Article
Chemistry, Multidisciplinary
Lauren A. Viarengo-Baker, Lauren E. Brown, Anna A. Rzepiela, Adrian Whitty
Summary: Macrocyclic compounds are increasingly studied for inhibiting challenging drug targets. This study identifies distinct regions in structure-property space for oral and non-oral macrocycle drugs, as well as commercially available synthetic MCs. Thirteen properties are identified for designing synthetic MCs that overlap with oral MC drugs, advancing understanding of bioactive and orally bioavailable MCs.
Review
Biochemistry & Molecular Biology
Austen Bernardi, W. F. Drew Bennett, Stewart He, Derek Jones, Dan Kirshner, Brian J. Bennion, Timothy S. Carpenter
Summary: Passive permeation is a key feature of many therapeutics, involving cellular membranes in biological systems. Various computational techniques, including machine learning, are utilized for characterizing passive permeability. The confluence of novel computational methods and advanced computers will lead to an exciting future for computationally driven permeability predictions.
Article
Chemistry, Medicinal
Dongjae Lee, Jieun Choi, Min June Yang, Chin-Ju Park, Jiwon Seo
Summary: This study investigates the influence of structural changes on chameleonic behavior and membrane permeability of the cyclosporin O (CsO) scaffold by controlling backbone and side chain modifications. The results show that beta-hydroxylation at specific positions enhances permeability, while the introduction of additional transannular H-bond slows down the permeation rate. These findings contribute to the discovery of potent macrocycles capable of targeting undruggable targets.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Pharmacology & Pharmacy
Vito Digiesi, Victor de la Oliva Roque, Maura Vallaro, Giulia Caron, Giuseppe Ermondi
Summary: The study found that cyclic peptides are increasingly important in drug discovery, but their poor permeability requires computational tools to predict it. Various tools based on different computational theories performed well in modeling and explaining the permeability of cyclic peptides, showing that lipophilicity is the main determinant and flexibility's impact on permeability is unclear.
EUROPEAN JOURNAL OF PHARMACEUTICS AND BIOPHARMACEUTICS
(2021)
Article
Chemistry, Medicinal
Stephanie M. Linker, Christian Schellhaas, Anna S. Kamenik, Mac M. Veldhuizen, Franz Waibl, Hans-Jorg Roth, Marianne Fouche, Stephane Rodde, Sereina Riniker
Summary: Cyclic peptides offer potential as drug targets due to their unique properties, but their permeability through membranes remains a challenge. Using molecular simulations, this study reveals the mechanism of membrane permeation by cyclic peptides at an atomic level. The findings provide insights into the design considerations for the permeation process, including the role of side chains as molecular anchors and the formation of a permeable closed conformation.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Chemistry, Medicinal
Ayahisa Watanabe, Shota Uehara, Takanori Akazawa, Motohiro Fujiu
Summary: Cyclic peptides, as a class of molecules targeting undruggable targets, have been gaining increasing attention. However, their cell permeability has remained challenging due to their molecular properties. This study proposes an alternative method using chromatographic capacity factor to assess the lipophilic permeability of cyclic peptides, offering insights into structural changes and optimization of their properties. Furthermore, the study demonstrates the intestinal membrane permeability of cyclic peptides using induced pluripotent stem cell-derived intestinal epithelial cells.
JOURNAL OF PHARMACEUTICAL SCIENCES
(2022)
Article
Multidisciplinary Sciences
Pritha Ghosh, Nishant Raj, Hitesh Verma, Monika Patel, Sohini Chakraborti, Bhavesh Khatri, Chandrashekar M. Doreswamy, S. R. Anandakumar, Srinivas Seekallu, M. B. Dinesh, Gajanan Jadhav, Prem Narayan Yadav, Jayanta Chatterjee
Summary: Solvent shielding of the amide hydrogen bond donor has been used to increase the membrane permeability of macrocyclic peptides, and this can also be achieved by masking the amide hydrogen bond acceptor. Thioamide substitution reduces the desolvation penalty and enhances the membrane permeability of the macrocycle. Thioamidation also improves the bioavailability and duration of action of the macrocyclic peptide.
NATURE COMMUNICATIONS
(2023)
Article
Chemistry, Medicinal
Jaru Taechalertpaisarn, Satoshi Ono, Okimasa Okada, Timothy C. Johnstone, R. Scott Lokey
Summary: Replacing hydrogen-bond donors in side chains can significantly improve the aqueous solubility and permeability of cyclic peptides.
JOURNAL OF MEDICINAL CHEMISTRY
(2022)
Article
Chemistry, Medicinal
Alexander C. Brueckner, Qiaolin Deng, Ann E. Cleves, Charles A. Lesburg, Juan C. Alvarez, Mikhail Y. Reibarkh, Edward C. Sherer, Ajay N. Jain
Summary: Macrocyclic peptides can tolerate larger amount of strain in protein-ligand complexes compared to small molecules and non-peptidic macrocycles. Low-energy conformer ensembles generated by xGen show favorable binding energy estimates while fitting experimental X-ray electron density maps.
