Predictive multiscale free energy simulations of hybrid transition metal catalysts
Lead Research Organisation:
University of Bristol
Department Name: Chemistry
Abstract
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Publications
Abramiuk M
(2024)
Biocatalytic pathways, cascades, cells and systems: general discussion.
in Faraday discussions
Acevedo-Rocha C
(2024)
Enzyme evolution, engineering and design: mechanism and dynamics: general discussion.
in Faraday discussions
Acevedo-Rocha C
(2024)
Artificial, biomimetic and hybrid enzymes: general discussion.
in Faraday discussions
Balint-Kurti G
(1991)
The calculation of product quantum state distributions and partial cross-sections in time-dependent molecular collision and photodissociation theory
in Computer Physics Communications
Beer M
(2024)
Dynamical responses predict a distal site that modulates activity in an antibiotic resistance enzyme.
in Chemical science
Bennie SJ
(2016)
A Projector-Embedding Approach for Multiscale Coupled-Cluster Calculations Applied to Citrate Synthase.
in Journal of chemical theory and computation
| Description | Insulin-regulated aminopeptidase (IRAP) is a zinc-dependent metalloenzyme involved in the regulation of glucose metabolism and insulin sensitivity identified as a novel target for combating diabetes-induced diseases. IRAP's catalytic domain catalyzes the N-terminal peptide bond hydrolysis of the natural substrate oxytocin, a neuroactive pep-tide linked to improved cognition and other elemental brain functions. Angiotensin IV and similar peptides are recognized as cognitive enhancers due to their ability to competitively inhibit proteolytic activity of IRAP, reducing the degradation of natural neuropeptides. Despite a very similar binding complex between the substrate and the inhibitor with IRAP, especially around the scissile bond, it is unclear why the enzyme metabolizes oxytocin but does not efficiently degrade angiotensin IV. We employed enhanced sampling QM/MM molecular dynamics simulations to explore free energy landscapes for reaction of these two peptides in IRAP. A significantly higher energy barrier for the formation of the oxyanion tetrahedral intermediate (TI) and higher overall barrier for the peptide cleavage was observed for the reaction of angiotensin IV. Electronic structure analysis (NBO and NCI) revealed the reasons for different reactivity, including stabilization of the on the sigma hole of the N-terminus disulfide in oxytocin by the hybridizing lone pair of the scissile peptide nitrogen. The interplay between weak non-covalent spodium bond and strong bi-dentate coordination of the catalytic Zn2+ by angiotensin IV caused larger deviation of valine C-Ca-Cß angle from the ideal tetrahedral, which destabilizes the TI. The results emphasise the importance of analysing dynamics, interactions and electronic properties of reaction intermediates and transition states in enzymes, and have implications for the de-sign and development of IRAP inhibitors for the treatment of memory disorders, neurodegenerative diseases, and diabetes. |
| Exploitation Route | ChemShell lets you model complex chemical systems with efficient methods that scale from your desktop to massively parallel supercomputers. https://chemshell.org |
| Sectors | Pharmaceuticals and Medical Biotechnology |
| URL | https://doi.org/10.26434/chemrxiv-2024-j0r6p |
| Description | Collaboration with Kuano.ai Simulations for enzyme inhibitors Founded in 2020, Kuano combines state-of-the-art simulation and AI to structure based drug discovery through a Quantum lens. |
| First Year Of Impact | 2024 |
| Sector | Pharmaceuticals and Medical Biotechnology |
| Description | Government urges funders to consider scrapping Researchfish |
| Geographic Reach | National |
| Policy Influence Type | Contribution to a national consultation/review |
| URL | https://www.gov.uk/government/publications/review-of-research-bureaucracy |
| Description | Large-Scale Computing Opportunities and Challenges. A Report from a Supercomputing Task Force for BBSRC and MRC |
| Geographic Reach | National |
| Policy Influence Type | Contribution to a national consultation/review |
| URL | https://doi.org/10.5281/zenodo.11079792 |
| Description | Science after Brexit: bright spots on the Horizon? |
| Geographic Reach | Europe |
| Policy Influence Type | Contribution to a national consultation/review |
