scholarly journals Structural Perspective on Revealing and Altering Molecular Functions of Genetic Variants Linked with Diseases

2019 ◽  
Vol 20 (3) ◽  
pp. 548 ◽  
Author(s):  
Yunhui Peng ◽  
Emil Alexov ◽  
Sankar Basu
Keyword(s):  
Drug Design ◽  
Structural Information ◽  
Radical Change ◽  
Biological Macromolecules ◽  
Free Energies ◽  
Biophysical Properties ◽  
Structure Based Drug Design ◽  
Promising Alternative ◽  
Intrinsically Disordered ◽  
Binding Free Energies

Structural information of biological macromolecules is crucial and necessary to deliver predictions about the effects of mutations—whether polymorphic or deleterious (i.e., disease causing), wherein, thermodynamic parameters, namely, folding and binding free energies potentially serve as effective biomarkers. It may be emphasized that the effect of a mutation depends on various factors, including the type of protein (globular, membrane or intrinsically disordered protein) and the structural context in which it occurs. Such information may positively aid drug-design. Furthermore, due to the intrinsic plasticity of proteins, even mutations involving radical change of the structural and physico–chemical properties of the amino acids (native vs. mutant) can still have minimal effects on protein thermodynamics. However, if a mutation causes significant perturbation by either folding or binding free energies, it is quite likely to be deleterious. Mitigating such effects is a promising alternative to the traditional approaches of designing inhibitors. This can be done by structure-based in silico screening of small molecules for which binding to the dysfunctional protein restores its wild type thermodynamics. In this review we emphasize the effects of mutations on two important biophysical properties, stability and binding affinity, and how structures can be used for structure-based drug design to mitigate the effects of disease-causing variants on the above biophysical properties.

scholarly journals Structural Perspective on Revealing and Altering Molecular Functions of Genetic Variants Linked with Diseases

2019 ◽  
Author(s):  
Yunhui Peng ◽  
Emil Alexov ◽  
Sankar Basu
Keyword(s):  
Drug Design ◽  
Structural Information ◽  
Chemical Properties ◽  
Radical Change ◽  
Biological Macromolecules ◽  
Free Energies ◽  
Structure Based Drug Design ◽  
Promising Alternative ◽  
Intrinsically Disordered ◽  
Binding Free Energies

Structural information of biological macromolecules is crucial and necessary to deliver predictions about the effects of mutations—whether polymorphic or deleterious (i.e., disease causing), wherein, thermodynamic parameters, namely, folding and binding free energies potentially serve as effective biomarkers. It may be emphasized that the effect of a mutation depends on various factors, including the type of protein (globular, membrane or intrinsically disordered protein) and the structural context to which it occurs. Such information may positively aid drug-design. Furthermore, due to the intrinsic plasticity of proteins, even mutations involving radical change of the structural and physico-chemical properties of the amino acids (native vs. mutant) can still have minimal effects of protein thermodynamics. However, if a mutation causes significant perturbation of either folding or binding free energies, it is quite likely to be deleterious. Mitigating such effects is a promising alternative to the traditional approaches of designing inhibitors. This can be done by structure-based in silico screening of small molecules for which binding to the dysfunctional protein restores its wild type thermodynamics. In this review we emphasize on the effects of mutations on two important biophysical characteristics, stability and binding affinity, and how structures can be used for structure-based drug design to mitigate the effects of disease-causing variants on the above biophysical characteristics.

scholarly journals Structural Perspective on Revealing and Altering Molecular Functions of Genetic Variants Linked with Diseases

2019 ◽  
Author(s):  
Yunhui Peng ◽  
Emil Alexov ◽  
Sankar Basu
Keyword(s):  
Structural Information ◽  
Chemical Properties ◽  
Intrinsically Disordered Protein ◽  
Radical Change ◽  
Biological Macromolecules ◽  
Free Energies ◽  
Structure Based Drug Design ◽  
Promising Alternative ◽  
Intrinsically Disordered ◽  
Binding Free Energies

Structural information of biological macromolecules is crucial and necessary to deliver predictions about the effects of mutations—whether polymorphic or deleterious (i.e., disease causing), wherein, thermodynamic parameters, namely, folding and binding free energies potentially serve as effective biomarkers. It is to be emphasized that the effect of a mutation depends on various factors, including the type of protein (globular, membrane or intrinsically disordered protein) and the structural context to which it occurs. Furthermore, due to the intrinsic plasticity of proteins, even mutations involving radical change of the structural and physico-chemical properties of the amino acids (native vs. mutant) can still have minimal effects of protein thermodynamics. However, if a mutation causes significant perturbation of either folding or binding free energies, it is quite likely to be deleterious. Mitigating such effects is a promising alternative to the traditional approaches of designing inhibitors. This can be done by structure-based in silico screening of small molecules for which binding to the dysfunctional protein restores its wild type thermodynamics. In this review we emphasize on the effects of mutations on two important biophysical characteristics, stability and binding affinity and how structures can be used for structure-based drug design to mitigate the effects of disease-causing variants on the above biophysical characteristics.