JOURNAL OF MEDICINAL CHEMISTRY
(2021)
Article
Chemistry, Multidisciplinary
Vincent Faugeras, Olivier Duclos, Didier Bazile, Abdou Rachid Thiam
Summary: This study focuses on the passive permeation of hydrophobic cyclic peptides inspired by somatostatin and investigates the impact of peptide cyclization and backbone methylation on translocation rates. The results show that cyclization improves peptide permeability, while methylation does not. Additionally, the study identifies membrane insertion and peptide intrinsic diffusion as two independent factors affecting permeability. Compared to other models, droplet interface bilayers (DIBs) provide intermediate membrane permeability values.
Article
Biochemistry & Molecular Biology
Theresa A. Ramelot, Jonathan Palmer, Gaetano T. Montelione, Gaurav Bhardwaj
Summary: Membrane-traversing peptides hold promise for targeting intracellular proteins and oral delivery. Despite challenges in designing peptides with diverse shapes and sizes, recent developments in the design and validation of chameleonic cyclic peptides have shown improved permeability through cell membranes while maintaining solubility and functional group exposure. This review discusses the principles, strategies, and considerations for rational design, discovery, and validation of permeable chameleonic peptides.
CURRENT OPINION IN STRUCTURAL BIOLOGY
(2023)
Review
Pharmacology & Pharmacy
Marina Buyanova, Dehua Pei
Summary: Intracellular protein-protein interactions are challenging targets for traditional drug modalities. Macrocyclic peptides have proven to be effective inhibitors, but they are generally impermeable to the cell membrane. Recent advances in MP science and technology have allowed for the development of cell-permeable MPs that can modulate intracellular PPI targets.
TRENDS IN PHARMACOLOGICAL SCIENCES
(2022)
Article
Chemistry, Medicinal
Benjamin Ries, Stephanie M. Linker, David F. Hahn, Gerhard Konig, Sereina Riniker
Summary: Ensembler is a Python package for method prototyping and deepening understanding of different MD methods, improving shareability, comparability, and reproducibility of scientific code developments. The implementation and usage of the package, along with an application example for free-energy calculation, are freely available on GitHub.
JOURNAL OF CHEMICAL INFORMATION AND MODELING
(2021)
Article
Chemistry, Physical
R. Gregor Weiss, Benjamin Ries, Shuzhe Wang, Sereina Riniker
Summary: The combination of MSM and MD simulations is a valuable approach for unraveling slow processes in molecular systems. This work introduces a specialized density-based clustering algorithm for Boltzmann-weighted data from MD simulations, which allows for a direct link to the free-energy notion.
JOURNAL OF CHEMICAL PHYSICS
(2021)
Article
Chemistry, Physical
Gerhard Koenig, Benjamin Ries, Philippe H. Huenenberger, Sereina Riniker
Summary: Alchemical free energy calculations often require intermediate states along a coupling parameter lambda to ensure phase space overlap for converged results. The lambda-EDS scheme combines minimum variance pathway and EDS methods to improve sampling efficiency, allowing larger steps along the alchemical pathway and eliminating the need for soft-core potentials.
JOURNAL OF CHEMICAL THEORY AND COMPUTATION
(2021)
Article
Chemistry, Multidisciplinary
Erika Erickson, Thomas J. Shakespeare, Felicia Bratti, Bonnie L. Buss, Rosie Graham, McKenzie A. Hawkins, Gerhard Koenig, William E. Michener, Joel Miscall, Kelsey J. Ramirez, Nicholas A. Rorrer, Michael Zahn, Andrew R. Pickford, John E. McGeehan, Gregg T. Beckham
Summary: This study compares the performance of two types of PET-hydrolyzing enzymes and finds that reaction temperature has the strongest influence on their performance. Both enzymes achieve higher levels of PET conversion for substrates with moderate crystallinity, and show different inhibition profiles to product accumulation.
Review
Chemistry, Organic
Manfred T. Reetz, Gerhard Konig
Summary: This study discusses the advantages of using n-butanol as a solvent to extract polar compounds from aqueous solutions, citing its high efficiency and sustainability from biomass sources, making it appealing from a climate perspective.
EUROPEAN JOURNAL OF ORGANIC CHEMISTRY
(2021)
Article
Biochemistry & Molecular Biology
Michael Zahn, Gerhard Konig, Huy Viet Cuong Pham, Barbara Seroka, Ryszard Lazny, Guangli Yang, Ouathek Ouerfelli, Zenon Lotowski, Thore Rohwerder
Summary: This study determined the crystal structures of Actinobacterial 2-hydroxyacyl-CoA lyase, shedding light on its substrate binding and reaction mechanism. The catalytic cycle of the enzyme was structurally portrayed, and the role of residue E493 in the catalytic process was confirmed through mutations. Water molecules were also found to potentially contribute to proton transfer. The unique feature of a large C-terminal lid domain in this enzyme restricts substrate size. Overall, these findings provide important insights for biotechnological applications.
