0000000000135744
AUTHOR
Thierry Langer
showing 5 related works from this author
Improving Small Molecule pKa Prediction Using Transfer Learning With Graph Neural Networks
2022
Enumerating protonation states and calculating microstate pKa values of small molecules is an important yet challenging task for lead optimization and molecular modeling. Commercial and non-commercial solutions have notable limitations such as restrictive and expensive licenses, high CPU/GPU hour requirements, or the need for expert knowledge to set up and use. We present a graph neural network model that is trained on 714,906 calculated microstate pKa predictions from molecules obtained from the ChEMBL database. The model is fine-tuned on a set of 5,994 experimental pKa values significantly improving its performance on two challenging test sets. Combining the graph neural network model wit…
Evaluating the stability of pharmacophore features using molecular dynamics simulations.
2016
Abstract Molecular dynamics simulations of twelve protein—ligand systems were used to derive a single, structure based pharmacophore model for each system. These merged models combine the information from the initial experimental structure and from all snapshots saved during the simulation. We compared the merged pharmacophore models with the corresponding PDB pharmacophore models, i.e., the static models generated from an experimental structure in the usual manner. The frequency of individual features, of feature types and the occurrence of features not present in the static model derived from the experimental structure were analyzed. We observed both pharmacophore features not visible in …
A Molecular Dynamics-Shared Pharmacophore Approach to Boost Early-Enrichment Virtual Screening: A Case Study on Peroxisome Proliferator-Activated Rec…
2016
Molecular dynamics (MD) simulations can be used, prior to virtual screening, to add flexibility to proteins and study them in a dynamic way. Furthermore, the use of multiple crystal structures of the same protein containing different co-crystallized ligands can help elucidate the role of the ligand on a protein's active conformation, and then explore the most common interactions between small molecules and the receptor. In this work, we evaluated the contribution of the combined use of MD on crystal structures containing the same protein but different ligands to examine the crucial ligand-protein interactions within the complexes. The study was carried out on peroxisome proliferator-activat…
Pharmacophore Models Derived from Molecular Dynamics Simulations of Protein-Ligand Complexes: A Case Study
2018
A single, merged pharmacophore hypothesis is derived combining 2000 pharmacophore models obtained during a 20 ns molecular dynamics simulation of a protein-ligand complex with one pharmacophore model derived from the initial PDB structure. This merged pharmacophore model contains all features that are present during the simulation and statistical information about the dynamics of the pharmacophore features. Based on the dynamics of the pharmacophore features we derive two distinctive feature patterns resulting in two different pharmacophore models for the analyzed system – the first model consists of features that are obtained from the PDB structure and the second uses two features that ca…
Common Hits Approach: Combining Pharmacophore Modeling and Molecular Dynamics Simulations.
2017
We present a new approach that incorporates flexibility based on extensive MD simulations of protein-ligand complexes into structure-based pharmacophore modeling and virtual screening. The approach uses the multiple coordinate sets saved during the MD simulations and generates for each frame a pharmacophore model. Pharmacophore models with the same pharmacophore features are pooled. In this way the high number of pharmacophore models that results from the MD simulation is reduced to only a few hundred representative pharmacophore models. Virtual screening runs are performed with every representative pharmacophore model; the screening results are combined and rescored to generate a single hi…