Predicting drug-target binding kinetics through multiscale simulations

Lead Research Organisation: University of Bristol
Department Name: Chemistry

Abstract

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Publications

10 25 50
 
Description Drug-target binding kinetics has recently emerged as a sometimes critical determinant of in vivo efficacy and toxicity. Its rational optimization to improve potency or reduce side effects of drugs is, however, extremely difficult. Molecular simula-tions can play a crucial role in identifying features and properties of small ligands and their protein targets affecting the bind-ing kinetics, but significant challenges include the long timescales involved in (un)binding events and the limited accuracy of empirical atomistic force-fields (lacking e.g. changes in electronic polarization). In an effort to overcome these hurdles, we propose a method that combines state-of-the-art enhanced sampling simulations and quantum mechanics/molecular mechan-ics (QM/MM) calculations at the BLYP/VDZ level to compute association free energy profiles and characterise the binding kinetics in terms of structure and dynamics of the transition state ensemble. We test our combined approach on the binding of the anticancer drug imatinib to Src kinase, a well-characterized target for cancer therapy with a complex binding mecha-nism involving significant conformational changes. The results indicate significant changes in polarization along the binding pathways, which affect the predicted binding kinetics. This is likely to be of widespread importance in ligand-target binding.

A Multiscale Simulation Approach to Modeling Drug-Protein Binding Kinetics
Susanta Haldar, Federico Comitani, Giorgio Saladino, Christopher Woods, Marc W. van der Kamp, Adrian J. Mulholland, and Francesco Luigi Gervasio
J. Chem. Theory Comput., 2018, 14 (11), pp 6093-6101
DOI: 10.1021/acs.jctc.8b00687
Publication Date (Web): September 13, 2018
Drug-target binding kinetics has recently emerged as a sometimes critical determinant of in vivo efficacy and toxicity. Its rational optimization to improve potency or reduce side effects of drugs is, however, extremely difficult. Molecular simulations can play a crucial role in identifying features and properties of small ligands and their protein targets affecting the binding kinetics, but significant challenges include the long time scales involved in (un)binding events and the limited accuracy of empirical atomistic force fields (lacking, e.g., changes in electronic polarization). In an effort to overcome these hurdles, we propose a method that combines state-of-the-art enhanced sampling simulations and quantum mechanics/molecular mechanics (QM/MM) calculations at the BLYP/VDZ level to compute association free energy profiles and characterize the binding kinetics in terms of structure and dynamics of the transition state ensemble. We test our combined approach on the binding of the anticancer drug Imatinib to Src kinase, a well-characterized target for cancer therapy with a complex binding mechanism involving significant conformational changes. The results indicate significant changes in polarization along the binding pathways, which affect the predicted binding kinetics. This is likely to be of widespread importance in binding of ligands to protein targets.

Enhanced sampling molecular dynamics simulations correctly predict the diverse activities of a series of stiff-stilbene G-quadruplex DNA ligands
Authors
Michael P O'Hagan, Susanta Haldar, Juan C Morales, Adrian J Mulholland, M Carmen Galan
Publication date
2021
Journal
Chemical Science
Volume
12
Issue
4
Pages
1415-1426
Publisher
Royal Society of Chemistry
Description
Ligands with the capability to bind G-quadruplexes (G4s) specifically, and to control G4 structure and behaviour, offer great potential in the development of novel therapies, technologies and functional materials. Most known ligands bind to a pre-formed topology, but G4s are highly dynamic and a small number of ligands have been discovered that influence these folding equilibria. Such ligands may be useful as probes to understand the dynamic nature of G4 in vivo, or to exploit the polymorphism of G4 in the development of molecular devices. To date, these fascinating molecules have been discovered serendipitously. There is a need for tools to predict such effects to drive ligand design and development, and for molecular-level understanding of ligand binding mechanisms and associated topological perturbation of G4 structures. Here we study the G4 binding mechanisms of a family of stiff-stilbene G4 ligands to...

