scholarly journals Estimation of the protein–ligand interaction energy for model building and validation

2017 ◽  
Vol 73 (3) ◽  
pp. 195-202 ◽  
Author(s):  
Daria A. Beshnova ◽  
Joana Pereira ◽  
Victor S. Lamzin
Keyword(s):  
Model Building ◽  
Data Bank ◽  
Binding Mode ◽  
Automated Identification ◽  
Ligand Interaction ◽  
New Approach ◽  
X Ray Crystallography ◽  
Protein Ligand Interactions ◽  
Ligand Interactions ◽  
Protein Ligand Interaction

Macromolecular X-ray crystallography is one of the main experimental techniques to visualize protein–ligand interactions. The high complexity of the ligand universe, however, has delayed the development of efficient methods for the automated identification, fitting and validation of ligands in their electron-density clusters. The identification and fitting are primarily based on the density itself and do not take into account the protein environment, which is a step that is only taken during the validation of the proposed binding mode. Here, a new approach, based on the estimation of the major energetic terms of protein–ligand interaction, is introduced for the automated identification of crystallographic ligands in the indicated binding site withARP/wARP. The applicability of the method to the validation of protein–ligand models from the Protein Data Bank is demonstrated by the detection of models that are `questionable' and the pinpointing of unfavourable interatomic contacts.

scholarly journals An Investigation of Small GTPases in relation to Liver Tumorigenesis Using Traditional Chinese Medicine

2014 ◽  
Vol 2014 ◽  
pp. 1-11 ◽  
Author(s):  
Tzu-Chieh Hung ◽  
Wen-Yuan Lee ◽  
Kuen-Bao Chen ◽  
Yueh-Chiu Chan ◽  
Calvin Yu-Chian Chen
Keyword(s):  
Molecular Dynamics ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Hydrophobic Interactions ◽  
Small Gtpases ◽  
Ligand Interaction ◽  
Protein Ligand Interactions ◽  
Ligand Interactions ◽  
Protein Ligand Interaction ◽  
Better Than

Recently, an important topic of liver tumorigenesis had been published in 2013. In this report, Ras and Rho had defined the relation of liver tumorigenesis. The traditional Chinese medicine (TCM) database has been screened for molecular compounds by simulating molecular docking and molecular dynamics to regulate Ras and liver tumorigenesis. Saussureamine C, S-allylmercaptocysteine, and Tryptophan are selected based on the highest docking score than other TCM compounds. The molecular dynamics are helpful in the analysis and detection of protein-ligand interactions. Based on the docking poses, hydrophobic interactions, and hydrogen bond variations, this research surmises are the main regions of important amino acids in Ras. In addition to the detection of TCM compound efficacy, we suggest Saussureamine C is better than the others for protein-ligand interaction.

Label-free fluorescence detection of protein–ligand interactions based on binding-induced enzymatic cleavage protection

2020 ◽  
Vol 44 (42) ◽  
pp. 18250-18255
Author(s):  
Lunxi Duan ◽  
Hongliang Yao ◽  
Yong Xie ◽  
Ke Pan
Keyword(s):  
Fluorescence Detection ◽  
Enzymatic Cleavage ◽  
Label Free ◽  
Ligand Interaction ◽  
Protein Ligand Interactions ◽  
Ligand Interactions ◽  
Protein Ligand Interaction

Label-free fluorescence monitoring protein–ligand interaction based on binding induced enzymatic cleavage protection.

scholarly journals Protein-Ligand Interactions of the D-Galactose/D-Glucose-Binding Protein as a Potential Sensing Probe of Glucose Biosensors

2012 ◽  
Vol 27 ◽  
pp. 373-379 ◽  
Author(s):  
Olga V. Stepanenko ◽  
Olesya V. Stepanenko ◽  
Alexander V. Fonin ◽  
Vladislav V. Verkhusha ◽  
Irina M. Kuznetsova ◽  
...  
Keyword(s):  
Guanidine Hydrochloride ◽  
Native State ◽  
Ligand Interaction ◽  
Protein Ligand Interactions ◽  
Limiting Step ◽  
Glucose Binding ◽  
Unfolded State ◽  
Ligand Interactions ◽  
Protein Ligand Interaction ◽  
Glucose Binding Protein

