struc2drug seminar
Drug design is a complex and lengthly process that can only yield successful results using a plethora of different experimental and computational methods. Many researchers work in Berlin at universities, research facilities and industry in the field of drug design or in neighboring disciplines.
struc2drug is a bimonthly seminar series promoting the exchange between researchers in the interdisciplinary field of structural biology and drug development in Berlin.
With this seminar, we want to
- bring together researchers from diverse disciplines of structural biology and drug design
- learn about different steps and methods involved in drug development
- create an interdisciplinary environment to think about upcoming challenges and possible solution
Figure: The struc2drug logo
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April 7, 2022 · 16:00-17:00 (CET)
Structure and activation of ion channels probed by cryo-electron microscopy (cryo-EM)
Mikhail Kudryashev & Vasilii Mikirtumov (Kudryashev lab, Max Delbrück Center for Molecular Medicine, Berlin)
The Kudryashev group aims at detailed understanding of the activation sequence of ion channels with the use of cryo-EM. The group focuses in particular on the effects of native lipid composition on the structure and function of the receptor.
Serotonin receptor 5-HT3 is a pentameric serotonin-gated ion channel located in central and peripheral nervous systems. It plays an important role in the regulation of electrical activity of neurons and can be targeted for numerous medical purposes such as pain, addiction and psychiatric disorders. Mikhail Kudryashev will demonstrate structural analysis of the activation of the receptor for which his group performed by high-resolution single particle cryo electron microscopy. Furthermore, he will give a perspective on structural analysis of ion channels in native membranes without purification by cryo electron tomography.
Ryanodine receptor isoform 1 (RyR1) is a calcium release channel predominantly expressed in skeletal muscle cells where it plays a key role in excitation-contraction coupling. RyR1 was extensively studied by single particle analysis cryo-electron microscopy (SPA cryo-EM) and the activation mechanism was proposed. However, the results were obtained in vitro on the detergent-solubilized receptor and require validation. Vasilii Mikirtumov will present preliminary results that show, by cryo-electron tomography and subtomogram averaging, it is possible to achieve resolutions allowing atomic model building, making it possible to investigate RyR1 gating mechanism in situ.
Check out our previous seminars
February 24, 2022 · 15:00-16:00 (CET)
Different drug targets require different computational approaches
Ariane Nunes Alves (TU Berlin/UniSysCat, Berlin) & David Machalz (Nuvisan ICB GmbH, Berlin)
It is well-known that the structure of protein binding pockets strongly influences small-molecule ligand binding. The peculiarity of many proteins or protein families, however, often demands a tailored approach. This is particularly in cases where key information is missing in well-studied targets or where the natural ligand is unknown or poorly characterized, such as in ‘orphaned’ proteins.
Ariane Nunes Alves presents a structural rationale for kinetic selectivity between two closely related kinases, focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (PYK2). Molecular dynamics simulations, in combination with τ-Random Accelerated Molecular Dynamics (τ-RAMD), were used to characterize inhibitor-kinase residence times. Simulation data, which was well-correlated by experiment, was used to explain why some inhibitors have long residence times when bound to FAK, but not when bound to PYK2, and revealed mechanistic insights of factors modulating residence times. This has implications for the design of inhibitors for both proteins where inhibition of FAK is insufficient to prevent signaling due to the compensatory activity of PYK2.
Drug-metabolism related cytochrome P450 enzymes (CYPs) have been extensively studied. However, other CYPs remain under-studied, such as the case in a promising breast cancer target, CYP4Z1. This enzyme is over-expressed in breast cancers and correlated with tumor progression but is not yet addressed by potent small molecule inhibitors. David Machalz and collaborators used an in silico/in vitro structure-based design pipeline to discover a potent inhibitor of the orphaned CYP4Z1, combining modeling and mutagenesis studies followed by a virtual screening campaign. Screening hits were confirmed by experiment, including the drug ozagrel and a new inhibitor, the binding of the latter rationalized by quantum chemistry and extensive molecular dynamics simulations. This new pharmacological tool will benefit future studies on the physiological and pathophysiological role of CYP4Z1, leading to new therapeutic approaches in targeting the enzyme.
