46 research outputs found
Interactivity:the missing link between virtual reality technology and drug discovery pipelines
The potential of virtual reality (VR) to contribute to drug design and
development has been recognised for many years. Hardware and software
developments now mean that this potential is beginning to be realised, and VR
methods are being actively used in this sphere. A recent advance is to use VR
not only to visualise and interact with molecular structures, but also to
interact with molecular dynamics simulations of 'on the fly' (interactive
molecular dynamics in VR, IMD-VR), which is useful not only for flexible
docking but also to examine binding processes and conformational changes.
iMD-VR has been shown to be useful for creating complexes of ligands bound to
target proteins, e.g., recently applied to peptide inhibitors of the SARS-CoV-2
main protease. In this review, we use the term 'interactive VR' to refer to
software where interactivity is an inherent part of the user VR experience
e.g., in making structural modifications or interacting with a physically
rigorous molecular dynamics (MD) simulation, as opposed to simply using VR
controllers to rotate and translate the molecule for enhanced visualisation.
Here, we describe these methods and their application to problems relevant to
drug discovery, highlighting the possibilities that they offer in this arena.
We suggest that the ease of viewing and manipulating molecular structures and
dynamics, and the ability to modify structures on the fly (e.g., adding or
deleting atoms) makes modern interactive VR a valuable tool to add to the
armoury of drug development methods.Comment: 19 pages, 3 figure
Free energy along drug-protein binding pathways interactively sampled in virtual reality
We describe a two-step approach for combining interactive molecular dynamics
in virtual reality (iMD-VR) with free energy (FE) calculation to explore the
dynamics of biological processes at the molecular level. We refer to this
combined approach as iMD-VR-FE. Stage one involves using a state-of-the-art
iMD-VR framework to generate a diverse range of protein-ligand unbinding
pathways, benefitting from the sophistication of human spatial and chemical
intuition. Stage two involves using the iMD-VR-sampled pathways as initial
guesses for defining a path-based reaction coordinate from which we can obtain
a corresponding free energy profile using FE methods. To investigate the
performance of the method, we apply iMD-VR-FE to investigate the unbinding of a
benzamidine ligand from a trypsin protein. The binding free energy calculated
using iMD-VR-FE is similar for each pathway, indicating internal consistency.
Moreover, the resulting free energy profiles can distinguish energetic
differences between pathways corresponding to various protein-ligand
conformations (e.g., helping to identify pathways that are more favourable) and
enable identification of metastable states along the pathways. The two-step
iMD-VR-FE approach offers an intuitive way for researchers to test hypotheses
for candidate pathways in biomolecular systems, quickly obtaining both
qualitative and quantitative insight
Circadian tumor infiltration and function of CD8+ T cells dictate immunotherapy efficacy.
The quality and quantity of tumor-infiltrating lymphocytes, particularly CD8 <sup>+</sup> T cells, are important parameters for the control of tumor growth and response to immunotherapy. Here, we show in murine and human cancers that these parameters exhibit circadian oscillations, driven by both the endogenous circadian clock of leukocytes and rhythmic leukocyte infiltration, which depends on the circadian clock of endothelial cells in the tumor microenvironment. To harness these rhythms therapeutically, we demonstrate that efficacy of chimeric antigen receptor T cell therapy and immune checkpoint blockade can be improved by adjusting the time of treatment during the day. Furthermore, time-of-day-dependent T cell signatures in murine tumor models predict overall survival in patients with melanoma and correlate with response to anti-PD-1 therapy. Our data demonstrate the functional significance of circadian dynamics in the tumor microenvironment and suggest the importance of leveraging these features for improving future clinical trial design and patient care
The effects of mutant Ras proteins on the cell signalome
The genetic alterations in cancer cells are tightly linked to signaling pathway dysregulation. Ras is a key molecule that controls several tumorigenesis-related processes, and mutations in RAS genes often lead to unbiased intensification of signaling networks that fuel cancer progression. In this article, we review recent studies that describe mutant Ras-regulated signaling routes and their cross-talk. In addition to the two main Ras-driven signaling pathways, i.e., the RAF/MEK/ERK and PI3K/AKT/mTOR pathways, we have also collected emerging data showing the importance of Ras in other signaling pathways, including the RAC/PAK, RalGDS/Ral, and PKC/PLC signaling pathways. Moreover, microRNA-regulated Ras-associated signaling pathways are also discussed to highlight the importance of Ras regulation in cancer. Finally, emerging data show that the signal alterations in specific cell types, such as cancer stem cells, could promote cancer development. Therefore, we also cover the up-to-date findings related to Ras-regulated signal transduction in cancer stem cells. © 2020, The Author(s)
Computational Methods Used in Hit-to-Lead and Lead Optimization Stages of Structure-Based Drug Discovery
GPCR modeling approaches are widely used in the hit-to-lead (H2L) and lead optimization (LO) stages of drug discovery. The aims of these modeling approaches are to predict the 3D structures of the receptor-ligand complexes, to explore the key interactions between the receptor and the ligand and to utilize these insights in the design of new molecules with improved binding, selectivity or other pharmacological properties. In this book chapter, we present a brief survey of key computational approaches integrated with hierarchical GPCR modeling protocol (HGMP) used in hit-to-lead (H2L) and in lead optimization (LO) stages of structure-based drug discovery (SBDD). We outline the differences in modeling strategies used in H2L and LO of SBDD and illustrate how these tools have been applied in three drug discovery projects
Ultrastructure de la cellulose dans les tissus de rosier cultivés in vitro
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