Structure-based protein-ligand interaction fingerprints for binding affinity prediction.
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ABSTRACT:
SUBMITTER: Wang DD
PROVIDER: S-EPMC8637032 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Discovery and optimization of small molecule inhibitors as therapeutic drugs have immensely benefited from rational structure-based drug design. With recent advances in high-resolution structure determination, computational power, and machine learning methodology, it is becoming more tractable to elucidate the structural basis of drug potency. However, the applicability of machine learning models to drug design is limited by the interpretability of the resulting models in terms of feature importance. Here, we take advantage of the large number of available inhibitor-bound HIV-1 protease structures and associated potencies to evaluate inhibitor diversity and machine learning models to predict ligand affinity. First, using a hierarchical clustering approach, we grouped HIV-1 protease inhibitors and identified distinct core structures. Explicit features including protein-ligand interactions were extracted from high-resolution cocrystal structures as 3D-based fingerprints. We found that a gradient boosting machine learning model with this explicit feature attribution can predict binding affinity with high accuracy. Finally, Shapley values were derived to explain local feature importance. We found specific van der Waals (vdW) interactions of key protein residues are pivotal for the predicted potency. Protein-specific and interpretable prediction models can guide the optimization of many small molecule drugs for improved potency.
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Project description:Accurate and affordable assessment of ligand-protein affinity for structure-based virtual screening (SB-VS) is a standing challenge. Hence, empirical postdocking filters making use of various types of structure-activity information may prove useful. Here, we introduce one such filter based upon three-dimensional structural protein-ligand interaction fingerprints (SPLIF). SPLIF permits quantitative assessment of whether a docking pose interacts with the protein target similarly to a known ligand and rescues active compounds penalized by poor initial docking scores. An extensive benchmark study on 10 diverse data sets selected from the DUD-E database has been performed in order to evaluate the absolute and relative efficiency of this method. SPLIF demonstrated an overall better performance than relevant standard methods.
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Project description:With the great advancements in experimental data, computational power and learning algorithms, artificial intelligence (AI) based drug design has begun to gain momentum recently. AI-based drug design has great promise to revolutionize pharmaceutical industries by significantly reducing the time and cost in drug discovery processes. However, a major issue remains for all AI-based learning model that is efficient molecular representations. Here we propose Dowker complex (DC) based molecular interaction representations and Riemann Zeta function based molecular featurization, for the first time. Molecular interactions between proteins and ligands (or others) are modeled as Dowker complexes. A multiscale representation is generated by using a filtration process, during which a series of DCs are generated at different scales. Combinatorial (Hodge) Laplacian matrices are constructed from these DCs, and the Riemann zeta functions from their spectral information can be used as molecular descriptors. To validate our models, we consider protein-ligand binding affinity prediction. Our DC-based machine learning (DCML) models, in particular, DC-based gradient boosting tree (DC-GBT), are tested on three most-commonly used datasets, i.e., including PDBbind-2007, PDBbind-2013 and PDBbind-2016, and extensively compared with other existing state-of-the-art models. It has been found that our DC-based descriptors can achieve the state-of-the-art results and have better performance than all machine learning models with traditional molecular descriptors. Our Dowker complex based machine learning models can be used in other tasks in AI-based drug design and molecular data analysis.
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Project description:Rational structure-based drug design relies on accurate predictions of protein-ligand binding affinity from structural molecular information. Although deep learning-based methods for predicting binding affinity have shown promise in computational drug design, certain approaches have faced criticism for their potential to inadequately capture the fundamental physical interactions between ligands and their macromolecular targets or for being susceptible to dataset biases. Herein, we propose to include bond-critical points based on the electron density of a protein-ligand complex as a fundamental physical representation of protein-ligand interactions. Employing a geometric deep learning model, we explore the usefulness of these bond-critical points to predict absolute binding affinities of protein-ligand complexes, benchmark model performance against existing methods, and provide a critical analysis of this new approach. The models achieved root-mean-squared errors of 1.4-1.8 log units on the PDBbind dataset, and 1.0-1.7 log units on the PDE10A dataset, not indicating significant advantages over benchmark methods, and thus rendering the utility of electron density for deep learning models context-dependent. The relationship between intermolecular electron density and corresponding binding affinity was analyzed, and Pearson correlation coefficients r > 0.7 were obtained for several macromolecular targets.