Visible-light photoswitching of ligand binding mode suggests G-quadruplex DNA as a target for photopharmacology
Authors
Michael P O'Hagan, Javier Ramos-Soriano, Susanta Haldar, Sadiyah Sheikh, Juan C Morales, Adrian J Mulholland, M Carmen Galan
Publication date
2020
Journal
Chemical Communications
Volume
56
Issue
38
Pages
5186-5189
Publisher
Royal Society of Chemistry
Description
We report the selective targeting of telomeric G4 DNA with a dithienylethene ligand and demonstrate the robust visible-light mediated switching of the G4 ligand binding mode and G-tetrad structure in physiologically-relevant conditions. The toxicity of the ligand to cervical cancer cells is modulated by the photoisomeric state of the ligand, indicating for the first time the potential of G4 to serve as a target for photopharmacological strategies.

A Photoresponsive Stiff-Stilbene Ligand Fuels the Reversible Unfolding of G-Quadruplex DNA
Authors
Michael P O'Hagan, Susanta Haldar, Marta Duchi, Thomas AA Oliver, Adrian J Mulholland, Juan C Morales, M Carmen Galan
Publication date
2019/3/22
Journal
Angewandte Chemie International Edition
Volume
58
Issue
13
Pages
4334-4338
Description
The polymorphic nature of G-quadruplex (G4) DNA structures points to a range of potential applications in nanodevices and an opportunity to control G4 in biological settings. Light is an attractive means for the regulation of oligonucleotide structure as it can be delivered with high spatiotemporal precision. However, surprisingly little attention has been devoted towards the development of ligands for G4 that allow photoregulation of G4 folding. We report a novel G4-binding chemotype derived from stiff-stilbene. Surprisingly however, whilst the ligand induces high stabilization in the potassium form of human telomeric DNA, it causes the unfolding of the same G4 sequence in sodium buffer. This effect can be reversed on demand by irradiation with 400 nm light through deactivation of the ligand by photo-oxidation. By fuelling the system with the photolabile ligand, the conformation of G4 DNA was switched five times.
Exploitation Route Drug-target binding kinetics has recently emerged as a sometimes critical determinant of in vivo efficacy and toxicity. Its rational optimization to improve potency or reduce side effects of drugs is, however, extremely difficult. Molecular simula-tions can play a crucial role in identifying features and properties of small ligands and their protein targets affecting the bind-ing kinetics, but significant challenges include the long timescales involved in (un)binding events and the limited accuracy of empirical atomistic force-fields (lacking e.g. changes in electronic polarization). In an effort to overcome these hurdles, we propose a method that combines state-of-the-art enhanced sampling simulations and quantum mechanics/molecular mechan-ics (QM/MM) calculations at the BLYP/VDZ level to compute association free energy profiles and characterise the binding kinetics in terms of structure and dynamics of the transition state ensemble. We test our combined approach on the binding of the anticancer drug imatinib to Src kinase, a well-characterized target for cancer therapy with a complex binding mecha-nism involving significant conformational changes. The results indicate significant changes in polarization along the binding pathways, which affect the predicted binding kinetics. This is likely to be of widespread importance in ligand-target binding.

The polymorphic nature of G-quadruplex (G4) DNA structures points to a range of potential applications in nanodevices and an opportunity to control G4 in biological settings. Light is an attractive means for the regulation of oligonucleotide structure as it can be delivered with high spatiotemporal precision. However, surprisingly little attention has been devoted towards the development of ligands for G4 that allow photoregulation of G4 folding. We report a novel G4-binding chemotype derived from stiff-stilbene. Surprisingly however, whilst the ligand induces high stabilization in the potassium form of human telomeric DNA, it causes the unfolding of the same G4 sequence in sodium buffer. This effect can be reversed on demand by irradiation with 400 nm light through deactivation of the ligand by photo-oxidation. By fuelling the system with the photolabile ligand, the conformation of G4 DNA was switched five times.

