scholarly journals KORP-PL: a coarse-grained knowledge-based scoring function for protein–ligand interactions

2020 ◽  
Author(s):  
Maria Kadukova ◽  
Karina dos Santos Machado ◽  
Pablo Chacón ◽  
Sergei Grudinin
Keyword(s):  
Joint Probability ◽  
Coarse Grained ◽  
Supplementary Information ◽  
Joint Probability Distribution ◽  
Pose Prediction ◽  
Scoring Functions ◽  
Widespread Application ◽  
Knowledge Based ◽  
Protein Ligand Interactions ◽  
Ligand Interactions

Abstract Motivation Despite the progress made in studying protein–ligand interactions and the widespread application of docking and affinity prediction tools, improving their precision and efficiency still remains a challenge. Computational approaches based on the scoring of docking conformations with statistical potentials constitute a popular alternative to more accurate but costly physics-based thermodynamic sampling methods. In this context, a minimalist and fast sidechain-free knowledge-based potential with a high docking and screening power can be very useful when screening a big number of putative docking conformations. Results Here, we present a novel coarse-grained potential defined by a 3D joint probability distribution function that only depends on the pairwise orientation and position between protein backbone and ligand atoms. Despite its extreme simplicity, our approach yields very competitive results with the state-of-the-art scoring functions, especially in docking and screening tasks. For example, we observed a twofold improvement in the median 5% enrichment factor on the DUD-E benchmark compared to Autodock Vina results. Moreover, our results prove that a coarse sidechain-free potential is sufficient for a very successful docking pose prediction. Availabilityand implementation The standalone version of KORP-PL with the corresponding tests and benchmarks are available at https://team.inria.fr/nano-d/korp-pl/ and https://chaconlab.org/modeling/korp-pl. Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals Assessing Molecular Docking Tools to Guide Targeted Drug Discovery of CD38 Inhibitors

2020 ◽  
Vol 21 (15) ◽  
pp. 5183 ◽  
Author(s):  
Eric D. Boittier ◽  
Yat Yin Tang ◽  
McKenna E. Buckley ◽  
Zachariah P. Schuurs ◽  
Derek J. Richard ◽  
...  
Keyword(s):  
Scoring Function ◽  
Pose Prediction ◽  
Scoring Functions ◽  
Molecular Fingerprints ◽  
Biologically Relevant ◽  
Protein Ligand Interactions ◽  
Molecular Features ◽  
Ligand Interactions ◽  
Model Protein ◽  
Scoring Accuracy

A promising protein target for computational drug development, the human cluster of differentiation 38 (CD38), plays a crucial role in many physiological and pathological processes, primarily through the upstream regulation of factors that control cytoplasmic Ca2+ concentrations. Recently, a small-molecule inhibitor of CD38 was shown to slow down pathways relating to aging and DNA damage. We examined the performance of seven docking programs for their ability to model protein-ligand interactions with CD38. A test set of twelve CD38 crystal structures, containing crystallized biologically relevant substrates, were used to assess pose prediction. The rankings for each program based on the median RMSD between the native and predicted were Vina, AD4 > PLANTS, Gold, Glide, Molegro > rDock. Forty-two compounds with known affinities were docked to assess the accuracy of the programs at affinity/ranking predictions. The rankings based on scoring power were: Vina, PLANTS > Glide, Gold > Molegro >> AutoDock 4 >> rDock. Out of the top four performing programs, Glide had the only scoring function that did not appear to show bias towards overpredicting the affinity of the ligand-based on its size. Factors that affect the reliability of pose prediction and scoring are discussed. General limitations and known biases of scoring functions are examined, aided in part by using molecular fingerprints and Random Forest classifiers. This machine learning approach may be used to systematically diagnose molecular features that are correlated with poor scoring accuracy.

KORP: knowledge-based 6D potential for fast protein and loop modeling

2019 ◽  
Vol 35 (17) ◽  
pp. 3013-3019 ◽  
Author(s):  
José Ramón López-Blanco ◽  
Pablo Chacón
Keyword(s):  
Structure Prediction ◽  
Protein Structures ◽  
Joint Probability ◽  
Protein Modeling ◽  
Supplementary Information ◽  
Joint Probability Distribution ◽  
Loop Modeling ◽  
Statistical Potentials ◽  
Knowledge Based ◽  
Backbone Atoms

Abstract Motivation Knowledge-based statistical potentials constitute a simpler and easier alternative to physics-based potentials in many applications, including folding, docking and protein modeling. Here, to improve the effectiveness of the current approximations, we attempt to capture the six-dimensional nature of residue–residue interactions from known protein structures using a simple backbone-based representation. Results We have developed KORP, a knowledge-based pairwise potential for proteins that depends on the relative position and orientation between residues. Using a minimalist representation of only three backbone atoms per residue, KORP utilizes a six-dimensional joint probability distribution to outperform state-of-the-art statistical potentials for native structure recognition and best model selection in recent critical assessment of protein structure prediction and loop-modeling benchmarks. Compared with the existing methods, our side-chain independent potential has a lower complexity and better efficiency. The superior accuracy and robustness of KORP represent a promising advance for protein modeling and refinement applications that require a fast but highly discriminative energy function. Availability and implementation http://chaconlab.org/modeling/korp. Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals ASFP (Artificial Intelligence based Scoring Function Platform): a web server for the development of customized scoring functions

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Xujun Zhang ◽  
Chao Shen ◽  
Xueying Guo ◽  
Zhe Wang ◽  
Gaoqi Weng ◽  
...  
Keyword(s):  
High Efficiency ◽  
Low Cost ◽  
Pearson Correlation ◽  
Scoring Function ◽  
Web Server ◽  
Scoring Functions ◽  
Protein Ligand Interactions ◽  
Prediction Module ◽  
Ligand Interactions ◽  
Benchmark Datasets

AbstractVirtual screening (VS) based on molecular docking has emerged as one of the mainstream technologies of drug discovery due to its low cost and high efficiency. However, the scoring functions (SFs) implemented in most docking programs are not always accurate enough and how to improve their prediction accuracy is still a big challenge. Here, we propose an integrated platform called ASFP, a web server for the development of customized SFs for structure-based VS. There are three main modules in ASFP: (1) the descriptor generation module that can generate up to 3437 descriptors for the modelling of protein–ligand interactions; (2) the AI-based SF construction module that can establish target-specific SFs based on the pre-generated descriptors through three machine learning (ML) techniques; (3) the online prediction module that provides some well-constructed target-specific SFs for VS and an additional generic SF for binding affinity prediction. Our methodology has been validated on several benchmark datasets. The target-specific SFs can achieve an average ROC AUC of 0.973 towards 32 targets and the generic SF can achieve the Pearson correlation coefficient of 0.81 on the PDBbind version 2016 core set. To sum up, the ASFP server is a powerful tool for structure-based VS.

A knowledge-based halogen bonding scoring function for predicting protein-ligand interactions

2013 ◽  
Vol 19 (11) ◽  
pp. 5015-5030 ◽  
Author(s):  
Yingtao Liu ◽  
Zhijian Xu ◽  
Zhuo Yang ◽  
Kaixian Chen ◽  
Weiliang Zhu
Keyword(s):  
Scoring Function ◽  
Halogen Bonding ◽  
Knowledge Based ◽  
Protein Ligand Interactions ◽  
Ligand Interactions
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