December 9, 2021 (online)
Deciphering interaction profiles with molecular dynamics simulations
Guillermo Pérez Hernández (Charité, Berlin) & Tim Hempel (FU, Berlin)
Molecular Dynamics (MD) is an established simulation method that yields atomic-level detail, giving insights into molecular processes at arbitrary time resolutions. Abstracting useful information from MD simulations, however, is a different story, in particular for drug development.
Guillermo: Molecular structures in motion tell a story that is sometimes hard to understand. From visual inspection to highly automated statistical analysis, different approaches yield different types of information. When are atomic-level details relevant, when are they anecdotal? Are we better off with ensembles and/or macrostates? Do simple correlations suffice? When do we use existing tools and when do we adapt new ones? I will try to provide some answers to these questions by presenting some work on different GPCR-systems.
Tim: In an effort to re-purpose approved drugs against COVID, we investigate the molecular inhibition mechanism of TMPRSS2, a SARS-CoV-2 spike protein activator. Through molecular dynamics simulations and Markov modeling, the binding process of the drugs camostat and nafamostat to TMPRSS2 is described in atomistic detail. We find that nafamostat has a higher Michaelis complex population than camostat, explaining the potency differences measured in our in-vitro assays. This mechanistic understanding is used to suggest a novel drug combination with late stage drug candidate otamixaban.
November 11, 2021 (online)
Development and application of high throughput screening
Saif Mohd (MDC, Berlin) & Theresa Melder (MDC, Berlin)
Saif is working on dynamin superfamily of proteins with focus on EHDs. This family consists of mechano-chemical proteins driven by GTP/ATP hydrolysis. His aim is to find inhibitor molecules via high throughput screening and to characterize them structurally and functionally.
Teresa develops a novel proteomic screening platform to explore the target landscape of bioactive compounds. Using unspecific UV-X-linking, drug-like substances are immobilized simultanously on functionalized cellulose membranes in an undirected manner and without any prior modification of the compounds being required. The constructed drug microarray is used to pull down interacting proteins from a whole cell extract in an affinity purification mass spectrometry (AP-MS) approach to identify specific targets.
July 15, 2021 (online)
Computational tools guiding drug discovery for ion channels and kinases
David Mauricio Ramírez Sánchez (Universidad Autónoma de Chile) & Dominique Sydow (Charité, Berlin)
This session is getting more computational again! We will discuss computational strategies guiding drug discovery for two important drug targets: ion channels and kinases.
David Mauricio Ramírez Sánchez will talk about two pore domain TASK channels linked to breast cancer, sleep apnea and atrial fibrillation.
Guided by the molecular basis of TASK1 and TASK3 channel modulation by known drugs, his group has designed new compounds using pharmacophore-based virtual screening. The best candidates are now optimized using medicinal chemistry.
Dominique Sydow, PhD student from the Volkamer Lab, will show how the structural information of kinase pockets can be encoded computationally and used to understand and predict (dis)similarities in this highly conserved protein class. These similarities can guide polypharmacology, off-target, and repurposing studies. Dominique will also shortly promote the TeachOpenCADD platform for everyone who is interested in learning Python programming in the context of cheminformatics and structural bioinformatics.
March 11, 2021 (online)
From ternary complex formation to target degradation - PROTACs profiling
Ulrike Scheib (Nuvisan ICB GmbH, Berlin) & David Schwefel (Charité, Berlin)
Ulrike Scheib will talk about biochemical and biophysical assays that are used to follow the key steps of proteolysis targeting chimeras (PROTACs).
In the second talk, David Schwefel will focus on the structural biology of multi-subunit ubiquitin ligases and targeted protein degradation.
January 14, 2021 (online)
Unravelling Molecular Mechanisms
Jens von Kries (FMP, Berlin) & Saeid Abdolvand (FMP, Berlin)
Jens von Kries will present the FMP Screening Unit, a high throughput technology platform for the screening of compound libraries and genome-wide RNA-interference. The unit manages the ChemBioNet screening collection, which includes 20,000 compounds, and is shared with different partners within Europe.