Reversible regulation of nucleic acid structure is a thriving area of research, and many DNA-based switches have been reported over the past decade. G-quadruplexes (G4) are a class of four-stranded oligonucleotide secondary structures that form from sequences rich in guanine. These fascinating structures have garnered interest from across many scientific disciplines because of their structural polymorphism, diverse roles in biology, and applications as therapeutic targets, catalysts, and as the basis of functional nanodevices. Switchable control of G-quadruplex topology offers exciting opportunities to further many of these applications, and a number of groups have demonstrated the regulation of DNA secondary structures by a variety of chemical triggers including pH8 and metal ions. Light offers significant advantages over chemical stimuli as it can be delivered with high spatiotemporal precision, allowing an additional level of control over the system. Previously, the groups of Ogasawara and Heckel have demonstrated the photoresponsive formation of G4 architectures through the incorporation of photoswitchable moieties within the oligonucleotide sequence. However, the requirement to engineer unnatural functionality into the biomolecule perhaps limits the scope of potential applications of these systems. Reversible regulation of G4 through a supramolecular approach, by employing a photoresponsive small-molecule ligand as a fuel, would allow complementary applications to be realized, particularly in situations where pre-modification of the nucleotide sequence is undesirable. The small number of light-triggered G4 ligands developed to date are mainly engineered to cause irreversible covalent modification of the DNA structure upon photoirradiation. A notable exception is an azobenzene derivative developed by Wang and co-workers that permits photoregulation of G4 folding and dissociation in aqueous media by isomerization of the azobenzene scaffold between the cis and the trans forms. However, the effects are significantly diminished under physiologically relevant ionic conditions where the conformational preference exerted by the high concentration of monovalent cations appears more difficult to overcome with a ligand-driven approach.

Multiscale simulation approaches to modeling drug-protein binding
Authors
Benjamin R Jagger, Sarah E Kochanek, Susanta Haldar, Rommie E Amaro, Adrian J Mulholland
Publication date
2020/4/1
Source
Current opinion in structural biology
Volume
61
Pages
213-221
Publisher
Elsevier Current Trends
Description
Simulations can provide detailed insight into the molecular processes involved in drug action, such as protein-ligand binding, and can therefore be a valuable tool for drug design and development. Processes with a large range of length and timescales may be involved, and understanding these different scales typically requires different types of simulation methodology. Ideally, simulations should be able to connect across scales, to analyze and predict how changes at one scale can influence another. Multiscale simulation methods, which combine different levels of treatment, are an emerging frontier with great potential in this area. Here we review multiscale frameworks of various types, and selected applications to biomolecular systems with a focus on drug-ligand binding.
Sectors Agriculture

Food and Drink

Chemicals

Digital/Communication/Information Technologies (including Software)

Education

Environment

Healthcare

Manufacturing

including Industrial Biotechology

Pharmaceuticals and Medical Biotechnology

URL https://mulhollandgroup.wordpress.com
 
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URL https://www.chemistryworld.com/news/ukri-finds-itself-in-hot-water-too-over-researchfish-cyberbullyi...
 
