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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

Modeling of mechanistic effects of neurotrophin modulators

Abstract (Expand)

Neurotrophins (NTs) are growth factors that are expressed in the central and peripheral nervous systems. They are implicated in different phases of the development and maintenance of the nervous system … and they can regulate neuronal survival, development, function, plasticity, as well as neuronal apoptosis. NTs can be used as therapeutics for the treatment of neurodegenerative disorders. However, their poor pharmacokinetic properties and their invasive administration to patients renders them inefficient for use as pharmaceuticals. A solution to this can be offered by small molecule NT mimetics, which can elicit NT mechanisms through binding to NT receptors, which are transmembrane (TM) glycoproteins. The mechanism of activation of NT receptors remains elusive and thus, in this thesis, I have investigated the mechanism of action of NT receptors and mimetics through molecular modeling and molecular dynamics (MD) simulations. I modeled and simulated the glycosylated state of the full extracellular (EC) domains of Tropomyosin receptor kinases A and B (TrkA, TrkB) NT receptors, which revealed that the glycans can shield the accessible surface area of the receptors and participate in the contact area between receptor and NT. Most importantly, glycosylation promoted the extended conformations of the EC domains, which might facilitate NT binding. Then, I performed coarse-grained MD simulations to study the possible arrangements of the TM helical homodimers of TrkA and TrkB receptors in micelles. The results revealed arrangements that could correspond to the active state of the receptors, while metadynamics simulations indicated a stronger binding for the TrkA helices by 10 kJ/mol compared to TrkB. Next, I modeled the full-length structures of the TrkA and TrkB receptors in their homodimeric, glycosylated state bound to their NTs. I embedded the receptors in a realistic model of a neuronal asymmetric membrane. I verified the proper behavior of the membrane and proteins with smaller systems comprising of the TM and intracellular monomers of the receptors. These test simulations revealed interactions between positively charged residues of the kinase domain of TrkA with negatively charged lipids of the inner leaflet of the membrane. These interactions were also formed in the full-length system, and they might stabilize the two kinase domains of the receptor dimer in an orientation that promotes activation, even though the kinase domains were not activated during the simulations. Also, in the full-length systems, the EC domains approached and lay down on the neuronal membrane, while interacting with membrane lipids, such as gangliosides, which are able to activate the NT receptors. Finally, I investigated the binding of small-molecule NT mimetics to the EC and TM domains of TrkA and TrkB receptors, with molecular docking and MD simulations. While plausible poses were 8 obtained, they were not able to explain the selectivity of the compounds for the receptors and the simulations showed that binding was weak. Due to the cholesterol core of the NT mimetics, I tested the ability of the compounds to enter the cell membrane with MD simulations. The compounds were able to spontaneously penetrate the membranes, indicating that their binding site could also lie in the TM region of the receptors. However, simulations with the compounds bound or close to the TM helices in the membrane environment, showed no specific binding. Further experimental exploration of the binding mechanism of these compounds is required. Overall, this thesis sheds light on the dynamic behavior of TrkA and TrkB NT receptors in membranes and the mechanistic insights provide a basis for future studies to develop NT mimetics.

Author: Christina Athanasiou

Date Published: 30th Oct 2023

Publication Type: Doctoral Thesis

Scaling Protein–Water Interactions in the Martini 3 Coarse-Grained Force Field to Simulate Transmembrane Helix Dimers in Different Lipid Environments

Abstract

Not specified

Authors: Ainara Claveras Cabezudo, Christina Athanasiou, Alexandros Tsengenes, Rebecca C. Wade

Date Published: 11th Apr 2023

Publication Type: Journal

Multiscale molecular simulations to investigate adenylyl cyclase‐based signaling in the brain

Abstract (Expand)

