Predicting drug-target binding kinetics through multiscale simulations
Lead Research Organisation:
University of Bristol
Department Name: Chemistry
Abstract
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Publications
Ainsley J
(2018)
Combined Quantum Mechanics and Molecular Mechanics Studies of Enzymatic Reaction Mechanisms.
in Advances in protein chemistry and structural biology
Ainsley J
(2018)
Structural Insights from Molecular Dynamics Simulations of Tryptophan 7-Halogenase and Tryptophan 5-Halogenase.
in ACS omega
Ali HS
(2019)
Entropy of Simulated Liquids Using Multiscale Cell Correlation.
in Entropy (Basel, Switzerland)
Althorpe SC
(2016)
Non-adiabatic reactions: general discussion.
in Faraday discussions
Amaro RE
(2020)
A Community Letter Regarding Sharing Biomolecular Simulation Data for COVID-19.
in Journal of chemical information and modeling
Amaro RE
(2020)
Biomolecular Simulations in the Time of COVID19, and After.
in Computing in science & engineering
Amaro RE
(2018)
Multiscale Methods in Drug Design Bridge Chemical and Biological Complexity in the Search for Cures.
in Nature reviews. Chemistry
Amos STA
(2021)
Membrane Interactions of a-Synuclein Revealed by Multiscale Molecular Dynamics Simulations, Markov State Models, and NMR.
in The journal of physical chemistry. B
Angulo G
(2016)
New methods: general discussion.
in Faraday discussions
Ansell TB
(2021)
Relative Affinities of Protein-Cholesterol Interactions from Equilibrium Molecular Dynamics Simulations.
in Journal of chemical theory and computation
| 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 |
| Description | Research data and policy |
| Geographic Reach | National |
| Policy Influence Type | Contribution to new or improved professional practice |
| URL | https://www.chemistryworld.com/news/ukri-finds-itself-in-hot-water-too-over-researchfish-cyberbullyi... |
| Description | UKRI research data capture approaches |
| Geographic Reach | National |
| Policy Influence Type | Contribution to new or improved professional practice |
| URL | https://www.researchprofessionalnews.com/rr-news-uk-research-councils-2023-1-researchfish-tweets-aga... |
| Description | Industrial PhD studentship |
| Amount | £30,000 (GBP) |
| Organisation | Heptares Therapeutics Ltd |
| Sector | Private |
| Country | United Kingdom |
| Start | 03/2017 |
| End | 02/2020 |
| Description | Oracle for Research Cloud Fellowship |
| Amount | $100,000 (USD) |
| Organisation | Oracle Corporation |
| Sector | Private |
| Country | United States |
| Start | 02/2023 |
| End | 12/2023 |
| Description | PREDACTED Predictive computational models for Enzyme Dynamics, Antimicrobial resistance, Catalysis and Thermoadaptation for Evolution and Desig |
| Amount | € 2,482,332 (EUR) |
| Funding ID | 101021207 |
| Organisation | European Research Council (ERC) |
| Sector | Public |
| Country | Belgium |
| Start | 10/2021 |
| End | 09/2026 |
| Description | https://gtr.ukri.org/person/2A2990B1-E1E1-4888-8848-7C256C3A3B43 |
| Amount | £20,009,000 (GBP) |
| Funding ID | https://gtr.ukri.org/person/2A2990B1-E1E1-4888-8848-7C256C3A3B43 |
| Organisation | United Kingdom Research and Innovation |
| Sector | Public |
| Country | United Kingdom |
| Start | 01/2006 |
| End | 02/2033 |
| 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 | 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. |