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352 Publications visible to you, out of a total of 352
Multiresolution molecular dynamics simulations reveal the interplay between conformational variability and functional interactions in membrane-bound cytochrome 2B4

Abstract (Expand)

Cytochrome P450 2B4 (CYP 2B4) is one of the best characterized CYPs and serves as a key model system for understanding the mechanisms of microsomal class II CYPs, which metabolize most known drugs. The …n drugs. The highly flexible nature of CYP 2B4 is apparent from crystal structures that show the active site with either a wide open or a closed heme binding cavity. Here, we investigated the conformational ensemble of the full-length CYP 2B4 in a phospholipid bilayer, using multiresolution molecular dynamics (MD) simulations. Coarse-grained MD simulations revealed two predominant orientations of CYP 2B4's globular domain with respect to the bilayer. Their refinement by atomistic resolution MD showed adaptation of the enzyme's interaction with the lipid bilayer, leading to open configurations that facilitate ligand access to the heme binding cavity. CAVER analysis of enzyme tunnels, AquaDuct analysis of water routes, and Random Acceleration Molecular Dynamics simulations of ligand dissociation support the conformation-dependent passage of molecules between the active site and the protein surroundings. Furthermore, simulation of the re-entry of the inhibitor bifonazole into the open conformation of CYP 2B4 resulted in binding at a transient hydrophobic pocket within the active site cavity that may play a role in substrate binding or allosteric regulation. Together, these results show how the open conformation of CYP 2B4 facilitates binding of substrates from and release of products to the membrane, whereas the closed conformation prolongs the residence time of substrates or inhibitors and selectively allows the passage of smaller reactants via the solvent and water channels.

Authors: Sungho Bosco Han, Jonathan Teuffel, Goutam Mukherjee, Rebecca C. Wade

Date Published: 18th Apr 2024

Publication Type: Journal

Myotubularin-related-protein-7 inhibits mutant (G12V) K-RAS by direct interaction

Abstract

Not specified

Authors: Philip Weidner, Daniel Saar, Michaela Söhn, Torsten Schroeder, Yanxiong Yu, Frank G. Zöllner, Norbert Ponelies, Xiaobo Zhou, André Zwicky, Florian N. Rohrbacher, Vijaya R. Pattabiraman, Matthias Tanriver, Alexander Bauer, Hazem Ahmed, Simon M. Ametamey, Philipp Riffel, Rony Seger, Jeffrey W. Bode, Rebecca C. Wade, Matthias P.A. Ebert, Birthe B. Kragelund, Elke Burgermeister

Date Published: 1st Apr 2024

Publication Type: Journal

The role of heparin in spike SARS-CoV-2 infection: From a model for heparan sulfates to a starting structure for antivirals

Abstract

Not specified

Authors: Giulia Paiardi, Maria Milanesi, Matheus Ferraz, Liv Zimmermann, Chiara Urbinati, Pasqua Oreste, Francesca Caccuri, Petr Chlanda, Marco Rusnati, Rebecca C. Wade

Date Published: 1st Feb 2024

Publication Type: Journal

A community effort in SARS‐CoV‐2 drug discovery

Abstract (Expand)

Abstract The COVID‐19 pandemic continues to pose a substantial threat to human lives and is likely to do so for years to come. Despite the availability of vaccines, searching for efficient small‐molecule …r efficient small‐molecule drugs that are widely available, including in low‐ and middle‐income countries, is an ongoing challenge. In this work, we report the results of an open science community effort, the “Billion molecules against COVID‐19 challenge”, to identify small‐molecule inhibitors against SARS‐CoV‐2 or relevant human receptors. Participating teams used a wide variety of computational methods to screen a minimum of 1 billion virtual molecules against 6 protein targets. Overall, 31 teams participated, and they suggested a total of 639,024 molecules, which were subsequently ranked to find ‘consensus compounds’. The organizing team coordinated with various contract research organizations (CROs) and collaborating institutions to synthesize and test 878 compounds for biological activity against proteases (Nsp5, Nsp3, TMPRSS2), nucleocapsid N, RdRP (only the Nsp12 domain), and (alpha) spike protein S. Overall, 27 compounds with weak inhibition/binding were experimentally identified by binding‐, cleavage‐, and/or viral suppression assays and are presented here. Open science approaches such as the one presented here contribute to the knowledge base of future drug discovery efforts in finding better SARS‐CoV‐2 treatments.

