rational design
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Development of information technologies in recent decades has facilitated also a great progress in the development of new drugs. Methods of Computer-Aided Drug Design allow us to explore the spatial interaction between the receptor and a potential drug. The review deals with a brief summary of these computational methods and is mainly focused on pharmacophore modelling, one of the modern approaches in drug design that has proved to be a useful tool.
521 s.
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
Described is a computer-assisted rational design of a DNA-bis-intercalator peptide library. The peptide library of 250 members was prepared and the most powerful binder identified. A value of the binding constant is almost two orders of magnitude higher than that of starting building block-9-aminoacridine. The binder affinity found toward calf thymus DNA is 30-fold of that of human prion peptide 106-126.
- MeSH
- aminakrin chemie MeSH
- design s pomocí počítače MeSH
- DNA vazebné proteiny chemie metabolismus MeSH
- DNA chemická syntéza chemie metabolismus MeSH
- financování organizované MeSH
- fluorescenční barviva chemie MeSH
- genová knihovna MeSH
- interkalátory chemie MeSH
- lidé MeSH
- molekulární modely MeSH
- peptidové fragmenty metabolismus MeSH
- priony metabolismus MeSH
- skot MeSH
- spektrometrie hmotnostní - ionizace laserem za účasti matrice MeSH
- techniky kombinatorické chemie MeSH
- thymus chemie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- skot MeSH
- zvířata MeSH
The purpose of this study was to identify new small molecules that possess activity on human toll-like receptor 4 associated with the myeloid differentiation protein 2 (hTLR4/MD2). Following current rational drug design principles, we firstly performed a ligand and structure based virtual screening of more than 130 000 compounds to discover until now unknown class of hTLR4/MD2 modulators that could be used as novel type of immunologic adjuvants. The core of the in silico study was molecular docking of flexible ligands in a partially flexible hTLR4/MD2 receptor model using a peta-flops-scale supercomputer. The most promising substances resulting from this study, related to anthracene-succimide hybrids, were synthesized and tested. The best prepared candidate exhibited 80% of Monophosphoryl Lipid A in vitro agonistic activity in cell lines expressing hTLR4/MD2.
- MeSH
- buněčné linie MeSH
- knihovny malých molekul chemická syntéza chemie farmakologie MeSH
- lidé MeSH
- ligandy MeSH
- molekulární struktura MeSH
- počítačová simulace * MeSH
- preklinické hodnocení léčiv MeSH
- racionální návrh léčiv * MeSH
- simulace molekulového dockingu MeSH
- toll-like receptor 4 antagonisté a inhibitory MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- MeSH
- chemické modely MeSH
- finanční podpora výzkumu jako téma MeSH
- lidé MeSH
- molekulární modely MeSH
- racionální návrh léčiv MeSH
- thiadiazoly chemie MeSH
- triózafosfátizomeráza chemie MeSH
- trypanocidální látky chemie MeSH
- Trypanosoma cruzi enzymologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- srovnávací studie 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
A new co-crystal of pharmaceutical active ingredient Apremilast was successfully designed in this work. The discovered co-crystal with benzoic acid significantly improves key properties like the dissolution and stability of an otherwise poorly soluble Apremilast. A crystallization process was developed, which includes efficient solvent selection and ternary phase diagram construction to minimize risks during scale up. To increase efficiency, we propose that both steps be combined into a single methodology based on solubility data. A suitable solvent for the co-crystallization process was selected and ternary phase diagrams were constructed using three different modifications of thermodynamic model of solid-liquid equilibria. Based on the obtained information, the co-crystallization process was scaled-up to 100 mL. This provides a feasible process to produce larger amounts of this promising pharmaceutical solid form of Apremilast necessary for further drug development.
The rational design of molecules with selective intracellular targeting is a great challenge for contemporary chemistry and life sciences. Here, we demonstrate a rational approach to development of compartment-specific fluorescent dyes from the γ-aryl substituted pentamethine family. These novel dyes exhibit an extraordinary affinity and selectivity for cardiolipin in inner mitochondrial membrane and possess excellent photostability, fluorescent properties, and low phototoxicity. Selective imaging of live and fixed mitochondria was achieved in various cell lines using nanomolar concentrations of these dyes. Their high localization specificity and low toxicity enables study of morphological changes, structural complexity, and dynamics of mitochondria playing a pivotal role in many pathological diseases. These far-red emitting dyes could also serve in a variety of biomedical applications.
- MeSH
- buněčné linie MeSH
- DNA analýza MeSH
- fluorescenční barviva analýza metabolismus MeSH
- kardiolipiny analýza metabolismus MeSH
- krystalografie rentgenová MeSH
- kultivované buňky MeSH
- kur domácí MeSH
- lidé MeSH
- ligandy MeSH
- mitochondrie metabolismus ultrastruktura MeSH
- molekulární modely MeSH
- myši MeSH
- nádorové buněčné linie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