Saeid Abdolvand will talk about his MD simulations of NaK-based AMPA receptor pore mimics in the presence of different mono- and divalent cations. These results provide insights into the different properties of selectivity filters and help to understand the mechanism of permeation in NaK channels and AMPA receptors.
November 19, 2020 (online)
Best Practices in Wet and Dry Lab
Matthew Kraushar (MPI Mol. Gen., Berlin) & Jaime Rodríguez-Guerra (Charité, Berlin / MSKCC, NYC)
In this session, we have the pleasure to listen to Matthew Kraushar and Jaime Rodríguez-Guerra talking about their tips on how to organize your life science project.
Matthew will talk about his experience designing and conducting large interdisciplinary biochemical projects from their birth at the bench to death in pubmed. He will present tips on early planning and sustainable organizational tools, including ways to communicate with collaboration partners.
Jaime will speak about how to plan and execute of a computational project with a focus on best practices in software development for maintainable, reproducible and understandable code.
September 9, 2020 (online)
Biomimetic and Stimuli-Responsive Materials for Biomedical Applications
Daniel Klinger (FU, Berlin) & Gregor Fuhrmann (HIPS, Saarbrücken)
Efficient delivery of therapeutics not only requires (nano)carriers to host and release drugs of often limited solubility, but also to address the complex structures of challenging biological barriers. Since this complexity prevents the utilization of a one-fits-all system, different (colloidal) carrier systems are being tailored to specific therapeutic needs. Among such delivery vehicles, this talk will focus on the potential of synthetic polymeric nanogels (NGs) and natural extracellular vesicles (EVs) as complementary approaches.
Daniel Klinger will present an overview of the research in the Klinger group where they combine different length scales in the synthetic design of stimuli-responsive NGs. He will give examples on how to adjust the carrier properties to deliver insoluble drugs, address challenging bio-barriers (e.g. skin), and target current threats (e.g. antimicrobial resistance). In addition, fundamental investigations to examine the potential of utilizing colloidal shape change as new targeting concept will be discussed.
Gregor Fuhrmann will present some of the recent efforts to better understand the biological role of EVs in infection and inflammation. He will provide an insight into the isolation and characterization of EVs and explain their potential loading with model compounds, from small molecule drugs to larger biomacromolecules. Moreover, he will present recent examples of combining EVs with novel biomaterial development, important foundations for their advanced biomedical development.
July 23, 2020 (online)
Nanobodies in Structural Biology and Therapy
Magdalena Schacherl (Charité, Berlin) & Amal Hassan (Charité, Berlin)
Nanobodies are versatile tools for structural biology and promising next-generation biodrugs. In this seminar, we will hear two talks on how the production and usage of nanobodies can facilitate protein structure determination and drug discovery. First, Magdalena Schacherl will introduce nanobodies and explain their use for structural biology research as well as their potential and application as therapeutics. Second, Amal Hassan will present her complex structure of the specific nanobody Nb11 with Gelsolin (GSN), a soluble protein responsible for a familial degenerative disease (AGel amyloidosis), solved at 1.9 Å resolution. This structural information, together with biochemical and biophysical studies, helped to decipher the pathological mechanism of a GSN disease-mutant.
January 16, 2020
Computational Chemistry in Industry
Jérémie Mortier (Bayer, Berlin) & Floriane Montanari (Bayer, Berlin)
Computational methods are employed in numerous ways in early drug development. In this seminar, we present two examples of how such methods are applied at Bayer to develop novel drugs. First, Jérémie Mortier will present an early synergistic research project applying computational molecular design to medicinal chemistry, in order to find drugs for KRAS. Since the discovery of the druggable allosteric binding site containing the G12C mutation, KRAS has attracted a lot of attention in oncology research and is now one of the most-studied anticancer targets. In the second talk, Floriane Montanari will explain how pharmacokinetic properties are predicted as part of the routine toolbox at Bayer. She discusses the continuous and reversible representation of compounds as SMILES and the application of deep learning methods to effectively predict physico-chemical properties of compounds in a multitask fashion.