In this paper we have studied peculiarities of protein-ligand interaction under different conditions. We have shown that guanidine hydrochloride (GdnHCI) unfolding-refolding of GGBP in the presence of glucose (Glc) is reversible, but the equilibrium curves of complex refolding-unfolding have been attained only after 10-day incubation of GGBP/Glc in the presence of GdnHCl. This effect has not been revealed at heat-induced GGBP/Glc denaturation. Slow equilibration between the native protein in GGBP/Glc complex and the unfolded state of protein in the GdnHCl presence is connected with increased viscosity of solution at moderate and high GdnHCl concentrations which interferes with diffusion of glucose molecules. Thus, the limiting step of the unfolding-refolding process of the complex GGBP/Glc is the disruption/tuning of the configuration fit between the protein in the native state and the ligand.

scholarly journals Multi-PLI: interpretable multi‐task deep learning model for unifying protein–ligand interaction datasets

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Fan Hu ◽  
Jiaxin Jiang ◽  
Dongqi Wang ◽  
Muchun Zhu ◽  
Peng Yin
Keyword(s):  
Deep Learning ◽  
Early Stage ◽  
Binary Classification ◽  
Ligand Interaction ◽  
Set Size ◽  
Protein Ligand Interactions ◽  
Ligand Interactions ◽  
Biological Interpretation ◽  
Protein Ligand Interaction ◽  
Deep Learning Model

AbstractThe assessment of protein–ligand interactions is critical at early stage of drug discovery. Computational approaches for efficiently predicting such interactions facilitate drug development. Recently, methods based on deep learning, including structure- and sequence-based models, have achieved impressive performance on several different datasets. However, their application still suffers from a generalizability issue because of insufficient data, especially for structure based models, as well as a heterogeneity problem because of different label measurements and varying proteins across datasets. Here, we present an interpretable multi-task model to evaluate protein–ligand interaction (Multi-PLI). The model can run classification (binding or not) and regression (binding affinity) tasks concurrently by unifying different datasets. The model outperforms traditional docking and machine learning on both binary classification and regression tasks and achieves competitive results compared with some structure-based deep learning methods, even with the same training set size. Furthermore, combined with the proposed occlusion algorithm, the model can predict the important amino acids of proteins that are crucial for binding, thus providing a biological interpretation.

scholarly journals SSnet: A Deep Learning Approach for Protein-Ligand Interaction Prediction

2019 ◽  
Author(s):  
Niraj Verma ◽  
Xingming Qu ◽  
Francesco Trozzi ◽  
Mohamed Elsaied ◽  
Nischal Karki ◽  
...  
Keyword(s):  
Deep Learning ◽  
Secondary Structure ◽  
Computational Prediction ◽  
Ligand Interaction ◽  
Structure Information ◽  
Protein Ligand Interactions ◽  
Intermediate Layers ◽  
Ligand Interactions ◽  
Protein Ligand Interaction ◽  
Curvature And Torsion

AbstractComputational prediction of Protein-Ligand Interaction (PLI) is an important step in the modern drug discovery pipeline as it mitigates the cost, time, and resources required to screen novel therapeutics. Deep Neural Networks (DNN) have recently shown excellent performance in PLI prediction. However, the performance is highly dependent on protein and ligand features utilized for the DNN model. Moreover, in current models, the deciphering of how protein features determine the underlying principles that govern PLI is not trivial. In this work, we developed a DNN framework named SSnet that utilizes secondary structure information of proteins extracted as the curvature and torsion of the protein backbone to predict PLI. We demonstrate the performance of SSnet by comparing against a variety of currently popular machine and non-machine learning models using various metrics. We visualize the intermediate layers of SSnet to show a potential latent space for proteins, in particular to extract structural elements in a protein that the model finds influential for ligand binding, which is one of the key features of SSnet. We observed in our study that SSnet learns information about locations in a protein where a ligand can bind including binding sites, allosteric sites and cryptic sites, regardless of the conformation used. We further observed that SSnet is not biased to any specific molecular interaction and extracts the protein fold information critical for PLI prediction. Our work forms an important gateway to the general exploration of secondary structure based deep learning, which is not just confined to protein-ligand interactions, and as such will have a large impact on protein research.

scholarly journals Investigation of Estrogen Receptor (ESR1) for Breast Cancer from Traditional Chinese Medicine

