A5085408487- Lipid Membrane Structure and Behavior
- Nanoparticle-Based Drug Delivery
- Protein Structure and Dynamics
- RNA Interference and Gene Delivery
- Computational Drug Discovery Methods
- Liver Disease Diagnosis and Treatment
- Monoclonal and Polyclonal Antibodies Research
- Advanced biosensing and bioanalysis techniques
- Cardiovascular Function and Risk Factors
- Machine Learning in Materials Science
- Enzyme Structure and Function
- RNA and protein synthesis mechanisms
- Mass Spectrometry Techniques and Applications
- Virus-based gene therapy research
- Signaling Pathways in Disease
- Immunotherapy and Immune Responses
- Receptor Mechanisms and Signaling
- vaccines and immunoinformatics approaches
- Metabolomics and Mass Spectrometry Studies
- CAR-T cell therapy research
- Surfactants and Colloidal Systems
- Protein Interaction Studies and Fluorescence Analysis
- Trace Elements in Health
- Eicosanoids and Hypertension Pharmacology
- Glycosylation and Glycoproteins Research
Boehringer Ingelheim (Germany)
2019-2025
Czech Academy of Sciences, Institute of Organic Chemistry and Biochemistry
2016-2020
University of Helsinki
2011-2019
Czech Academy of Sciences
2016-2017
Data Harbor (United States)
2015
Savitribai Phule Pune University
2012
Arginine-rich cell-penetrating peptides do not enter cells by directly passing through a lipid membrane; they instead passively vesicles and live inducing membrane multilamellarity fusion. The molecular picture of this penetration mode, which differs qualitatively from the previously proposed direct mechanism, is provided dynamics simulations. kinetics vesicle agglomeration fusion an iconic peptide-nonaarginine-are documented via real-time fluorescence techniques, while induction...
Cholesterol is an important component of all biological membranes as well drug delivery liposomes. We show here that increasing the level cholesterol in a phospholipid membrane decreases surface charge physiological environment. Through molecular dynamics simulation we have shown Na+ ion binding. Complementary experimental ζ – potential measurements decreased with content, indicative reduced charge. Both experiments and simulations been carried out on both saturated...
Despite doxorubicin being commonly used in chemotherapy there still remain significant holes our knowledge regarding its delivery efficacy and an observed resistance mechanism that is postulated to involve the cell membrane. One possible efflux by protein P-gp, which found predominantly cholesterol enriched domains. Thereby, a hypothesis for vulnerability of through P-gp enhanced affinity ordered rich regions plasma Thus, we have studied doxorubicin's interaction with model membranes rich,...
Abstract Key to the fragment optimisation process within drug design is need accurately capture changes in affinity that are associated with a given set of chemical modifications. Due weakly binding nature fragments, this has proven be challenging task, despite recent advancements leveraging experimental and computational methods. In work, we evaluate use Absolute Binding Free Energy (ABFE) calculations guiding decisions, retrospectively calculating free energies for 59 ligands across 4...
Hydrophobins represent an important group of proteins from both a biological and nanotechnological standpoint. They are the means through which filamentous fungi affect their environment to promote growth, properties at interfaces have resulted in numerous applications. In our study we combined protein docking, molecular dynamics simulation, electron cryo-microscopy gain atomistic level insight into surface structure films composed two class II hydrophobins: HFBI HFBII produced by...
The stimulation of the immune system using oncolytic adenoviruses (OAds) has attracted significant interest and several studies suggested that OAds immunogenicity might be important for their efficacy. Therefore, we developed a versatile rapid to adsorb tumor-specific major histocompatibility complex class I (MHC-I) peptides onto viral surface drive response toward tumor epitopes. By studying model epitope SIINFEKL, demonstrated peptide-coated OAd (PeptiCRAd) retains its infectivity cross...
Absolute binding free energies play a crucial role in drug development, particularly as part of the lead discovery process. In recent work, we showed how
PEGylation is an effective mechanism to prolong the bloodstream lifetime, and thus efficacy, of drug delivery liposomes. The through which poly(ethylene glycol) (PEG) increases lifetime is, however, not completely understood. interaction with salt ions found in known play a role this. We have used all-atom molecular dynamics simulation study effect PEGylated lipid density, concentration, KCl CaCl(2) salts addition NaCl. Increasing concentration formulation from 1:18 1:9 molar density...
Adsorption of metal cations onto a cellular membrane changes its properties, such as interactions with charged moieties or the propensity for fusion. It is, however, unclear whether cells can regulate ion adsorption and related functions via locally adjusting their composition. We employed fluorescence techniques computer simulations to determine how presence cholesterol-a key molecule inducing heterogeneity-affects sodium calcium zwitterionic phosphatidylcholine bilayers. found that...