scholarly journals Structural Perspective on Revealing and Altering Molecular Mechanisms of Genetic Variants Linked with Diseases

2018 ◽  
Author(s):  
Yunhui Peng ◽  
Emil Alexov ◽  
Sankar Basu
Keyword(s):  
Molecular Mechanisms ◽  
Structural Information ◽  
Chemical Properties ◽  
Radical Change ◽  
Biological Macromolecules ◽  
Free Energies ◽  
Structure Based Drug Design ◽  
Promising Alternative ◽  
Intrinsically Disordered ◽  
Binding Free Energies

Structural information of biological macromolecules is crucial and necessary to deliver predictions about the effects of mutations—whether polymorphic or deleterious (i.e., disease causing), wherein, thermodynamic parameters, namely, folding and binding free energies potentially serve as effective biomarkers. It is to be emphasized that the effect of a mutation depends on various factors, including the type of protein (globular, membrane or intrinsically disordered protein) and the structural context to which it occurs. Furthermore, due to the intrinsic plasticity of proteins, even mutations involving radical change of the structural and physico-chemical properties of the amino acids (native vs. mutant) can still have minimal effects of protein thermodynamics. However, if a mutation causes significant perturbation of either folding or binding free energies, it is quite likely to be deleterious. Mitigating such effects is a promising alternative to the traditional approaches of designing inhibitors. This can be done by structure-based in silico screening of small molecules for which binding to the dysfunctional protein restores its wild type thermodynamics. In this review we emphasize on the effects of mutations on two important biophysical characteristics, stability and binding affinity and how structures can be used for structure-based drug design to mitigate the effects of disease-causing variants on the above biophysical characteristics.

scholarly journals Alchemical Absolute Protein-Ligand Binding Free Energies for Drug Design

2021 ◽  
Author(s):  
Yuriy Khalak ◽  
Gary Tresdern ◽  
Matteo Aldeghi ◽  
Hannah Magdalena Baumann ◽  
David L. Mobley ◽  
...  
Keyword(s):  
Free Energy ◽  
Drug Discovery ◽  
Drug Design ◽  
Ligand Binding ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Free Energies ◽  
Energy Calculations ◽  
Binding Free Energy Calculations ◽  
Binding Free Energies

The recent advances in relative protein-ligand binding free energy calculations have shown the value of alchemical methods in drug discovery. Accurately assessing absolute binding free energies, although highly desired, remains...

scholarly journals Applications of Cryo-EM in small molecule and biologics drug design

2021 ◽  
Author(s):  
Joshua A. Lees ◽  
Joao M. Dias ◽  
Seungil Han
Keyword(s):  
Drug Design ◽  
Structural Characterization ◽  
Viral Vectors ◽  
Biological Macromolecules ◽  
Structure Based Drug Design ◽  
X Ray Crystallography ◽  
Technological Advances ◽  
High Resolution Analysis ◽  
Resolution Analysis

Electron cryo-microscopy (cryo-EM) is a powerful technique for the structural characterization of biological macromolecules, enabling high-resolution analysis of targets once inaccessible to structural interrogation. In recent years, pharmaceutical companies have begun to utilize cryo-EM for structure-based drug design. Structural analysis of integral membrane proteins, which comprise a large proportion of druggable targets and pose particular challenges for X-ray crystallography, by cryo-EM has enabled insights into important drug target families such as G protein-coupled receptors (GPCRs), ion channels, and solute carrier (SLCs) proteins. Structural characterization of biologics, such as vaccines, viral vectors, and gene therapy agents, has also become significantly more tractable. As a result, cryo-EM has begun to make major impacts in bringing critical therapeutics to market. In this review, we discuss recent instructive examples of impacts from cryo-EM in therapeutics design, focusing largely on its implementation at Pfizer. We also discuss the opportunities afforded by emerging technological advances in cryo-EM, and the prospects for future development of the technique.

scholarly journals Insights into Structures and Dynamics of Flavivirus Proteases from NMR Studies

2020 ◽  
Vol 21 (7) ◽  
pp. 2527 ◽  
Author(s):  
Qingxin Li ◽  
CongBao Kang
Keyword(s):  
Nmr Spectroscopy ◽  
Drug Design ◽  
Conformational Changes ◽  
Structural Information ◽  
Protein Structures ◽  
Rational Drug Design ◽  
Solution Nmr ◽  
Nmr Studies ◽  
Structure Based Drug Design ◽  
Additional Information

