drug design Dotaz Zobrazit nápovědu
Many enzymes contain tunnels and gates that are essential to their function. Gates reversibly switch between open and closed conformations and thereby control the traffic of small molecules-substrates, products, ions, and solvent molecules-into and out of the enzyme's structure via molecular tunnels. Many transient tunnels and gates undoubtedly remain to be identified, and their functional roles and utility as potential drug targets have received comparatively little attention. Here, we describe a set of general concepts relating to the structural properties, function, and classification of these interesting structural features. In addition, we highlight the potential of enzyme tunnels and gates as targets for the binding of small molecules. The different types of binding that are possible and the potential pharmacological benefits of such targeting are discussed. Twelve examples of ligands bound to the tunnels and/or gates of clinically relevant enzymes are used to illustrate the different binding modes and to explain some new strategies for drug design. Such strategies could potentially help to overcome some of the problems facing medicinal chemists and lead to the discovery of more effective drugs.
- Klíčová slova
- drug binding, drug design, protein gates, protein tunnels, selectivity, specificity,
- MeSH
- cílená molekulární terapie * MeSH
- enzymy metabolismus MeSH
- lidé MeSH
- molekulární modely MeSH
- racionální návrh léčiv MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Názvy látek
- enzymy MeSH
Quantum mechanical (QM) methods have been gaining importance in structure-based drug design where a reliable description of protein-ligand interactions is of utmost significance. However, strategies i. e. QM/MM, fragmentation or semiempirical (SQM) methods had to be pursued to overcome the unfavorable scaling of QM methods. Various SQM-based approaches have significantly contributed to the accuracy of docking and improvement of lead compounds. Parametrizations of SQM and implicit solvent methods in our laboratory have been instrumental to obtain a reliable SQM-based scoring function. The experience gained in its application for activity ranking of ligands binding to tens of protein targets resulted in setting up a faster SQM/COSMO scoring approach, which outperforms standard scoring methods in native pose identification for two dozen protein targets with ten thousand poses. Recently, SQM/COSMO was effectively applied in a proof-of-concept study of enrichment in virtual screening. Due to its superior performance, feasibility and chemical generality, we propose the SQM/COSMO approach as an efficient tool in structure-based drug design.
- Klíčová slova
- in silico drug design, protein-ligand binding, quantum mechanics, semiempirical methods, virtual screening,
- MeSH
- kvantová teorie * MeSH
- ligandy MeSH
- molekulární struktura MeSH
- proteiny chemie MeSH
- racionální návrh léčiv * MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Názvy látek
- ligandy MeSH
- proteiny MeSH
The semiempirical quantum mechanical (SQM) methods used in drug design are commonly parametrized and tested on data sets of systems that may not be representative models for drug-biomolecule interactions in terms of both size and chemical composition. This is addressed here with a new benchmark data set, PLF547, derived from protein-ligand complexes, consisting of complexes of ligands with protein fragments (such as amino-acid side chains), with interaction energies based on MP2-F12 and DLPNO-CCSD(T) calculations. From these, composite benchmark interaction energies are also built for complexes of the ligand with the complete active site of the protein (PLA15 data set). These data sets are used to test multiple SQM methods with corrections for noncovalent interactions; the role of the solvation model in the calculations is tested as well.
- MeSH
- kvantová teorie * MeSH
- léčivé přípravky * MeSH
- ligandy MeSH
- racionální návrh léčiv MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- léčivé přípravky * MeSH
- ligandy MeSH
Monkeypox, or mpox, is a disease that has recently resurfaced and spread across the globe. Despite the availability of an FDA-approved vaccine (JYNNEOS) and an effective drug (tecovirimat), concerns remain over the possible recurrence of a viral pandemic. Like any other virus, mpox virus must overcome the immune system to replicate. Viruses have evolved various strategies to overcome both innate and adaptive immunity. Poxviruses possess an unusual nuclease, poxin, which cleaves 2'-3'-cGAMP, a cyclic dinucleotide, which is an important second messenger in the cGAS-STING signaling pathway. Here, we present the crystal structure of mpox poxin. The structure reveals a conserved, predominantly β-sheet fold and highlights the high conservation of the cGAMP binding site and of the catalytic residues His17, Tyr138, and Lys142. This research suggests that poxin inhibitors could be effective against multiple poxviruses.
- MeSH
- lidé MeSH
- opičí neštovice * MeSH
- Poxviridae * MeSH
- racionální návrh léčiv MeSH
- signální transdukce MeSH
- virus opičích neštovic MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
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
- Názvy látek
- EGFR protein, human MeSH Prohlížeč
- erbB receptory MeSH
- inhibitory proteinkinas MeSH
- ligandy MeSH
Phenolic group in therapeutic drugs can be used for a prodrug modification to overcome various undesirable drug properties that may become pharmacological, pharmaceutical or pharmacokinetic barriers for application. Several strategies have been used in order to overcome the limited bioavailability of phenolic drugs. Classical design represents a nonspecific chemical approach to mask undesirable drug properties, limited bioavailability or chemical instability. Targeted prodrug design represents a new strategy for directed and efficient drug delivery. Particularly, targeting the prodrug to specific enzyme or specific membrane transporter has potential as selective drug delivery system mainly in cancer therapy. The article brings examples of ester, sulphate, carbamate, carbonate, phosphate and ether prodrugs as well as the limitations of these prodrug strategies. Some specific enzyme targets are also presented.