2014 ◽  
Vol 2014 ◽  
pp. 1-12 ◽  
Author(s):  
Tzu-Chieh Hung ◽  
Wen-Yuan Lee ◽  
Kuen-Bao Chen ◽  
Yueh-Chiu Chan ◽  
Calvin Yu-Chian Chen
Keyword(s):  
Breast Cancer ◽  
Molecular Dynamics ◽  
Estrogen Receptor ◽  
Chinese Medicine ◽  
Traditional Chinese Medicine ◽  
Hydrophobic Interactions ◽  
Ligand Interaction ◽  
Protein Ligand Interactions ◽  
Ligand Interactions ◽  
Protein Ligand Interaction

Recently, an important topic of breast cancer had been published in 2013. In this report, estrogen receptor (ESR1) had defined the relation of hormone-cause breast cancer. The screening of traditional Chinese medicine (TCM) database has found the molecular compounds by simulating molecular docking and molecular dynamics to regulate ESR1. S-Allylmercaptocysteine and 5-hydroxy-L-tryptophan are selected according to the highest docking score than that of other TCM compounds and Raloxifene (control). The simulation from molecular dynamics is helpful in analyzing and detecting the protein-ligand interactions. After a comparing the control and the Apo form, then based on the docking poses, hydrophobic interactions, hydrogen bond and structure variations, this research postulates that S-allylmercaptocysteine may be more appropriate than other compounds for protein-ligand interaction.

scholarly journals SSnet: A Deep Learning Approach for Protein-Ligand Interaction Prediction

2021 ◽  
Vol 22 (3) ◽  
pp. 1392
Author(s):  
Niraj Verma ◽  
Xingming Qu ◽  
Francesco Trozzi ◽  
Mohamed Elsaied ◽  
Nischal Karki ◽  
...  
Keyword(s):  
Deep Learning ◽  
Secondary Structure ◽  
De Novo ◽  
Computational Prediction ◽  
Ligand Interaction ◽  
Structure Information ◽  
Protein Ligand Interactions ◽  
Ligand Interactions ◽  
Protein Ligand Interaction ◽  
Curvature And Torsion

Computational prediction of Protein-Ligand Interaction (PLI) is an important step in the modern drug discovery pipeline as it mitigates the cost, time, and resources required to screen novel therapeutics. Deep Neural Networks (DNN) have recently shown excellent performance in PLI prediction. However, the performance is highly dependent on protein and ligand features utilized for the DNN model. Moreover, in current models, the deciphering of how protein features determine the underlying principles that govern PLI is not trivial. In this work, we developed a DNN framework named SSnet that utilizes secondary structure information of proteins extracted as the curvature and torsion of the protein backbone to predict PLI. We demonstrate the performance of SSnet by comparing against a variety of currently popular machine and non-Machine Learning (ML) models using various metrics. We visualize the intermediate layers of SSnet to show a potential latent space for proteins, in particular to extract structural elements in a protein that the model finds influential for ligand binding, which is one of the key features of SSnet. We observed in our study that SSnet learns information about locations in a protein where a ligand can bind, including binding sites, allosteric sites and cryptic sites, regardless of the conformation used. We further observed that SSnet is not biased to any specific molecular interaction and extracts the protein fold information critical for PLI prediction. Our work forms an important gateway to the general exploration of secondary structure-based Deep Learning (DL), which is not just confined to protein-ligand interactions, and as such will have a large impact on protein research, while being readily accessible for de novo drug designers as a standalone package.

scholarly journals SuCOS is Better than RMSD for Evaluating Fragment Elaboration and Docking Poses

2019 ◽  
Author(s):  
Susan Leung ◽  
Michael Bodkin ◽  
Frank von Delft ◽  
Paul Brennan ◽  
Garrett Morris
Keyword(s):  
Binding Mode ◽  
Docking Studies ◽  
Binding Modes ◽  
False Negatives ◽  
Ligand Interaction ◽  
Cross Docking ◽  
Protein Ligand Interaction ◽  
Feature Overlap ◽  
Better Than ◽  
Fragment Based Drug Discovery