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Title An expandable, modular de novo protein platform for precision redox engineering 
Description Pioneering study signals new era of environment-friendly programmable bioelectronics Image shows the design of a protein nanowire, with the green arrow indicating electron flow. Ross Anderson Image shows structural analysis of the protein-based wire, comparing the model of the designed protein (shown in red) with the experimentally determined structure (in grey). Ross Anderson Press release issued: 25 July 2023 Researchers have created a unique microscopic toolkit of 'green' tuneable electrical components, paving the way for a new generation of bioelectronic devices and sensors. The University of Bristol-led study, published today in The Proceedings of the National Academy of Sciences (PNAS), demonstrates how to make conductive, biodegradable wires from designed proteins. These could be compatible with conventional electronic components made from copper or iron, as well as the biological machinery responsible for generating energy in all living organisms. The miniscule wires are the size of transistors on silicon chips or one thousandth of the breadth of the finest human hair. They are made completely of natural amino acids and heme molecules, found in proteins such as hemoglobin, which transports oxygen in red blood cells. Harmless bacteria were used for their manufacture, eliminating the need for potentially complex and environmentally damaging procedures commonly used in the production of synthetic molecules. Lead author Ross Anderson, Professor of Biological Chemistry at the University of Bristol, said: "While our designs take inspiration from the protein-based electronic circuits necessary for all life on Earth, they are free from much of the complexity and instability that can prevent the exploitation of their natural equivalents on our own terms. We can also build these minute electronic components to order, specifying their properties in a way that is not possible with natural proteins." Leading experts in biomolecular engineering and simulation worked together to produce this unique new method of designing tailor-made proteins with tuneable electronic properties. The multidisciplinary team used advanced computational tools to design simple building blocks that could be combined into longer, wire-like protein chains for conducting electrons. They were able to visualise the structures of these wires using protein X-ray crystallography and electron cryo-microscopy (cryo-EM), techniques which allow structures to be viewed in the finest detail. Pushing the technical boundaries of cryo-EM, images of the smallest individual protein ever studied were obtained with this technique. Ultimately, these nanoscale designer wires have the potential to be used in a wide range of applications, including biosensors for the diagnosis of diseases and detection of environmental pollutants. It is also hoped this invention will form the foundation of new electrical circuits for creating tailor-made catalysts for green industrial biotechnology and artificial photosynthetic proteins for capturing solar energy. The breakthrough was possible thanks to a £4.9 million grant from the Biotechnology and Biological Science Research Council (BBSRC), the UK's largest bioscience funder, which resulted in a five-year project entitled 'The Circuits of Life' involving the Universities of Bristol, Portsmouth, East Anglia, and University College London (UCL). The team harnessed their expertise in protein design, electron transfer, biomolecular simulation, structural biology and spectroscopy, gaining insight into how electrons flow through natural biological molecules, a fundamental process which underpins cellular respiration and photosynthesis. Further advances are expected as the project, which began last year, progresses, presenting significant opportunities to help meet the transition to net zero and more sustainable industrial processes. Co-author Adrian Mulholland, Professor of Chemistry at the University of Bristol, said: "These proteins show how protein design is increasingly delivering practically useful tools. They offer exciting possibilities as components for engineering biology and also are great systems for investigating the fundamental mechanisms of biological electron transfer." Paper 'An expandable, modular de novo protein platform for precision redox engineering' by George H. Hutchins, Claire E.M. Noble, Adrian Bunzel et al published in PNAS 
Type Of Material Technology assay or reagent 
Year Produced 2023 
Provided To Others? Yes  
Impact Pioneering study signals new era of environment-friendly programmable bioelectronics Image shows the design of a protein nanowire, with the green arrow indicating electron flow. Ross Anderson Image shows structural analysis of the protein-based wire, comparing the model of the designed protein (shown in red) with the experimentally determined structure (in grey). Ross Anderson Press release issued: 25 July 2023 Researchers have created a unique microscopic toolkit of 'green' tuneable electrical components, paving the way for a new generation of bioelectronic devices and sensors. The University of Bristol-led study, published today in The Proceedings of the National Academy of Sciences (PNAS), demonstrates how to make conductive, biodegradable wires from designed proteins. These could be compatible with conventional electronic components made from copper or iron, as well as the biological machinery responsible for generating energy in all living organisms. The miniscule wires are the size of transistors on silicon chips or one thousandth of the breadth of the finest human hair. They are made completely of natural amino acids and heme molecules, found in proteins such as hemoglobin, which transports oxygen in red blood cells. Harmless bacteria were used for their manufacture, eliminating the need for potentially complex and environmentally damaging procedures commonly used in the production of synthetic molecules. Lead author Ross Anderson, Professor of Biological Chemistry at the University of Bristol, said: "While our designs take inspiration from the protein-based electronic circuits necessary for all life on Earth, they are free from much of the complexity and instability that can prevent the exploitation of their natural equivalents on our own terms. We can also build these minute electronic components to order, specifying their properties in a way that is not possible with natural proteins." Leading experts in biomolecular engineering and simulation worked together to produce this unique new method of designing tailor-made proteins with tuneable electronic properties. The multidisciplinary team used advanced computational tools to design simple building blocks that could be combined into longer, wire-like protein chains for conducting electrons. They were able to visualise the structures of these wires using protein X-ray crystallography and electron cryo-microscopy (cryo-EM), techniques which allow structures to be viewed in the finest detail. Pushing the technical boundaries of cryo-EM, images of the smallest individual protein ever studied were obtained with this technique. Ultimately, these nanoscale designer wires have the potential to be used in a wide range of applications, including biosensors for the diagnosis of diseases and detection of environmental pollutants. It is also hoped this invention will form the foundation of new electrical circuits for creating tailor-made catalysts for green industrial biotechnology and artificial photosynthetic proteins for capturing solar energy. The breakthrough was possible thanks to a £4.9 million grant from the Biotechnology and Biological Science Research Council (BBSRC), the UK's largest bioscience funder, which resulted in a five-year project entitled 'The Circuits of Life' involving the Universities of Bristol, Portsmouth, East Anglia, and University College London (UCL). The team harnessed their expertise in protein design, electron transfer, biomolecular simulation, structural biology and spectroscopy, gaining insight into how electrons flow through natural biological molecules, a fundamental process which underpins cellular respiration and photosynthesis. Further advances are expected as the project, which began last year, progresses, presenting significant opportunities to help meet the transition to net zero and more sustainable industrial processes. Co-author Adrian Mulholland, Professor of Chemistry at the University of Bristol, said: "These proteins show how protein design is increasingly delivering practically useful tools. They offer exciting possibilities as components for engineering biology and also are great systems for investigating the fundamental mechanisms of biological electron transfer." Paper 'An expandable, modular de novo protein platform for precision redox engineering' by George H. Hutchins, Claire E.M. Noble, Adrian Bunzel et al published in PNAS 
URL https://www.bristol.ac.uk/news/2023/july/protein-nanowires.html
 