- MeSH
- antitumorózní látky aplikace a dávkování farmakokinetika farmakologie MeSH
- biologická dostupnost MeSH
- fenoly chemie MeSH
- léčivé přípravky aplikace a dávkování metabolismus MeSH
- lidé MeSH
- nádory farmakoterapie patofyziologie MeSH
- prekurzory léčiv MeSH
- racionální návrh léčiv * MeSH
- systémy cílené aplikace léků * MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Názvy látek
- antitumorózní látky MeSH
- fenoly MeSH
- léčivé přípravky MeSH
- prekurzory léčiv 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.
Recent advancements in deep learning and generative models have significantly expanded the applications of virtual screening for drug-like compounds. Here, we introduce a multitarget transformer model, PCMol, that leverages the latent protein embeddings derived from AlphaFold2 as a means of conditioning a de novo generative model on different targets. Incorporating rich protein representations allows the model to capture their structural relationships, enabling the chemical space interpolation of active compounds and target-side generalization to new proteins based on embedding similarities. In this work, we benchmark against other existing target-conditioned transformer models to illustrate the validity of using AlphaFold protein representations over raw amino acid sequences. We show that low-dimensional projections of these protein embeddings cluster appropriately based on target families and that model performance declines when these representations are intentionally corrupted. We also show that the PCMol model generates diverse, potentially active molecules for a wide array of proteins, including those with sparse ligand bioactivity data. The generated compounds display higher similarity known active ligands of held-out targets and have comparable molecular docking scores while maintaining novelty. Additionally, we demonstrate the important role of data augmentation in bolstering the performance of generative models in low-data regimes. Software package and AlphaFold protein embeddings are freely available at https://github.com/CDDLeiden/PCMol.
- MeSH
- konformace proteinů MeSH
- ligandy MeSH
- molekulární modely * MeSH
- proteiny * chemie metabolismus MeSH
- racionální návrh léčiv * MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- ligandy MeSH
- proteiny * MeSH
To solve recurring problems in drug discovery, matched molecular pair (MMP) analysis is used to understand relationships between chemical structure and function. For the MMP analysis of large data sets (>10,000 compounds), available tools lack flexible search and visualization functionality and require computational expertise. Here, we present Matcher, an open-source application for MMP analysis, with novel search algorithms and fully automated querying-to-visualization that requires no programming expertise. Matcher enables unprecedented control over the search and clustering of MMP transformations based on both variable fragment and constant environment structure, which is critical for disentangling relevant and irrelevant data to a given problem. Users can exert such control through a built-in chemical sketcher and with a few mouse clicks can navigate between resulting MMP transformations, statistics, property distribution graphs, and structures with raw experimental data, for confident and accelerated decision making. Matcher can be used with any collection of structure/property data; here, we demonstrate usage with a public ChEMBL data set of about 20,000 small molecules with CYP3A4 and/or hERG inhibition data. Users can reproduce all examples demonstrated herein via unique links within Matcher's interface-a functionality that anyone can use to preserve and share their own analyses. Matcher and all its dependencies are open-source, can be used for free, and are available with containerized deployment from code at https://github.com/Merck/Matcher. Matcher makes large structure/property data sets more transparent than ever before and accelerates the data-driven solution of common problems in drug discovery.
The aim of this review is to outline the recent advances in chitosan molecular modeling, especially its usage as a prodrug or drug in a field of antibacterial, anticarcinogenic and antioxidant activity. Polymeric materials like peptides, polysaccharides and other natural products have recently attracted attention as biodegradabile drug carriers. They can optimize clinical drug application, minimize the undesirable drug properties and improve drug efficiency. They are used for the slow release of effective components as depot forms, to improve membrane permeability, solubility and site-specific targeting. Chitosan is such a prospective cationic polysaccharide which has shown number of functions in many fields, including bio medicinal, pharmaceutical, preservative, microbial and others. This article discusses the structure characteristics of chitosan, a number of factors such as degree of polymerization, level of deacetylation, types of quarternisation, installation of various hydrophilic substituents, metal complexation, and combination with other active agents. Biodegradable, non-toxic and non-allergenic nature of chitosan encourages its potential use as a carrier for drug delivery systems in all above mentioned targets. The use of chitosan prodrug conjugates is aimed at the site-specific transport to the target cells use, for example, a spacer tetrapeptide Gly-Phe-Leu-Gly, promotion of drug incorporation into cells via endocytosis, hybridization or synergism of two types of drugs or a drug with a bioactive carrier. The design of chitosan macromolecule prodrugs is also discussed.
- MeSH
- antibakteriální látky chemie terapeutické užití MeSH
- antioxidancia chemie terapeutické užití MeSH
- antitumorózní látky chemie terapeutické užití MeSH
- chitosan chemie farmakologie terapeutické užití MeSH
- molekulární modely MeSH
- molekulární struktura MeSH
- nosiče léků MeSH
- prekurzory léčiv chemie farmakologie terapeutické užití MeSH
- racionální návrh léčiv MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Názvy látek
- antibakteriální látky MeSH
- antioxidancia MeSH
- antitumorózní látky MeSH
- chitosan MeSH
- nosiče léků MeSH
- prekurzory léčiv MeSH