One of the fundamental assumptions of fragment-based drug discovery is that the fragment’s binding mode will be conserved upon elaboration into larger compounds. The most common way of quantifying binding mode similarity is Root Mean Square Deviation (RMSD), but Protein Ligand Interaction Fingerprint (PLIF) similarity and shape-based metrics are sometimes used. We introduce SuCOS, an open-source shape and chemical feature overlap metric. We explore the strengths and weaknesses of RMSD, PLIF similarity, and SuCOS on a dataset of X-ray crystal structures of paired elaborated larger and smaller molecules bound to the same protein. Our redocking and cross-docking studies show that SuCOS is superior to RMSD and PLIF similarity. When redocking, SuCOS produces fewer false positives and false negatives than RMSD and PLIF similarity; and in cross-docking, SuCOS is better at differentiating experimentally-observed binding modes of an elaborated molecule given the pose of its non-elaborated counterpart. Finally we show that SuCOS performs better than AutoDock Vina at differentiating actives from decoy ligands using the DUD-E dataset. SuCOS is available at https://github.com/susanhleung/SuCOS . <br>

scholarly journals SuCOS is Better than RMSD for Evaluating Fragment Elaboration and Docking Poses

2019 ◽  
Author(s):  
Susan Leung ◽  
Michael Bodkin ◽  
Frank von Delft ◽  
Paul Brennan ◽  
Garrett Morris
Keyword(s):  
Binding Mode ◽  
Docking Studies ◽  
Binding Modes ◽  
False Negatives ◽  
Ligand Interaction ◽  
Cross Docking ◽  
Protein Ligand Interaction ◽  
Feature Overlap ◽  
Better Than ◽  
Fragment Based Drug Discovery

One of the fundamental assumptions of fragment-based drug discovery is that the fragment’s binding mode will be conserved upon elaboration into larger compounds. The most common way of quantifying binding mode similarity is Root Mean Square Deviation (RMSD), but Protein Ligand Interaction Fingerprint (PLIF) similarity and shape-based metrics are sometimes used. We introduce SuCOS, an open-source shape and chemical feature overlap metric. We explore the strengths and weaknesses of RMSD, PLIF similarity, and SuCOS on a dataset of X-ray crystal structures of paired elaborated larger and smaller molecules bound to the same protein. Our redocking and cross-docking studies show that SuCOS is superior to RMSD and PLIF similarity. When redocking, SuCOS produces fewer false positives and false negatives than RMSD and PLIF similarity; and in cross-docking, SuCOS is better at differentiating experimentally-observed binding modes of an elaborated molecule given the pose of its non-elaborated counterpart. Finally we show that SuCOS performs better than AutoDock Vina at differentiating actives from decoy ligands using the DUD-E dataset. SuCOS is available at https://github.com/susanhleung/SuCOS . <br>

scholarly journals Flavonoids as Putative Epi-Modulators: Insight into Their Binding Mode with BRD4 Bromodomains Using Molecular Docking and Dynamics

Biomolecules ◽  
2018 ◽  
Vol 8 (3) ◽  
pp. 61 ◽  
Author(s):  
Fernando Prieto-Martínez ◽  
José Medina-Franco
Keyword(s):  
Kinase Inhibitors ◽  
Binding Mode ◽  
Binding Modes ◽  
Ligand Interaction ◽  
Bet Inhibitors ◽  
Protein Ligand Interaction ◽  
Brd4 Inhibition ◽  
Dynamics Simulations ◽  
Insight Into

Flavonoids are widely recognized as natural polydrugs, given their anti-inflammatory, antioxidant, sedative, and antineoplastic activities. Recently, different studies showed that flavonoids have the potential to inhibit bromodomain and extraterminal (BET) bromodomains. Previous reports suggested that flavonoids bind between the Z and A loops of the bromodomain (ZA channel) due to their orientation and interactions with P86, V87, L92, L94, and N140. Herein, a comprehensive characterization of the binding modes of fisetin and the biflavonoid, amentoflavone, is discussed. To this end, both compounds were docked with BET bromodomain 4 (BRD4) using four docking programs. The results were post-processed with protein–ligand interaction fingerprints. To gain further insight into the binding mode of the two natural products, the docking results were further analyzed with molecular dynamics simulations. The results showed that amentoflavone makes numerous contacts in the ZA channel, as previously described for flavonoids and kinase inhibitors. It was also found that amentoflavone can potentially make contacts with non-canonical residues for BET inhibition. Most of these contacts were not observed with fisetin. Based on these results, amentoflavone was experimentally tested for BRD4 inhibition, showing activity in the micromolar range. This work may serve as the basis for scaffold optimization and the further characterization of flavonoids as BET inhibitors.

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