Pharmacophore modeling Dotaz Zobrazit nápovědu
Pharmacophore modeling is a widely used strategy for finding new hit molecules. Since not all protein targets have available 3D structures, ligand-based approaches are still useful. Currently, there are just a few free ligand-based pharmacophore modeling tools, and these have a lot of restrictions, e.g., using a template molecule for alignment. We developed a new approach to 3D pharmacophore representation and matching which does not require pharmacophore alignment. This representation can be used to quickly find identical pharmacophores in a given set. Based on this representation, a 3D pharmacophore ligand-based modeling approach to search for pharmacophores which preferably match active compounds and do not match inactive ones was developed. The approach searches for 3D pharmacophore models starting from 2D structures of available active and inactive compounds. The implemented approach was successfully applied for several retrospective studies. The results were compared to a 2D similarity search, demonstrating some of the advantages of the developed 3D pharmacophore models. Also, the generated 3D pharmacophore models were able to match the 3D poses of known ligands from their protein-ligand complexes, confirming the validity of the models. The developed approach is available as an open-source software tool: http://www.qsar4u.com/pages/pmapper.php and https://github.com/meddwl/psearch.
- Klíčová slova
- 3D pharmacophore hash, 3D pharmacophore signatures, ligand-based modeling, pharmacophore modeling,
- MeSH
- antagonisté adenosinového receptoru A2 chemie MeSH
- cholinesterasové inhibitory chemie MeSH
- inhibitory cytochromu P450 CYP3A chemie MeSH
- ligandy MeSH
- molekulární modely * MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antagonisté adenosinového receptoru A2 MeSH
- cholinesterasové inhibitory MeSH
- inhibitory cytochromu P450 CYP3A MeSH
- ligandy MeSH
Cobalt bis(dicarbollide) (COSAN) is a metallacarborane used as a versatile pharmacophore to prepare biologically active hybrid organic-inorganic compounds or to improve the pharmacological properties of nucleosides, antisense oligonucleotides, and DNA intercalators. Despite these applications, COSAN interactions with nucleic acids remain unclear, limiting further advances in metallacarborane-based drug development. Although some studies showed that COSAN intercalates into DNA, COSAN-containing intercalators do not, and while COSAN shows low cytotoxicity, intercalators are often highly toxic. The present study aimed at comprehensively characterizing interactions between COSAN and DNA using a wide range of techniques, including UV-Vis absorption, circular (CD) and linear (LD) dichroism, nuclear magnetic resonance (NMR) spectroscopy, thermal denaturation, viscosity, differential scanning calorimetry (DSC), isothermal titration calorimetry (ITC), and equilibrium dialysis measurements. Our results showed that COSAN has no effect on DNA structure, length, stability, or hybridization, with no or only faint signs of COSAN binding to DNA. Moreover, DNA is not necessary for COSAN to induce cytotoxicity at high concentrations, as shown by in vitro experiments. These findings demonstrate that COSAN is a DNA-neutral pharmacophore, thus confirming the general safety and biocompatibility of metallacarboranes and opening up new opportunities for further developing metallacarborane-based drugs.
- MeSH
- cirkulární dichroismus MeSH
- DNA chemie MeSH
- farmakofor * MeSH
- interkalátory MeSH
- kobalt * chemie MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- DNA MeSH
- interkalátory MeSH
- kobalt * MeSH
Pharmacophore models are widely used for the identification of promising primary hits in compound large libraries. Recent studies have demonstrated that pharmacophores retrieved from protein-ligand molecular dynamic trajectories outperform pharmacophores retrieved from a single crystal complex structure. However, the number of retrieved pharmacophores can be enormous, thus, making it computationally inefficient to use all of them for virtual screening. In this study, we proposed selection of distinct representative pharmacophores by the removal of pharmacophores with identical three-dimensional (3D) pharmacophore hashes. We also proposed a new conformer coverage approach in order to rank compounds using all representative pharmacophores. Our results for four cyclin-dependent kinase 2 (CDK2) complexes with different ligands demonstrated that the proposed selection and ranking approaches outperformed the previously described common hits approach. We also demonstrated that ranking, based on averaged predicted scores obtained from different complexes, can outperform ranking based on scores from an individual complex. All developments were implemented in open-source software pharmd.
