Ewa I Chudyk

Ewa I Chudyk
Vertex Pharmaceuticals

PhD

About

17
Publications
2,980
Reads
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395
Citations
Additional affiliations
November 2013 - present
Technische Universität München
Position
  • PostDoc Position
October 2013 - July 2014
Technische Universität München
Position
  • PostDoc Position
October 2009 - September 2013
University of Bristol
Position
  • PhD Student

Publications

Publications (17)
Article
Class A β-lactamases cause clinically relevant resistance to β-lactam antibiotics. Carbapenem degradation is a particular concern. We present an efficient QM/MM molecular simulation protocol that accurately predicts the activity of β-lactamases against carbapenems. Simulations take <24 CPU hours, a >99% reduction, and do not require fitting against...
Preprint
div>Breakdown of β-lactam antibiotics by β-lactamases is one of the most common resistance mechanisms against these drugs. Here, we present a computationally efficient combined quantum mechanics/molecular mechanics simulation protocol for hydrolysis of the β-lactamase acylenzyme with meropenem, a carbapenem antibiotic. Starting from the previously...
Article
In recent years there has been a paradigm shift in how data is being used to progress early drug discovery campaigns from hit identification to candidate selection. Significant developments in data mining methods and the accessibility of tools for research scientists have been instrumental in reducing drug discovery timelines and in increasing the...
Article
There are countless reports citing the importance of diversity in the academic, industrial and government workplace (1, 2). But to achieve this goal, diverse role models need to have impact early in the education of young people encouraged and attracted to STEM-related studies.
Chapter
The understanding of binding interactions between any protein and a small molecule plays a key role in the rationalization of affinity and selectivity. It is essential for an efficient structure-based drug design (SBDD) process. FMO enables ab initio approaches to be applied to systems that conventional quantum-mechanical (QM) methods would find ch...
Article
Full-text available
The understanding of binding interactions between any protein and a small molecule plays a key role in the rationalization of affinity and selectivity and is essential for an efficient structure-based drug discovery (SBDD) process. Clearly, to begin SBDD, a structure is needed, and although there has been fantastic progress in solving G-protein-cou...
Article
Inhibition of the non-receptor tyrosine kinase ITK may represent a novel treatment for allergic asthma. In our previous reports we described the discovery of sulfonylpyridine (SAP), benzothiazole (BZT), indazole (IND), and tetrahydroindazole (THI) series as novel ITK inhibitors, and how computational tools such as dihedral scans and docking were us...
Article
Our interpretation of ligand-protein interactions is often informed by high-resolution structures, which represent the cornerstone of structure-based drug design. However, visual inspection and molecular mechanics ap-proaches cannot explain the full complexity of molecular interactions. Quantum Mechanics approaches are often too computationally exp...
Article
Computational methods play a pivotal role in the early stages of small molecule drug discovery and are widely applied in virtual screening, structure optimization, and compound activity profiling. Over the past half century in medicinal chemistry, almost all the attention has been directed to protein–ligand binding and computational tools were crea...
Chapter
Full-text available
The study of molecular behavior at high levels of theoretical accuracy has entered into a new age in computational drug discovery where quantum mechanical (QM) methods are becoming increasingly popular. Theoretically rigorous calculations can be prohibitively computationally expensive and time consuming. These two factors have necessitated the deve...
Article
Full-text available
Carbapenems, ‘last resort’ antibiotics for many bacterial infections, can now be broken down by several class A β-lactamases (i.e. carbapenemases). Here, carbapenemase activity is predicted through QM/MM dynamics simulations of acyl-enzyme deacylation, requiring only the 3D structure of the apo-enzyme. This may assist in anticipating resistance and...
Article
Fatty acid amide hydrolase (FAAH) is a member of the amidase signature family, and is responsible for the hydrolytic deactivation of fatty acid amide neuromodulators, such as anandamide. FAAH carries an unusual catalytic triad consisting of Lys-Ser-Ser, which uniquely enables the enzyme to cleave amides and esters at similar rates. The acylation of...
Article
Carbapenems are the most potent β-lactam antibiotics and key drugs for treating infections by Gram-negative bacteria. In such organisms, β-lactam resistance arises principally from β-lactamase production. Although carbapenems escape the activity of most β-lactamases, due in the class A enzymes to slow deacylation of the covalent acylenzyme intermed...
Article
QM/MM modelling of FAAH inactivation by O-biphenyl-3-yl carbamates identifies the deprotonation of Ser241 as the key reaction step, explaining why FAAH is insensitive to the electron-donor effect of conjugated substituents; this may aid design of new inhibitors with improved selectivity and in vivo potency.
Article
Self-consistent charge density functional tight binding (SCC-DFTB) is a promising method for hybrid quantum mechanics/molecular mechanics (QM/MM) simulations of enzyme-catalyzed reactions. The acylation reaction of fatty acid amide hydrolase (FAAH), a promising drug target, was investigated by applying a SCC-DFTB/CHARMM27 scheme. Calculated potenti...

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Projects

Project (1)
Project
The Big Data in BioMolecular Systems meeting 9 September 2016, School of Pharmacy, UCL, London, UK https://bigdatamgms.wordpress.com/ Registration is now open! The conference Big Data in Biomolecular Systems will take place on Friday 9th September 2016 at the School of Pharmacy, UCL, London. The aim of the conference is to discuss recent progress in managing, analysing and storing big data pertaining to biomolecular systems. The main topics of the meeting include big data and healthcare, big data and biomolecular simulations, functional genomics, biological networks, network pharmacology, functional bioinformatics and chemical data collections. Please refer to our provisional schedule for more details on planned sessions and speakers. Both academic and industrial presenters are welcome for talks and posters. Registration is now open and the closing date is the 15th August 2016. However, as the number of people we can accommodate in the venue is limited please make sure you register as soon as possible. So far the confirmed list of invited speakers is as follows: Prof. Charlotte Deane, University of Oxford Dr Jon Fuller, KNIME Dr Ed Griffen, Medchemica Ltd. Prof. Charlie Laughton, University of Nottingham & The MuG consortium Dr Christian Lemmen, BioSolveIT GmbH Dr Dean Plumbley, Stratified Medical, London Prof. Natasa Przulj, University College London Dr Arvind Ramanathan, Oak Ridge National Laboratory Prof. Carlos P. Sosa, University of Minnesota & Mayo Clinic Dr Bryn Williams-Jones, Open PHACTS Foundation The Big Data in Biomolecular Systems meeting is organised by the Molecular Graphics and Modelling Society (MGMS): http://www.mgms.org/ We look forward to meeting you in September!