JOURNAL OF BIOLOGICAL CHEMISTRY
(2022)
Article
Biochemistry & Molecular Biology
Benjamin Ries, Karl Normak, R. Gregor Weiss, Salome Rieder, Emilia P. Barros, Candide Champion, Gerhard Konig, Sereina Riniker
Summary: This study presents an automated procedure for determining the parameters of the RE-EDS method, improving its robustness and usability. The performance of the method in calculating relative binding free energies is demonstrated through simulations of a series of checkpoint kinase 1 inhibitors.
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN
(2022)
Article
Multidisciplinary Sciences
Gerhard Koenig, Pandian Sokkar, Niclas Pryk, Sascha Heinrich, David Moeller, Giuseppe Cimicata, Donna Matzov, Pascal Dietze, Walter Thiel, Anat Bashan, Julia Elisabeth Bandow, Johannes Zuegg, Ada Yonath, Frank Schulz, Elsa Sanchez-Garcia
Summary: Antibiotic resistance poses a major threat to global health, but computational methods can aid in the development of new antibacterial agents and provide rapid decision-making. The best-designed compounds exhibit excellent activity in both in vitro and in vivo experiments, showing promising inhibitory effects against priority pathogens identified by the World Health Organization.
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
(2021)
Article
Multidisciplinary Sciences
Erika Erickson, Japheth E. Gado, Luisana Avilan, Felicia Bratti, Richard K. Brizendine, Paul A. Cox, Raj Gill, Rosie Graham, Dong-Jin Kim, Gerhard Koenig, William E. Michener, Saroj Poudel, Kelsey J. Ramirez, Thomas J. Shakespeare, Michael Zahn, Eric S. Boyd, Christina M. Payne, Jennifer L. DuBois, Andrew R. Pickford, Gregg T. Beckham, John E. McGeehan
Summary: This study expands the number and diversity of thermotolerant scaffolds for enzymatic PET deconstruction by using bioinformatics and machine learning to mine 74 putative thermotolerant PET hydrolases. The study identifies new PET-active biocatalysts and discovers protein folds and accessory domains associated with PET deconstruction.
NATURE COMMUNICATIONS
(2022)
Article
Chemistry, Multidisciplinary
Luisana Avilan, Bruce R. Lichtenstein, Gerhard Koenig, Michael Zahn, Mark D. Allen, Liliana Oliveira, Matilda Clark, Victoria Bemmer, Rosie Graham, Harry P. Austin, Graham Dominick, Christopher W. Johnson, Gregg T. Beckham, John E. McGeehan, Andrew R. Pickford
Summary: Enzyme-based depolymerization is a viable approach for recycling PET, but the concentration-dependent inhibition of IsPETase hinders its effectiveness. This study finds that the inhibition depends on incubation time, solution conditions, and PET surface area. Furthermore, this inhibition is also observed in other mesophilic PET-degrading enzymes, but not in the highly thermostable HotPETase. This work highlights the limitations of using natural mesophilic hydrolases for PET hydrolysis and the potential benefits of enhancing their thermostability.
Article
Chemistry, Medicinal
Stephanie M. Linker, Christian Schellhaas, Anna S. Kamenik, Mac M. Veldhuizen, Franz Waibl, Hans-Jorg Roth, Marianne Fouche, Stephane Rodde, Sereina Riniker
Summary: Cyclic peptides offer potential as drug targets due to their unique properties, but their permeability through membranes remains a challenge. Using molecular simulations, this study reveals the mechanism of membrane permeation by cyclic peptides at an atomic level. The findings provide insights into the design considerations for the permeation process, including the role of side chains as molecular anchors and the formation of a permeable closed conformation.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Pharmacology & Pharmacy
Johanna Dieplinger, Christina Moser, Gerhard Koenig, Joana T. Pinto, Amrit Paudel
Summary: This study investigated the effect of different saccharides on enzyme activity during protein drying. The results showed that trehalose dihydrate (TD) increased the activity of catalase, while hydroxypropyl beta-cyclodextrins (HPB) preserved the activity of trypsin during both miniaturized drying (MD) and spray drying (SD). Molecular docking and simulation revealed the difference in binding affinity between HP and HPB with trypsin. The experimental and modeling results shed light on the importance of protein and saccharide size in preserving activity during drying.
Article
Chemistry, Physical
Alissa Bleem, Eugene Kuatsjah, Gerald N. Presley, Daniel J. Hinchen, Michael Zahn, David C. Garcia, William E. Michener, Gerhard Konig, Konstantinos Tornesakis, Marco N. Allemann, Richard J. Giannone, John E. McGeehan, Gregg T. Beckham, Joshua K. Michener
Summary: This study identified a Rieske-type guaiacol O-demethylase, GdmA, and its reductase partner GdmB in Novosphingobium aromaticivorans. The GdmAB combination showed high efficiency in guaiacol turnover, providing new options for microbial conversion of lignin-derived substrates.
Article
Chemistry, Multidisciplinary
Jinfeng Chen, Gerhard Konig
Summary: The study tested the ability of the CHARMM Drude polarizable force field to reproduce the conformational substates of amino acids, and improved the agreement with quantum-mechanical energy surfaces through reparameterization. The corrected force field showed similar average reorganization energies compared to the AM1 and PM3 semi-empirical methods.
JOURNAL OF COMPUTATIONAL BIOPHYSICS AND CHEMISTRY
(2022)