| URL | https://digital-strategy.ec.europa.eu/en/news/united-kingdom-joins-horizon-europe-programme#:~:text=... |
| Description | AMR Global Development Award 2017 |
| Amount | £88,000 (GBP) |
| Funding ID | MR/R014922/1 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 09/2017 |
| End | 03/2018 |
| Description | BBSRC Tools and Techniques: Computational tools for enzyme engineering: bridging the gap between enzymologists and expert simulation |
| Amount | £146,027 (GBP) |
| Funding ID | BB/L018756/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 06/2014 |
| End | 01/2016 |
| Description | BBSRC sLoLa: Innovative Routes to Monoterpene Hydrocarbons and Their High Value Derivatives |
| Amount | £3,038,984 (GBP) |
| Funding ID | BB/M000354/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 09/2010 |
| End | 09/2019 |
| Description | BEORHN: Bacterial Enzymatic Oxidation of Reactive Hydroxylamine in Nitrification via Combined Structural Biology and Molecular Simulation |
| Amount | £181,398 (GBP) |
| Funding ID | BB/V016768/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 01/2022 |
| End | 12/2024 |
| Description | Biocatalysis and Biotransformation: A 5th Theme for the National Catalysis Hub |
| Amount | £3,053,639 (GBP) |
| Funding ID | EP/M013219/1 |
| Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 01/2015 |
| End | 12/2019 |
| Description | BristolBridge has contributed to the University of Bristol being the UK's largest recipient of RCUK AMR cross-council funding awards both in number (7) and value (£5.268M). 6 related AMR grants awarded with BristolBridge PIs/Co-Is include MRC-led AMR. |
| Amount | £5,268,000 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 09/2016 |
| End | 09/2019 |
| Description | CCP-BioSim: Biomolecular Simulation at the Life Sciences Interface |
| Amount | £235,706 (GBP) |
| Funding ID | EP/M022609/1 |
| Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 06/2015 |
| End | 04/2021 |
| Description | CCP-BioSim: Biomolecular simulation at the life sciences interface |
| Amount | £287,541 (GBP) |
| Funding ID | EP/J010588/1 |
| Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 09/2011 |
| End | 09/2015 |
| Description | CCPBioSim: Biomolecular Simulation at the Life Science Interface |
| Amount | £345,687 (FKP) |
| Funding ID | EP/T026308/1 |
| Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 11/2020 |
| End | 10/2025 |
| Description | Carbapenem Antibiotic Resistance in Enterobacteriaceae: Understanding Interactions of KPC Carbapenemases with Substrates and Inhibitors |
| Amount | £668,396 (GBP) |
| Funding ID | MR/T016035/1 |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 01/2020 |
| End | 01/2023 |
| Description | Confidence in Concept 'Developing a mobile device for rapid antimicrobial resistance detection in primary care' |
| Amount | £74,685 (GBP) |
| Organisation | Medical Research Council (MRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 05/2017 |
| End | 05/2018 |
| Description | EPSRC |
| Amount | £188,950 (GBP) |
| Funding ID | E/EP/G007705/1 |
| Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 09/2013 |
| End | 03/2014 |
| Description | Inquire: Software for real-time analysis of binding |
| Amount | £105,748 (GBP) |
| Funding ID | BB/K016601/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 08/2013 |
| End | 09/2014 |
| Description | Nicotinic Ligand Development to Target Smoking Cessation and Gain a Molecular Level Understanding of Partial Agonism |
| Amount | £724,553 (GBP) |
| Funding ID | EP/N024117/1 |
| Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 05/2016 |
| End | 11/2019 |
| 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 | 09/2021 |
| End | 09/2026 |
| Description | Synthetic Biology Research Centre. BrisSynBio: Bristol Centre for Synthetic Biology |
| Amount | £13,528,180 (GBP) |
| Funding ID | BB/L01386X/1 |
| Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
| Sector | Public |
| Country | United Kingdom |
| Start | 06/2014 |
| End | 07/2019 |
| 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 | 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 |
| Description | Biomolecular simulation for TB drug lead discovery |
| Organisation | Ubon Ratchathani University |
| Country | Thailand |
| Sector | Academic/University |
