století MeSH
• dějiny lékárnictví MeSH
• farmaceutická chemie MeSH
• farmaceutický výzkum dějiny   MeSH
• vyvíjení léků dějiny   MeSH
• Check Tag
• dějiny 20. století MeSH
• Publikační typ
• monografie MeSH
• osobní vyprávění MeSH

• Konspekt
• Farmacie. Farmakologie
• NLK Obory
• farmacie a farmakologie
• dějiny lékařství