Authors: Johannes Schimunek, Philipp Seidl, Katarina Elez, Tim Hempel, Tuan Le, Frank Noé, Simon Olsson, Lluís Raich, Robin Winter, Hatice Gokcan, Filipp Gusev, Evgeny M. Gutkin, Olexandr Isayev, Maria G. Kurnikova, Chamali H. Narangoda, Roman Zubatyuk, Ivan P. Bosko, Konstantin V. Furs, Anna D. Karpenko, Yury V. Kornoushenko, Mikita Shuldau, Artsemi Yushkevich, Mohammed Benabderrahmane, Patrick Bousquet-Melou, Ronan Bureau, Beatrice Charton, Bertrand Cirou, Gérard Gil, William J. Allen, Suman Sirimulla, Stanley Watowich, Nick Antonopoulos, Nikolaos Epitropakis, Agamemnon Krasoulis, Vassilis Pitsikalis, Stavros Theodorakis, Igor Kozlovskii, Anton Maliutin, Alexander Medvedev, Petr Popov, Mark Zaretckii, Hamid Eghbal-zadeh, Christina Halmich, Sepp Hochreiter, Andreas Mayr, Peter Ruch, Michael Widrich, Francois Berenger, Ashutosh Kumar, Yoshihiro Yamanishi, Kam Zhang, Emmanuel Bengio, Yoshua Bengio, Moksh Jain, Maksym Korablyov, Cheng-Hao Liu, Marcous Gilles, Enrico Glaab, Kelly Barnsley, Suhasini M. Iyengar, Mary Jo Ondrechen, V. Joachim Haupt, Florian Kaiser, Michael Schroeder, Luisa Pugliese, Simone Albani, Christina Athanasiou, Andrea Beccari, Paolo Carloni, Giulia D'Arrigo, Eleonora Gianquinto, Jonas Goßen, Anton Hanke, Benjamin P. Joseph, Daria B. Kokh, Sandra Kovachka, Candida Manelfi, Goutam Mukherjee, Abraham Muñiz-Chicharro, Francesco Musiani, Ariane Nunes-Alves, Giulia Paiardi, Giulia Rossetti, S. Kashif Sadiq, Francesca Spyrakis, Carmine Talarico, Alexandros Tsengenes, Rebecca Wade, Conner Copeland, Jeremiah Gaiser, Daniel R. Olson, Amitava Roy, Vishwesh Venkatraman, Travis J. Wheeler, Haribabu Arthanari, Klara Blaschitz, Marco Cespugli, Vedat Durmaz, Konstantin Fackeldey, Patrick D. Fischer, Christoph Gorgulla, Christian Gruber, Karl Gruber, Michael Hetmann, Jamie E. Kinney, Krishna M. Padmanabha Das, Shreya Pandita, Amit Singh, Georg Steinkellner, Guilhem Tesseyre, Gerhard Wagner, Zi-Fu Wang, Ryan J. Yust, Dmitry S. Druzhilovskiy, Dmitry Filimonov, Pavel V. Pogodin, Vladimir Poroikov, Anastassia V. Rudik, Leonid A. Stolbov, Alexander V. Veselovsky, Maria De Rosa, Giada De Simone, Maria R. Gulotta, Jessica Lombino, Nedra Mekni, Ugo Perricone, Arturo Casini, Amanda Embree, D. Benjamin Gordon, David Lei, Katelin Pratt, Christopher A. Voigt, Kuang-Yu Chen, Yves Jacob, Tim Krischuns, Pierre Lafaye, Agnès Zettor, M. Luis Rodríguez, Kris M. White, Daren Fearon, Frank von Delft, Martin A. Walsh, Dragos Horvath, Charles L. Brooks, Babak Falsafi, Bryan Ford, Adolfo García-Sastre, Sang Yup Lee, Nadia Naffakh, Alexandre Varnek, Guenter Klambauer, Thomas M. Hermans

Date Published: 2024

Publication Type: Journal

An engineered variant of MECR reductase reveals indispensability of long-chain acyl-ACPs for mitochondrial respiration

Abstract (Expand)