Abstract Adenylyl cyclases (ACs) play a key role in many signaling cascades. ACs catalyze the production of cyclic AMP from ATP and this function is stimulated or inhibited by the binding of their …ed by the binding of their cognate stimulatory or inhibitory Gα subunits, respectively. Here we used simulation tools to uncover the molecular and subcellular mechanisms of AC function, with a focus on the AC5 isoform, extensively studied experimentally. First, quantum mechanical/molecular mechanical free energy simulations were used to investigate the enzymatic reaction and its changes upon point mutations. Next, molecular dynamics simulations were employed to assess the catalytic state in the presence or absence of Gα subunits. This led to the identification of an inactive state of the enzyme that is present whenever an inhibitory Gα is associated, independent of the presence of a stimulatory Gα. In addition, the use of coevolution‐guided multiscale simulations revealed that the binding of Gα subunits reshapes the free‐energy landscape of the AC5 enzyme by following the classical population‐shift paradigm. Finally, Brownian dynamics simulations provided forward rate constants for the binding of Gα subunits to AC5, consistent with the ability of the protein to perform coincidence detection effectively. Our calculations also pointed to strong similarities between AC5 and other AC isoforms, including AC1 and AC6. Findings from the molecular simulations were used along with experimental data as constraints for systems biology modeling of a specific AC5‐triggered neuronal cascade to investigate how the dynamics of downstream signaling depend on initial receptor activation. This article is categorized under: Structure and Mechanism > Computational Biochemistry and Biophysics Molecular and Statistical Mechanics > Molecular Dynamics and Monte‐Carlo Methods Software > Molecular Modeling

Authors: Siri C. van Keulen, Juliette Martin, Francesco Colizzi, Elisa Frezza, Daniel Trpevski, Nuria Cirauqui Diaz, Pietro Vidossich, Ursula Rothlisberger, Jeanette Hellgren Kotaleski, Rebecca C. Wade, Paolo Carloni

Date Published: 2023

Publication Type: Journal

Identification of antiparasitic drug targets using a multi-omics workflow in the acanthocephalan model

Abstract (Expand)

Abstract Background With the expansion of animal production, parasitic helminths are gaining increasing economic importance. However, application of several established deworming agents can harm treated …er, application of several established deworming agents can harm treated hosts and environment due to their low specificity. Furthermore, the number of parasite strains showing resistance is growing, while hardly any new anthelminthics are being developed. Here, we present a bioinformatics workflow designed to reduce the time and cost in the development of new strategies against parasites. The workflow includes quantitative transcriptomics and proteomics, 3D structure modeling, binding site prediction, and virtual ligand screening. Its use is demonstrated for Acanthocephala (thorny-headed worms) which are an emerging pest in fish aquaculture. We included three acanthocephalans ( Pomphorhynchus laevis, Neoechinorhynchus agilis , Neoechinorhynchus buttnerae ) from four fish species (common barbel, European eel, thinlip mullet, tambaqui). Results The workflow led to eleven highly specific candidate targets in acanthocephalans. The candidate targets showed constant and elevated transcript abundances across definitive and accidental hosts, suggestive of constitutive expression and functional importance. Hence, the impairment of the corresponding proteins should enable specific and effective killing of acanthocephalans. Candidate targets were also highly abundant in the acanthocephalan body wall, through which these gutless parasites take up nutrients. Thus, the candidate targets are likely to be accessible to compounds that are orally administered to fish. Virtual ligand screening led to ten compounds, of which five appeared to be especially promising according to ADMET, GHS, and RO5 criteria: tadalafil, pranazepide, piketoprofen, heliomycin, and the nematicide derquantel. Conclusions The combination of genomics, transcriptomics, and proteomics led to a broadly applicable procedure for the cost- and time-saving identification of candidate target proteins in parasites. The ligands predicted to bind can now be further evaluated for their suitability in the control of acanthocephalans. The workflow has been deposited at the Galaxy workflow server under the URL tinyurl.com/yx72rda7 .

Authors: Hanno Schmidt, Katharina Mauer, Manuel Glaser, Bahram Sayyaf Dezfuli, Sören Lukas Hellmann, Ana Lúcia Silva Gomes, Falk Butter, Rebecca C. Wade, Thomas Hankeln, Holger Herlyn

Date Published: 1st Dec 2022

Publication Type: Journal

MatchTope: A tool to predict the cross reactivity of peptides complexed with Major Histocompatibility Complex I

Abstract

Not specified

Authors: Marcus Fabiano de Almeida Mendes, Marcelo de Souza Bragatte, Priscila Vianna, Martiela Vaz de Freitas, Ina Pöhner, Stefan Richter, Rebecca C. Wade, Francisco Mauro Salzano, Gustavo Fioravanti Vieira

Date Published: 28th Oct 2022

Publication Type: Journal

Anti-trypanosomatid structure-based drug design – lessons learned from targeting the folate pathway

Abstract

Not specified

Authors: Joanna Panecka-Hofman, Ina Poehner, Rebecca C. Wade

Date Published: 2nd Sep 2022

Publication Type: Journal

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