November 14, 2019
Mechanistic Insights in GPCR Signal Transduction
Martha Sommer (Charité, Berlin) & Marcel Bermudez (FU, Berlin)
The importance of G protein-coupled receptor (GPCR) signal transduction research for medicine and human health cannot be overstated. While the field has undergone a revolution of understanding thanks to many technical advancements, GPCR signal transduction as a whole is not fully understood. Notably, potentially misleading paradigms regarding the complexities of GPCR signal transduction must be re-evaluated. In this seminar, we will present two research perspectives on GPCR signal transduction: 1) Ligand-dependent modulation of GPCR activity, including phenomena like partial agonism and biased signaling, and 2) Revisioning how GPCRs recruit, activate and bind their regulatory arrestin proteins. The seminar will conclude with a brief introduction of ERNEST, an EU-funded COST Action (consortium) focused on a holistic understanding of GPCR signal transduction and tackling the unresolved issues in the field.
September 9, 2019
Ribosomal Biogenesis - a New Target for Antibiotics
Rainer Nikolay (Charité, Berlin) & Theresa Noonan (FU, Berlin)
Ribosome Biogenesis: First, we will give an introduction how ribosomal subunits are produced by bacterial cells in a process known as ribosome biogenesis. During this process, ribosomal subunits are assembled in a stepwise manner. Highly resolved structural snapshots of intermediate states occurring along this pathway are available for Computer-aided Drug Design. Compounds with Antibiotic Potential: Furthermore, we will present our approach involving the structure based computational search for compounds interfering with the biogenesis of bacterial ribosomes. We will introduce some methods used in Computer-aided Drug Design, and describe how we used these along the journey from identifying suitable protein targets to identifying potential hits.
July 11, 2019
Flyin’ high - Mass Spectrometry, GPCRs and Recreational Drugs
Dennis Kwiatkowski (Charité, Berlin) & Nicolas Heyder (Charité, Berlin)
Why scientist needed LSD and THC to understand GPCRs: Structural breakthroughs in GPCR structural biology are based on the usage of high affinity ligands. Recent advances in structure determination have accumulated in a wave of GPCR structures. We would like you to be a part of a joined excursion through the scientific usage of recreational drugs.
May 9, 2019
Structure Elucidation: X-ray Crystallography & Cryo Electron Microscopy
Sasa Petrovic (MDC, Berlin) & Ferdinand Krupp (Charité, Berlin)
Structural determination is an important step during drug development, allowing the characterization of target proteins, protein-ligand complexes and forming the basis for CADD methods. In this lecture, we will introduce two major methods and discuss their advantages, disadvantages and complementarity. In the first part, X-ray crystallography is presented as the major method to solve protein structures in a high-throughput manner. In the second part, cryo electron microscopy is highlighted, which is used to elucidate structures of large and flexible biomolecules.
March 14, 2019
Finding Small Organic Molecules - From Synthesis to In Silico Screening
Yelena Mostinski (FMP, Berlin) & Marcel Bermudez (FU, Berlin)
Small organic molecules (SOMs) represent by far the main group of pharmaceuticals and are of utmost importance as tools for pharma- cological studies and structural biology. In this lecture, we will discuss the relevance of SOMs from two perspectives. In the first part, we highlight the role of synthesis-driven approaches for the identification of primary candidates, target identification, hit-to-lead and lead optimization. The second part will focus on three-dimensional pharmacophores as a computational approach to discover novel SOMs and mechanistically understand their bioactivity.
January 10, 2019
Drug Development: Past, Present & Future
Ferdinand Krupp (Charité, Berlin) & Dominique Sydow (Charité, Berlin)
The first use of drugs for medical and recreational reasons reaches back to the roots of humans. In this first talk of our seminar series struc2drug, we will give a brief overview of the usage of healing substances ranging from ancient Egypt, over the first identification of active compounds in the 18th century to modern drug discovery strategies. We will introduce the main steps of drug development, including computational and experimental methods, which will serve as topics for future talks in this seminar series. Additionally, we invite you to discuss with us your expectations and interests regarding topics and methods to be covered.