Title SWISH a new Hamiltonian Replica Exchange-based computational algorithm 
Description We developed a novel and effective computational approach to predict cryptic binding sites on targets of pharmaceutical interest. 
Type Of Material Computer model/algorithm 
Year Produced 2016 
Provided To Others? Yes  
Impact The method has been described in an high-impact publication (JACS) and in a number of high-profile blogs in drug discovery. The PI has been invited by Pfizer and other pharmaceutical companies to give talks about the method. 
 
Description Collaboration with Bristol university on predicting drug-target binding kinetics 
Organisation University of Bristol
Department School of Chemistry
Country United Kingdom 
Sector Academic/University 
PI Contribution We contributed our enhanced sampling simulation algorithms including TS-PPTIS. Our approach will be combined with Prof. Mulholland's QM/MM algorithms to accurately predict binding kinetics.
Collaborator Contribution Prof. Mulholland's contributed his QMMM algorithms as well as Waterswap to the combined computational platform.
Impact A combined computational platform to predict binding kinetics and model the transition state ensemble.
Start Year 2015
 
Description Industrial collaboration with EVOTEC 
Organisation Evotec
Country Germany 
Sector Private 
PI Contribution We helped EVOTEC to rationalize the binding mode of a novel allosteric modulator of FGFR. By using our novel "SWISH" Hamiltonian Replica exchange algorithm, we predicted a previously unknown binding cavity in the D3 domain of FGFR3c, which was then validated by NMR spectroscopy.
Collaborator Contribution Evotec provided a plethora of unpublished experimental data on the binding mode and on the biological effect of the new tool compound in cells.
Impact The collaboration is multi-disciplinary involving Computational Chemistry, Chemical Biology, Structural Biology, Cellular Biology and Drug Discovery. A new manuscript is in preparation and will soon be submitted to a very prominent and high-impact journal. The PI (FLG) has been invited to a number of high-profile national international (ACS-meeting) conferences to discuss the results.
Start Year 2016
 
Title Confidential 
Description Confidential 
IP Reference Confidential 
Protection Patent / Patent application
Year Protection Granted 2024
Licensed Commercial In Confidence
Impact Confidential
 
Title FESetup 
Description FESetup FESetup is a tool to automate the setup of (relative) alchemical free energy simulations like thermodynamic integration (TI) and free energy perturbation (FEP) as well as post-processing methods like MM-PBSA and LIE. FESetup can also be used for general simulation setup ("equilibration") through an abstract MD engine. The latest releases are available from the project web page. 
Type Of Technology Software 
Year Produced 2017 
Impact FESetup FESetup is a tool to automate the setup of (relative) alchemical free energy simulations like thermodynamic integration (TI) and free energy perturbation (FEP) as well as post-processing methods like MM-PBSA and LIE. FESetup can also be used for general simulation setup ("equilibration") through an abstract MD engine. The latest releases are available from the project web page. 
 
Title Plug-in and scripts for enhanced-sampling molecular simulations. 
Description We developed a new interoperable plug-in compatible with PLUMED and many widely-used MD codes (such as GROMACS) to run our TS-PPTIS approach for binding kinetics. The tool can be used to predict ligand and folding binding kinetics. 
Type Of Technology Software 
Year Produced 2016 
Open Source License? Yes  
Impact The tool is able to accurately predict the binding kinetics of drugs to their biological targets, paving the avenue to the rational design of new molecules with fine-tuned biomedical effects.