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Theoretical studies of protein-ligand binding

Misini Ignjatovic, Majda LU (2019)
Abstract
Understanding how drugs work is of great importance, since it can facilitate drug discovery, both time- and costwise. At the same time, it is important to have methods that can help predict how well does a potential drug molecule bind to its target. Computational methods can in many ways contribute to drug design process. In this thesis, we employ different computational approaches to study the binding of various ligands to galectin-3 protein, which is an excellent model system and an interesting therapeutic target. We study the effects of solvation
thermodynamics, protein and ligand conformational entropy, as well as specific protein–ligand interactions. Our results indicate that accurate modelling of protein–ligand binding requires... (More)
Understanding how drugs work is of great importance, since it can facilitate drug discovery, both time- and costwise. At the same time, it is important to have methods that can help predict how well does a potential drug molecule bind to its target. Computational methods can in many ways contribute to drug design process. In this thesis, we employ different computational approaches to study the binding of various ligands to galectin-3 protein, which is an excellent model system and an interesting therapeutic target. We study the effects of solvation
thermodynamics, protein and ligand conformational entropy, as well as specific protein–ligand interactions. Our results indicate that accurate modelling of protein–ligand binding requires careful consideration of solvation and protein ligand conformational entropy, since they contribute significantly to protein-ligand binding free energies. We also compared different methods used to study the water structure and thermodynamics in the protein–ligand binding site, where we showed that solvent-exposure of the binding site may dictate the choice of the method. Moreover, we participated in the D3R and SAMPL6 blind challenges, where we tested the performance of different methods used to estimate binding affinities. We have showed that the predictions of relative binding affinities improve if displaced water molecules are included in the free-energy perturbation calculations and if the ligand is treated by quantum mechanical methods. (Less)
Abstract (Swedish)
Understanding how drugs work is of great importance, since it can facilitate drug discovery, both time- and costwise. At the same time, it is important to have methods that can help predict how well does a potential drug molecule bind to its target. Computational methods can in many ways contribute to drug design process. In this thesis, we employ different computational approaches to study the binding of various ligands to galectin-3 protein, which is an excellent model system and an interesting therapeutic target. We study the effects of solvation
thermodynamics, protein and ligand conformational entropy, as well as specific protein–ligand interactions. Our results indicate that accurate modelling of protein–ligand binding requires... (More)
Understanding how drugs work is of great importance, since it can facilitate drug discovery, both time- and costwise. At the same time, it is important to have methods that can help predict how well does a potential drug molecule bind to its target. Computational methods can in many ways contribute to drug design process. In this thesis, we employ different computational approaches to study the binding of various ligands to galectin-3 protein, which is an excellent model system and an interesting therapeutic target. We study the effects of solvation
thermodynamics, protein and ligand conformational entropy, as well as specific protein–ligand interactions. Our results indicate that accurate modelling of protein–ligand binding requires careful consideration of solvation and protein ligand conformational entropy, since they contribute significantly to protein-ligand binding free energies. We also compared different methods used to study the water structure and thermodynamics in the protein–ligand binding site, where we showed that solvent-exposure of the binding site may dictate the choice of the method. Moreover, we participated in the D3R and SAMPL6 blind challenges, where we tested the performance of different methods used to estimate binding affinities. We have showed that the predictions of relative binding affinities improve if displaced water molecules are included in the free-energy perturbation calculations and if the ligand is treated by quantum mechanical methods. (Less)
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author
supervisor
opponent
  • Professor Gohlke, Holger, Heinrich-Heine-University, Düsseldorf, Germany
organization
publishing date
type
Thesis
publication status
published
subject
keywords
Protein-ligand binding, MD, GIST, GCMC, FEP, Solvation, Entropy, Water, QM/MM-FEP, Protein-ligand binding, MD, GIST, GCMC, FEP, Solvation, Entropy, Water, QM/MM-FEP
pages
212 pages
publisher
Lund University (Media-Tryck)
defense location
Lecture hall B, Center for Chemistry and Chemical Engineering (Kemicentrum), Naturvetarvägen 14, Lund
defense date
2019-06-05 09:15:00
ISBN
978-91-7422-662-1
978-91-7422-663-8
language
English
LU publication?
yes
id
200a1e41-d328-4573-80ea-5b64dded0bad
date added to LUP
2019-05-09 11:13:08
date last changed
2019-05-13 18:03:07
@phdthesis{200a1e41-d328-4573-80ea-5b64dded0bad,
  abstract     = {Understanding how drugs work is of great importance, since it can facilitate drug discovery, both time- and costwise. At the same time, it is important to have methods that can help predict how well does a potential drug molecule bind to its target. Computational methods can in many ways contribute to drug design process. In this thesis, we employ different computational approaches to study the binding of various ligands to galectin-3 protein, which is an excellent model system and an interesting therapeutic target. We study the effects of solvation<br/>thermodynamics, protein and ligand conformational entropy, as well as specific protein–ligand interactions. Our results indicate that accurate modelling of protein–ligand binding requires careful consideration of solvation and protein ligand conformational entropy, since they contribute significantly to protein-ligand binding free energies. We also compared different methods used to study the water structure and thermodynamics in the protein–ligand binding site, where we showed that solvent-exposure of the binding site may dictate the choice of the method. Moreover, we participated in the D3R and SAMPL6 blind challenges, where we tested the performance of different methods used to estimate binding affinities. We have showed that the predictions of relative binding affinities improve if displaced water molecules are included in the free-energy perturbation calculations and if the ligand is treated by quantum mechanical methods.},
  author       = {Misini Ignjatovic, Majda},
  isbn         = {978-91-7422-662-1},
  language     = {eng},
  month        = {06},
  publisher    = {Lund University (Media-Tryck)},
  school       = {Lund University},
  title        = {Theoretical studies of protein-ligand binding},
  url          = {https://lup.lub.lu.se/search/ws/files/64022442/MMI_thesis_open.pdf},
  year         = {2019},
}