Nuclear magnetic resonance (NMR) spectroscopy plays important roles in structural biology and drug discovery, as it is a powerful tool to understand protein structures, dynamics, and ligand binding under physiological conditions. The protease of flaviviruses is an attractive target for developing antivirals because it is essential for the maturation of viral proteins. High-resolution structures of the proteases in the absence and presence of ligands/inhibitors were determined using X-ray crystallography, providing structural information for rational drug design. Structural studies suggest that proteases from Dengue virus (DENV), West Nile virus (WNV), and Zika virus (ZIKV) exist in open and closed conformations. Solution NMR studies showed that the closed conformation is predominant in solution and should be utilized in structure-based drug design. Here, we reviewed solution NMR studies of the proteases from these viruses. The accumulated studies demonstrated that NMR spectroscopy provides additional information to understand conformational changes of these proteases in the absence and presence of substrates/inhibitors. In addition, NMR spectroscopy can be used for identifying fragment hits that can be further developed into potent protease inhibitors.

The potential of cryo-electron microscopy for structure-based drug design

2017 ◽  
Vol 61 (5) ◽  
pp. 543-560 ◽  
Author(s):  
Andreas Boland ◽  
Leifu Chang ◽  
David Barford
Keyword(s):  
Electron Microscopy ◽  
Drug Discovery ◽  
Drug Design ◽  
Structural Information ◽  
Biological Molecules ◽  
Ligand Complex ◽  
Structure Based Drug Design ◽  
Technical Developments ◽  
Cryo Electron Microscopy ◽  
Therapeutic Development

Structure-based drug design plays a central role in therapeutic development. Until recently, protein crystallography and NMR have dominated experimental approaches to obtain structural information of biological molecules. However, in recent years rapid technical developments in single particle cryo-electron microscopy (cryo-EM) have enabled the determination to near-atomic resolution of macromolecules ranging from large multi-subunit molecular machines to proteins as small as 64 kDa. These advances have revolutionized structural biology by hugely expanding both the range of macromolecules whose structures can be determined, and by providing a description of macromolecular dynamics. Cryo-EM is now poised to similarly transform the discipline of structure-based drug discovery. This article reviews the potential of cryo-EM for drug discovery with reference to protein ligand complex structures determined using this technique.

scholarly journals The Growing Role of Electron Microscopy in Anti-parasitic Drug Discovery

2019 ◽  
Vol 25 (39) ◽  
pp. 5279-5290
Author(s):  
R.M. Johnson ◽  
S. Rawson ◽  
M.J. McPhillie ◽  
C.W.G. Fishwick ◽  
S.P. Muench
Keyword(s):  
Electron Microscopy ◽  
Drug Discovery ◽  
High Resolution ◽  
Drug Design ◽  
Structural Information ◽  
Protein Structures ◽  
Parasite Protein ◽  
Structure Based Drug Design ◽  
Dramatic Rise ◽  
Review Reports

Background: Parasite diseases are a huge burden on human health causing significant morbidity and mortality. However, parasite structure based drug discovery programmes have been hindered by a lack of high resolution structural information from parasite derived proteins and have often relied upon homology models from mammalian systems. The recent renaissance in electron microscopy (EM) has caused a dramatic rise in the number of structures being determined at high resolution and subsequently enabled it to be thought of as a tool in drug discovery. Results: In this review, we discuss the challenges associated with the structural determination of parasite proteins including the difficulties in obtaining sufficient quantities of protein. We then discuss the reasons behind the resurgence in EM, how it may overcome some of these challenges and provide examples of EM derived parasite protein structures. Finally, we discuss the challenges which EM needs to overcome before it is used as a mainstream technique in anti-parasite drug discovery. Conclusions: This review reports the progress that has been made in obtaining sufficient quantities of proteins for structural studies and the role EM may play in future structure based drug design programs. The outlook for future structure based drug design programs against some of the most devastating parasite diseases looks promising.

scholarly journals Rapid non-empirical approaches for estimating relative binding free energies.

1995 ◽  
Vol 42 (4) ◽  
pp. 525-535 ◽  
Author(s):  
A E Mark ◽  
Y Xu ◽  
H Liu ◽  
W F Van Gunsteren
Keyword(s):  
Free Energy Perturbation ◽  
Free Energies ◽  
Empirical Methods ◽  
Structure Based Drug Design ◽  
Perturbation Formula ◽  
Relative Binding ◽  
Novel Approach ◽  
Energy Perturbation ◽  
Empirical Approaches ◽  
Binding Free Energies

Rapid non-empirical methods for estimating binding free energies are reviewed. A novel approach based on the application of the free energy perturbation formula to a biased ensemble is presented. Preliminary results demonstrating the applicability of this approach in protein systems are shown and the potential of this method in structure-based drug design is discussed.

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