- Klíčová slova
- molecular dynamics, pharmacophore, virtual screening,
- MeSH
- cyklin-dependentní kinasa 2 chemie metabolismus MeSH
- inhibitory proteinkinas chemie farmakologie MeSH
- knihovny malých molekul chemie farmakologie MeSH
- lidé MeSH
- ligandy MeSH
- objevování léků metody MeSH
- počítačová simulace MeSH
- simulace molekulární dynamiky * MeSH
- simulace molekulového dockingu metody MeSH
- vazba proteinů MeSH
- vazebná místa MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- cyklin-dependentní kinasa 2 MeSH
- inhibitory proteinkinas MeSH
- knihovny malých molekul MeSH
- ligandy MeSH
In silico methods like molecular docking and pharmacophore modeling are established strategies in lead identification. Their successful application for finding new active molecules for a target is reported by a plethora of studies. However, once a potential lead is identified, lead optimization, with the focus on improving potency, selectivity, or pharmacokinetic parameters of a parent compound, is a much more complex task. Even though in silico molecular modeling methods could contribute a lot of time and cost-saving by rationally filtering synthetic optimization options, they are employed less widely in this stage of research. In this review, we highlight studies that have successfully used computer-aided SAR analysis in lead optimization and want to showcase sound methodology and easily accessible in silico tools for this purpose.
- Klíčová slova
- Docking, Lead optimization, Molecular modeling, Pharmacophore modeling, Structure-activity relationship,
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
The most widely used QSAR approaches are mainly based on 2D molecular representation which ignores stereoconfiguration and conformational flexibility of compounds. 3D QSAR uses a single conformer of each compound which is difficult to choose reasonably. 4D QSAR uses multiple conformers to overcome the issues of 2D and 3D methods. However, many of existing 4D QSAR models suffer from the necessity to pre-align conformers, while alignment-independent approaches often ignore stereoconfiguration of compounds. In this study we propose a QSAR modeling approach based on transforming chirality-aware 3D pharmacophore descriptors of individual conformers into a set of latent variables representing the whole conformer set of a molecule. This is achieved by clustering together all conformers of all training set compounds. The final representation of a compound is a bit string encoding cluster membership of its conformers. In our study we used Random Forest, but this representation can be used in combination with any machine learning method. We compared this approach with conventional 2D and 3D approaches using multiple data sets and investigated the sensitivity of the approach proposed to tuning parameters: number of conformers and clusters.
The authors would like to add the funding number to the published article [...].
- Publikační typ
- tisková chyba MeSH
Beta-site APP cleaving enzyme1 (BACE1) catalyzes the rate determining step in the generation of Aβ peptide and is widely considered as a potential therapeutic drug target for Alzheimer's disease (AD). Active site of BACE1 contains catalytic aspartic (Asp) dyad and flap. Asp dyad cleaves the substrate amyloid precursor protein with the help of flap. Currently, there are no marketed drugs available against BACE1 and existing inhibitors are mostly pseudopeptide or synthetic derivatives. There is a need to search for a potent inhibitor with natural scaffold interacting with flap and Asp dyad. This study screens the natural database InterBioScreen, followed by three-dimensional (3D) QSAR pharmacophore modeling, mapping, in silico ADME/T predictions to find the potential BACE1 inhibitors. Further, molecular dynamics of selected inhibitors were performed to observe the dynamic structure of protein after ligand binding. All conformations and the residues of binding region were stable but the flap adopted a closed conformation after binding with the ligand. Bond oligosaccharide interacted with the flap as well as catalytic dyad via hydrogen bond throughout the simulation. This led to stabilize the flap in closed conformation and restricted the entry of substrate. Carbohydrates have been earlier used in the treatment of AD because of their low toxicity, high efficiency, good biocompatibility, and easy permeability through the blood-brain barrier. Our finding will be helpful in identify the potential leads to design novel BACE1 inhibitors for AD therapy.