| PI Contribution | The enoyl-acyl carrier protein reductase InhA of Mycobacterium tuberculosis is an attractive, validated target for antituberculosis drug development. Moreover, direct inhibitors of InhA remain effective against InhA variants with mutations associated with isoniazid resistance, offering the potential for activity against MDR isolates. Here, structure-based virtual screening supported by biological assays was applied to identify novel InhA inhibitors as potential antituberculosis agents. High-speed Glide SP docking was initially performed against two conformations of InhA differing in the orientation of the active site Tyr158. The resulting hits were filtered for drug-likeness based on Lipinski's rule and avoidance of PAINS-like properties and finally subjected to Glide XP docking to improve accuracy. Sixteen compounds were identified and selected for in vitro biological assays, of which two (compounds 1 and 7) showed MIC of 12.5 and 25 µg/mL against M. tuberculosis H37Rv, respectively. Inhibition assays against purified recombinant InhA determined IC50 values for these compounds of 0.38 and 0.22 µM, respectively. A crystal structure of the most potent compound, compound 7, bound to InhA revealed the inhibitor to occupy a hydrophobic pocket implicated in binding the aliphatic portions of InhA substrates but distant from the NADH cofactor, i.e., in a site distinct from those occupied by the great majority of known InhA inhibitors. This compound provides an attractive starting template for ligand optimization aimed at discovery of new and effective compounds against M. tuberculosis that act by targeting InhA. |
| Collaborator Contribution | Discovery of new and potent InhA inhibitors as antituberculosis agents: Structure-based virtual screening validated by biological assays and X-ray crystallography. Tuberculosis (TB) caused by Mycobacterium tuberculosis (M. tuberculosis) remains a major worldwide public health problem, especially in areas of high population density and low- and middle-income countries. It is the leading cause of death by infectious disease and the ninth leading overall cause of death worldwide. World Health Organization (WHO) data identified 1.6 million TB deaths and 10 million new TB cases in 2017. (1) Although TB is considered treatable, this is threatened by the spread of drug-resistant strains; it is estimated that globally there are 4.9 million cases of patients infected with multidrug-resistant tuberculosis (MDR-TB) strains resistant to isoniazid and rifampicin, the two most important anti-TB agents. In 2017, 558 000 new cases of TB were identified that were resistant to rifampicin (RR-TB), the most effective first-line drug, with 82% of these MDR-TB. About 8% of TB patients worldwide are estimated to be infected with rifampicin-susceptible, isoniazid-resistant strains (HR-TB). (2) The M. tuberculosis enoyl-acyl carrier protein (ACP) reductase (M. tuberculosis InhA) is an attractive potential target for development of new antituberculosis drugs. InhA catalyzes the NADH-specific reduction of 2-trans-enoyl-ACP (Figure 1A) in the elongation cycle of the fatty acid synthase type II (FAS II) pathway, the final step of fatty acid biosynthesis in M. tuberculosis. (3,4) InhA is the primary target of isoniazid (INH), the second first-line drug for tuberculosis treatment. (5-7) However, the inhibitory activity of isoniazid is reduced by mutations either in InhA or, more commonly, in the KatG catalase-peroxidase responsible for converting the INH prodrug into its active form. (8-10) Thus, identifying inhibitors that directly bind to InhA without the requirement for activation by KatG (direct InhA inhibitors) may represent a valid strategy to overcome isoniazid resistance. (11,12) Hence multiple academic and pharmaceutical efforts have led to the discovery of direct InhA inhibitors. (13-18) However, most of the direct InhA inhibitors so far identified display good InhA inhibitory activity in vitro but poor activity against M. tuberculosis. (13,19-21) Figure 1 Figure 1. NADH-specific reduction of 2-trans-enoyl-ACP catalyzed by InhA (A), in and out conformations of Tyr158 side chain (B). Tyr158 in the in conformation (yellow) in the ternary InhA structure complexed with the C16 substrate analogue THT (trans-2-hexadecenoyl-(N-acetylcysteamine)-thioester (yellow carbon atom) and NAD+ (gray) and Tyr158 in the out conformation (pink) in the binary InhA structure complexed with NAD+ (gray). PDB codes of these structures are 1BVR (3) and 1ENY, (6) respectively. The interactions of InhA with substrate, cofactor, and inhibitors have been extensively studied. (22) One outcome of these investigations is the identification of the active site residue Tyr158 as important both to stabilizing the substrate during the catalytic reaction of M. tuberculosis InhA and to the binding of direct InhA inhibitors. (3,4,23) Two different conformations of the Tyr158 side chain have been identified in binding of direct InhA inhibitors (Figure 1B), an "in" conformation associated with the ternary InhA complex (substrate/cofactor-bound form) and an "out" conformation resembling that observed in the binary InhA complex (cofactor-bound form). (19-24) In the present work, we have applied structure-based virtual screening to select candidate InhA inhibitors from the compound library of the Specs database (www.specs.net), seeking to account for the mobility of Tyr158 by including both conformations of this residue in the screening workflow. This protocol identified two compounds that showed both inhibitory activity against M. tuberculosis cell growth and submicromolar inhibition of purified InhA in in vitro activity assays. A crystal structure for the complex of the most potent of these with InhA identified inhibitor binding in a hydrophobic active site pocket utilized in substrate binding and with Tyr158 in the in conformation. These findings demonstrate that these approaches can identify compounds with InhA inhibitory activity that are active against M. tuberculosis. Further experiments and simulations in progress. |
| Impact | Training in interactive virtual reality, molecular modelling, simulation and structural biology. Exchange visits. Biological assays. Publications: 1: Pakamwong B, Thongdee P, Kamsri B, Phusi N, Taveepanich S, Chayajarus K, Kamsri P, Punkvang A, Hannongbua S, Sangswan J, Suttisintong K, Sureram S, Kittakoop P, Hongmanee P, Santanirand P, Leanpolchareanchai J, Spencer J, Mulholland AJ, Pungpo P. Ligand-Based Virtual Screening for Discovery of Indole Derivatives as Potent DNA Gyrase ATPase Inhibitors Active against Mycobacterium tuberculosis and Hit Validation by Biological Assays. J Chem Inf Model. 2024 Aug 12;64(15):5991-6002. doi: 10.1021/acs.jcim.4c00511. Epub 2024 Jul 12. PMID: 38993154; PMCID: PMC11323271. 2: Kamsri B, Kamsri P, Punkvang A, Chimprasit A, Saparpakorn P, Hannongbua S, Spencer J, Oliveira ASF, Mulholland AJ, Pungpo P. Signal Propagation in the ATPase Domain of Mycobacterium tuberculosis DNA Gyrase from Dynamical- Nonequilibrium Molecular Dynamics Simulations. Biochemistry. 2024 Jun 4;63(11):1493-1504. doi: 10.1021/acs.biochem.4c00161. Epub 2024 May 14. PMID: 38742407; PMCID: PMC11154950. 3: Kamsri B, Pakamwong B, Thongdee P, Phusi N, Kamsri P, Punkvang A, Ketrat S, Saparpakorn P, Hannongbua S, Sangswan J, Suttisintong K, Sureram S, Kittakoop P, Hongmanee P, Santanirand P, Leanpolchareanchai J, Goudar KE, Spencer J, Mulholland AJ, Pungpo P. Bioisosteric Design Identifies Inhibitors of Mycobacterium tuberculosis DNA Gyrase ATPase Activity. J Chem Inf Model. 2023 May 8;63(9):2707-2718. doi: 10.1021/acs.jcim.2c01376. Epub 2023 Apr 19. PMID: 37074047. 4: Thongdee P, Hanwarinroj C, Pakamwong B, Kamsri P, Punkvang A, Leanpolchareanchai J, Ketrat S, Saparpakorn P, Hannongbua S, Ariyachaokun K, Suttisintong K, Sureram S, Kittakoop P, Hongmanee P, Santanirand P, Mukamolova GV, Blood RA, Takebayashi Y, Spencer J, Mulholland AJ, Pungpo P. Virtual Screening Identifies Novel and Potent Inhibitors of Mycobacterium tuberculosis PknB with Antibacterial Activity. J Chem Inf Model. 2022 Dec 26;62(24):6508-6518. doi: 10.1021/acs.jcim.2c00531. Epub 2022 Aug 22. PMID: 35994014. 5: Hanwarinroj C, Thongdee P, Sukchit D, Taveepanich S, Kamsri P, Punkvang A, Ketrat S, Saparpakorn P, Hannongbua S, Suttisintong K, Kittakoop P, Spencer J, Mulholland AJ, Pungpo P. In silico design of novel quinazoline-based compounds as potential Mycobacterium tuberculosis PknB inhibitors through 2D and 3D-QSAR, molecular dynamics simulations combined with pharmacokinetic predictions. J Mol Graph Model. 2022 Sep;115:108231. doi: 10.1016/j.jmgm.2022.108231. Epub 2022 May 28. PMID: 35667143. 