Machine learning offers great promise for fast and accurate binding affinity predictions. However, current models lack robust evaluation fail on tasks encountered in (hit-to-) lead optimisation, such as ranking the of a congeneric series ligands, thereby limiting their application drug discovery. Here, we address these issues by first introducing novel attention-based graph neural network model called AEV-PLIG (atomic environment vector-protein ligand interaction graph). Second, introduce...
Abstract GPR55 is an orphan G protein-coupled receptor (GPCR) and represents a promising drug target for cancer, inflammation, metabolic diseases. The endogenous activation of lipid GPCRs can be solely mediated by membrane components different lipids have been proposed as activators GPR55, such cannabinoids lysophosphatidylinositols. Here, we determine high-resolution cryo-electron microscopy structures the activated in complex with heterotrimeric 13 two structurally diverse ligands:...
Calcium ion is the ubiquitous messenger in cells and plays a key role neuronal signaling fusion of synaptic vesicles. These vesicles are typically ∼20–50 nm diameter, thus their interaction with calcium ions cannot be modeled faithfully conventional flat membrane bilayer setup. Within our newly developed molecular dynamics simulations setup, we characterize here interactions curved interfaces atomistic detail. The present together time-dependent fluorescence shift experiments suggest that...
The colloidal stability, in vitro toxicity, cell association, and vivo pharmacokinetic behavior of liposomes decorated with monomethoxy-poly(ethylene glycol)-lipids (mPEG-lipids) different chemical features were comparatively investigated. Structural differences the mPEG-lipids used study included: (a) surface-anchoring moiety [1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), cholesterol (Chol), cholane (Chln)]; (b) mPEG molecular weight (2 kDa mPEG45 5 mPEG114); (c) shape (linear...
PEGylation has been used successfully to increase the circulation time of drug delivery liposomes by providing an external steric sheath. In all FDA approved PEGylated liposomes, cholesterol is a key component. continuation our previous work we have simulated membrane with added formulation determine effect on structure cholesterol–PEG interaction. We show that, like case for liquid crystalline membrane, PEG enters into lipid bilayer, however, in specific fashion: winds along β face...
Tolerance toward tumor antigens, which are shared by normal tissues, have often limited the efficacy of cancer vaccines. However, wild type epitopes can be tweaked to activate cross-reactive T-cell clones, resulting in antitumor activity. The design these analogs (i.e., heteroclitic peptides) difficult and time-consuming since no automated silico tools available. Hereby we describe development an framework improve selection peptides. Epitope Discovery Improvement System (EDIS) was first...
The enzyme catechol-O-methyltransferase (COMT) has water soluble (S-COMT) and membrane associated (MB-COMT), bitopic, isoforms. Of these MB-COMT is a drug target in relation to the treatment of Parkinson's disease. Using combination computational experimental protocols, we have determined substrate selection mechanism specific MB-COMT. We show: (1) substrates with preferred affinity for over S-COMT orient fashion conducive catalysis from surface (2) binding COMT its cofactor ADOMET induces...
Predicting the costructure of small-molecule ligands and their respective target proteins has been a long-standing problem in drug discovery. For weak binding compounds typically identified fragment-based screening (FBS) campaigns, determination correct site mode is usually done experimentally via X-ray crystallography. many targets pharmaceutical interest, however, establishing an system which allows for sufficient throughput to support discovery project not possible. In this case,...
Machine learning offers a promising approach for fast and accurate binding affin- ity predictions. However, current models often fail to generalise beyond their training data are not robustly evaluated on diverse range of benchmarks, limiting application in drug discovery projects. In this work, we address these issues by intro- ducing novel graph neural network model called AEV-PLIG (Atomic Environment Vector - Protein Ligand Interaction Graph), which encodes protein-ligand interactions via...
Novel cationic agent liposomes performed better<italic>in silico</italic>translating in higher cellular uptake with reduced toxicity.
Liposome-based drug delivery systems composed of DOPE stabilized with cholesteryl hemisuccinate (CHMS) have been proposed as a mechanism pH-triggered release the anionic form (CHSa) is protonated (CHS) at reduced pH; PEGylation known to decrease this pH sensitivity. In manuscript, we set out use molecular dynamics (MD) simulations model all-atom resolution provide insight into why incorporation poly(ethyleneglycol) (PEG) DOPE–CHMS liposomes reduces their sensitivity; also address two...