Abstract Mitochondrial fatty acid synthesis (mtFAS) is essential for respiratory function. MtFAS generates the octanoic acid precursor for lipoic acid synthesis, but the role of longer fatty acid …thesis, but the role of longer fatty acid products has remained unclear. The structurally well-characterized component of mtFAS, human 2E -enoyl-ACP reductase (MECR) rescues respiratory growth and lipoylation defects of a Saccharomyces cerevisiae Δ etr1 strain lacking native mtFAS enoyl reductase. To address the role of longer products of mtFAS, we employed in silico molecular simulations to design a MECR variant with a shortened substrate binding cavity. Our in vitro and in vivo analyses indicate that the MECR G165Q variant allows synthesis of octanoyl groups but not long chain fatty acids, confirming the validity of our computational approach to engineer substrate length specificity. Furthermore, our data imply that restoring lipoylation in mtFAS deficient yeast strains is not sufficient to support respiration and that long chain acyl-ACPs generated by mtFAS are required for mitochondrial function.

Authors: M. Tanvir Rahman, M. Kristian Koski, Joanna Panecka-Hofman, Werner Schmitz, Alexander J. Kastaniotis, Rebecca C. Wade, Rik K. Wierenga, J. Kalervo Hiltunen, Kaija J. Autio

Date Published: 1st Dec 2023

Publication Type: Journal

Comparative analysis of drug-salt-polymer interactions by experiment and molecular simulation improves biopharmaceutical performance

Abstract (Expand)

Abstract The propensity of poorly water-soluble drugs to aggregate at supersaturation impedes their bioavailability. Supersaturated amorphous drug-salt-polymer systems provide an emergent approach to …r systems provide an emergent approach to this problem. However, the effects of polymers on drug-drug interactions in aqueous phase are largely unexplored and it is unclear how to choose an optimal salt-polymer combination for a particular drug. Here, we describe a comparative experimental and computational characterization of amorphous solid dispersions containing the drug celecoxib, and a polymer, polyvinylpyrrolidone vinyl acetate (PVP-VA) or hydroxypropyl methylcellulose acetate succinate, with or without Na + /K + salts. Classical models for drug-polymer interactions fail to identify the best drug-salt-polymer combination. In contrast, more stable drug-polymer interaction energies computed from molecular dynamics simulations correlate with prolonged stability of supersaturated amorphous drug-salt-polymer systems, along with better dissolution and pharmacokinetic profiles. The celecoxib-salt-PVP-VA formulations exhibit excellent biopharmaceutical performance, offering the prospect of a low-dosage regimen for this widely used anti-inflammatory, thereby increasing cost-effectiveness, and reducing side-effects.

Authors: Sumit Mukesh, Goutam Mukherjee, Ridhima Singh, Nathan Steenbuck, Carolina Demidova, Prachi Joshi, Abhay T. Sangamwar, Rebecca C. Wade

Date Published: 1st Dec 2023

Publication Type: Journal

Wird KI neue Medikamente gegen Herzkrankheiten hervorbringen?

Abstract (Expand)

Zusammenfassung Angesichts der umwälzenden Auswirkungen, die künstliche Intelligenz (KI) auf Wissenschaft, Medizin und darüber hinaus hat, betrachten wir hier das Potenzial von KI für die Entdeckung …enzial von KI für die Entdeckung neuer Medikamente gegen Herzkrankheiten. Wir definieren KI im weitesten Sinne als den Einsatz von maschinellem Lernen, einschließlich Statistik und Deep Learning, um Muster in Datensätzen zu erkennen, die für Vorhersagen genutzt werden können. Jüngste Durchbrüche in der Fähigkeit, sehr große Datenmengen zu berücksichtigen, haben einen Boom in der KI-gestützten Arzneimittelentdeckung sowohl in der Wissenschaft als auch in der Industrie ausgelöst. Viele neue Unternehmen verfügen bereits über Arzneimittel-Pipelines, die bis in die klinische Erprobung reichen, aber noch keine Medikamente gegen Herzkrankheiten enthalten. Wir beschreiben hier den Einsatz von KI für die Entdeckung von niedermolekularen Medikamenten und Biologika, einschließlich therapeutischer Peptide, sowie für die Vorhersage von Wirkungen wie Kardiotoxizität. Der konzertierte Einsatz von KI zusammen mit physikbasierten Simulationen und experimentellen Rückkopplungsschleifen wird notwendig sein, um das Potenzial der KI für die Arzneimittelentdeckung und die Entwicklung von Präzisionsarzneimitteln für Herzkrankheiten voll auszuschöpfen.

Authors: Manuel Glaser, Julia Ritterhof, Patrick Most, Rebecca C. Wade

Date Published: 20th Nov 2023

Publication Type: Journal

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