- Klíčová slova
- 3D QSAR pharmacophore modeling, Alzheimer’s disease, Asp dyad, flap, molecular dynamics, oligosaccharide, virtual screening, β-secretase,
- MeSH
- algoritmy MeSH
- aspartátové endopeptidasy antagonisté a inhibitory metabolismus MeSH
- biologické přípravky chemie farmakologie MeSH
- enoxaparin farmakologie MeSH
- heparitinsulfát farmakologie MeSH
- inhibiční koncentrace 50 MeSH
- inhibitory enzymů chemie farmakologie MeSH
- krystalografie rentgenová MeSH
- kvantitativní vztahy mezi strukturou a aktivitou * MeSH
- lidé MeSH
- ligandy MeSH
- oligosacharidy chemie MeSH
- preklinické hodnocení léčiv * MeSH
- sekretasy antagonisté a inhibitory metabolismus MeSH
- simulace molekulární dynamiky * MeSH
- vodíková vazba MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- aspartátové endopeptidasy MeSH
- BACE1 protein, human MeSH Prohlížeč
- biologické přípravky MeSH
- enoxaparin MeSH
- heparitinsulfát MeSH
- inhibitory enzymů MeSH
- ligandy MeSH
- oligosacharidy MeSH
- sekretasy MeSH
Leukotrienes (LTs) are pro-inflammatory lipid mediators derived from arachidonic acid (AA) with roles in inflammatory and allergic diseases. The biosynthesis of LTs is initiated by transfer of AA via the 5-lipoxygenase-activating protein (FLAP) to 5-lipoxygenase (5-LO). FLAP inhibition abolishes LT formation exerting anti-inflammatory effects. The soluble epoxide hydrolase (sEH) converts AA-derived anti-inflammatory epoxyeicosatrienoic acids (EETs) to dihydroxyeicosatetraenoic acids (di-HETEs). Its inhibition consequently also counteracts inflammation. Targeting both LT biosynthesis and the conversion of EETs with a dual inhibitor of FLAP and sEH may represent a novel, powerful anti-inflammatory strategy. We present a pharmacophore-based virtual screening campaign that led to 20 hit compounds of which 4 targeted FLAP and 4 were sEH inhibitors. Among them, the first dual inhibitor for sEH and FLAP was identified, N-[4-(benzothiazol-2-ylmethoxy)-2-methylphenyl]-N'-(3,4-dichlorophenyl)urea with IC50 values of 200 nM in a cell-based FLAP test system and 20 nM for sEH activity in a cell-free assay.
- MeSH
- antiflogistika chemie farmakologie MeSH
- bezbuněčný systém MeSH
- epoxid hydrolasy antagonisté a inhibitory MeSH
- inhibitory enzymů chemie farmakologie MeSH
- inhibitory proteinu aktivujícího 5-lipoxygenasu chemie farmakologie MeSH
- leukotrieny biosyntéza MeSH
- lidé MeSH
- molekulární modely MeSH
- molekulární struktura MeSH
- počítačová simulace MeSH
- preklinické hodnocení léčiv MeSH
- proteiny aktivující 5-lipoxygenasu metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antiflogistika MeSH
- epoxid hydrolasy MeSH
- inhibitory enzymů MeSH
- inhibitory proteinu aktivujícího 5-lipoxygenasu MeSH
- leukotrieny MeSH
- proteiny aktivující 5-lipoxygenasu MeSH
In the constant search for new pharmacological compounds, molecular hybridisation is a well-known technique whereby two or more known pharmacophoric subunits are combined to create a new "hybrid" compound. This hybrid is expected to maintain the characteristics of the original compounds whilst demonstrating improvements to their pharmacological action. Accordingly, we report here a series of molecular hybrid compounds based upon eugenol and chloramphenicol pharmacophores. The hybrid compounds were screened for their in vitro antimicrobial potential against Gram-negative and Gram-positive bacteria and also rapidly growing mycobacteria (RGM). The results highlight that the antimicrobial profiles of the hybrid compounds improve in a very clear fashion when moving through the series. The most prominent results were found when comparing the activity of the hybrid compounds against some of the multidrug-resistant clinical isolates of Pseudomonas aeruginosa, methicillin-resistant clinical isolates of Staphylococcus aureus (MRSA) and clinical isolates of rapidly growing mycobacteria.
- Klíčová slova
- Antimicrobial, Chloramphenicol, Eugenol, Hybridisation, Rapidly growing mycobacteria,
- MeSH
- antibakteriální látky terapeutické užití MeSH
- antiinfekční látky * farmakologie MeSH
- chloramfenikol farmakologie MeSH
- eugenol farmakologie MeSH
- farmakofor MeSH
- methicilin rezistentní Staphylococcus aureus * MeSH
- mikrobiální testy citlivosti MeSH
- Staphylococcus aureus MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- antibakteriální látky MeSH
- antiinfekční látky * MeSH
- chloramfenikol MeSH
- eugenol MeSH
The application of the pharmacophore concept to design new drugs is discussed. The focus is on the application of computer-assisted drug design methods (CADD) in the discovery of new leads.