6: Hanwarinroj C, Phusi N, Kamsri B, Kamsri P, Punkvang A, Ketrat S, Saparpakorn P, Hannongbua S, Suttisintong K, Kittakoop P, Spencer J, Mulholland AJ, Pungpo P. Discovery of novel and potent InhA inhibitors by an in silico screening and pharmacokinetic prediction. Future Med Chem. 2022 May;14(10):717-729. doi: 10.4155/fmc-2021-0348. Epub 2022 Apr 29. PMID: 35485258. 7: Pakamwong B, Thongdee P, Kamsri B, Phusi N, Kamsri P, Punkvang A, Ketrat S, Saparpakorn P, Hannongbua S, Ariyachaokun K, Suttisintong K, Sureram S, Kittakoop P, Hongmanee P, Santanirand P, Spencer J, Mulholland AJ, Pungpo P. Identification of Potent DNA Gyrase Inhibitors Active against Mycobacterium tuberculosis. J Chem Inf Model. 2022 Apr 11;62(7):1680-1690. doi: 10.1021/acs.jcim.1c01390. Epub 2022 Mar 29. PMID: 35347987. 8: Kamsri P, Hanwarinroj C, Phusi N, Pornprom T, Chayajarus K, Punkvang A, Suttipanta N, Srimanote P, Suttisintong K, Songsiriritthigul C, Saparpakorn P, Hannongbua S, Rattanabunyong S, Seetaha S, Choowongkomon K, Sureram S, Kittakoop P, Hongmanee P, Santanirand P, Chen Z, Zhu W, Blood RA, Takebayashi Y, Hinchliffe P, Mulholland AJ, Spencer J, Pungpo P. Discovery of New and Potent InhA Inhibitors as Antituberculosis Agents: Structure-Based Virtual Screening Validated by Biological Assays and X-ray Crystallography. J Chem Inf Model. 2020 Jan 27;60(1):226-234. doi: 10.1021/acs.jcim.9b00918. Epub 2019 Dec 27. PMID: 31820972. 9: Kamsri P, Punkvang A, Hannongbua S, Suttisintong K, Kittakoop P, Spencer J, Mulholland AJ, Pungpo P. In silico study directed towards identification of the key structural features of GyrB inhibitors targeting MTB DNA gyrase: HQSAR, CoMSIA and molecular dynamics simulations. SAR QSAR Environ Res. 2019 Nov;30(11):775-800. doi: 10.1080/1062936X.2019.1658218. PMID: 31607177. 10: Punkvang A, Kamsri P, Mulholland A, Spencer J, Hannongbua S, Pungpo P. Simulations of Shikimate Dehydrogenase from Mycobacterium tuberculosis in Complex with 3-Dehydroshikimate and NADPH Suggest Strategies for MtbSDH Inhibition. J Chem Inf Model. 2019 Apr 22;59(4):1422-1433. doi: 10.1021/acs.jcim.8b00834. Epub 2019 Mar 14. PMID: 30840825. |
| Start Year | 2015 |
| Title | Confidential |
| Description | Confidential |
| IP Reference | Confidential |
| Protection | Patent / Patent application |
| Year Protection Granted | 2024 |
| Licensed | Commercial In Confidence |
| Impact | Confidential |
| Title | jc14269/CCP-vr-portfolio: First release of DL_POLY simulations in Narupa i-MD. |
| Description | First release. |
| Type Of Technology | Software |
| Year Produced | 2020 |
| Impact | As molecular scientists have made progress in their ability to engineer nanoscale molecular structure, we face new challenges in our ability to engineer molecular dynamics (MD) and flexibility. Dynamics at the molecular scale differs from the familiar mechanics of everyday objects because it involves a complicated, highly correlated, and three-dimensional many-body dynamical choreography which is often nonintuitive even for highly trained researchers. We recently described how interactive molecular dynamics in virtual reality (iMD-VR) can help to meet this challenge, enabling researchers to manipulate real-time MD simulations of flexible structures in 3D. In this article, we outline various efforts to extend immersive technologies to the molecular sciences, and we introduce "Narupa," a flexible, open-source, multiperson iMD-VR software framework which enables groups of researchers to simultaneously cohabit real-time simulation environments to interactively visualize and manipulate the dynamics of molecular structures with atomic-level precision. We outline several application domains where iMD-VR is facilitating research, communication, and creative approaches within the molecular sciences, including training machines to learn potential energy functions, biomolecular conformational sampling, protein-ligand binding, reaction discovery using "on-the-fly" quantum chemistry, and transport dynamics in materials. We touch on iMD-VR's various cognitive and perceptual affordances and outline how these provide research insight for molecular systems. By synergistically combining human spatial reasoning and design insight with computational automation, technologies such as iMD-VR have the potential to improve our ability to understand, engineer, and communicate microscopic dynamical behavior, offering the potential to usher in a new paradigm for engineering molecules and nano-architectures. |
| URL | https://zenodo.org/record/3685789 |