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Project description:Accurate prediction of the binding affinities of small-molecule ligands to their biological targets is fundamental for structure-based drug design but remains a very challenging task. In this paper, we have performed computational studies to predict the binding models of 31 small-molecule Smac (the second mitochondria-derived activator of caspase) mimetics to their target, the XIAP (X-linked inhibitor of apoptosis) protein, and their binding affinities. Our results showed that computational docking was able to reliably predict the binding models, as confirmed by experimentally determined crystal structures of some Smac mimetics complexed with XIAP. However, all the computational methods we have tested, including an empirical scoring function, two knowledge-based scoring functions, and MM-GBSA (molecular mechanics and generalized Born surface area), yield poor to modest prediction for binding affinities. The linear correlation coefficient (r(2)) value between the predicted affinities and the experimentally determined affinities was found to be between 0.21 and 0.36. Inclusion of ensemble protein-ligand conformations obtained from molecular dynamic simulations did not significantly improve the prediction. However, major improvement was achieved when the free-energy change for ligands between their free- and bound-states, or "ligand-reorganization free energy", was included in the MM-GBSA calculation, and the r(2) value increased from 0.36 to 0.66. The prediction was validated using 10 additional Smac mimetics designed and evaluated by an independent group. This study demonstrates that ligand reorganization free energy plays an important role in the overall binding free energy between Smac mimetics and XIAP. This term should be evaluated for other ligand-protein systems and included in the development of new scoring functions. To our best knowledge, this is the first computational study to demonstrate the importance of ligand reorganization free energy for the prediction of protein-ligand binding free energy.
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Project description:Protein-RNA recognition is highly affinity-driven and regulates a wide array of cellular functions. In this study, we have curated a binding affinity data set of 40 protein-RNA complexes, for which at least one unbound partner is available in the docking benchmark. The data set covers a wide affinity range of eight orders of magnitude as well as four different structural classes. On average, we find the complexes with single-stranded RNA have the highest affinity, whereas the complexes with the duplex RNA have the lowest. Nevertheless, free energy gain upon binding is the highest for the complexes with ribosomal proteins and the lowest for the complexes with tRNA with an average of -5.7 cal/mol/Å2 in the entire data set. We train regression models to predict the binding affinity from the structural and physicochemical parameters of protein-RNA interfaces. The best fit model with the lowest maximum error is provided with three interface parameters: relative hydrophobicity, conformational change upon binding and relative hydration pattern. This model has been used for predicting the binding affinity on a test data set, generated using mutated structures of yeast aspartyl-tRNA synthetase, for which experimentally determined ΔG values of 40 mutations are available. The predicted ΔGempirical values highly correlate with the experimental observations. The data set provided in this study should be useful for further development of the binding affinity prediction methods. Moreover, the model developed in this study enhances our understanding on the structural basis of protein-RNA binding affinity and provides a platform to engineer protein-RNA interfaces with desired affinity.
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Project description:Protein-ligand interactions are increasingly profiled at high-throughput, playing a vital role in lead compound discovery and drug optimization. Accurate prediction of binding pose and binding affinity constitutes a pivotal challenge in advancing our computational understanding of protein-ligand interactions. However, inherent limitations still exist, including high computational cost for conformational search sampling in traditional molecular docking tools, and the unsatisfactory molecular representation learning and intermolecular interaction modeling in deep learning-based methods. Here we propose a geometry-aware attention-based deep learning model, GAABind, which effectively predicts the pocket-ligand binding pose and binding affinity within a multi-task learning framework. Specifically, GAABind comprehensively captures the geometric and topological properties of both binding pockets and ligands, and employs expressive molecular representation learning to model intramolecular interactions. Moreover, GAABind proficiently learns the intermolecular many-body interactions and simulates the dynamic conformational adaptations of the ligand during its interaction with the protein through meticulously designed networks. We trained GAABind on the PDBbindv2020 and evaluated it on the CASF2016 dataset; the results indicate that GAABind achieves state-of-the-art performance in binding pose prediction and shows comparable binding affinity prediction performance. Notably, GAABind achieves a success rate of 82.8% in binding pose prediction, and the Pearson correlation between predicted and experimental binding affinities reaches up to 0.803. Additionally, we assessed GAABind's performance on the severe acute respiratory syndrome coronavirus 2 main protease cross-docking dataset. In this evaluation, GAABind demonstrates a notable success rate of 76.5% in binding pose prediction and achieves the highest Pearson correlation coefficient in binding affinity prediction compared with all baseline methods.
| S-EPMC10724026 | biostudies-literature
Project description:BackgroundAccurate prediction of protein-ligand binding affinity is important for lowering the overall cost of drug discovery in structure-based drug design. For accurate predictions, many classical scoring functions and machine learning-based methods have been developed. However, these techniques tend to have limitations, mainly resulting from a lack of sufficient energy terms to describe the complex interactions between proteins and ligands. Recent deep-learning techniques can potentially solve this problem. However, the search for more efficient and appropriate deep-learning architectures and methods to represent protein-ligand complex is ongoing.ResultsIn this study, we proposed a deep-neural network model to improve the prediction accuracy of protein-ligand complex binding affinity. The proposed model has two important features, descriptor embeddings with information on the local structures of a protein-ligand complex and an attention mechanism to highlight important descriptors for binding affinity prediction. The proposed model performed better than existing binding affinity prediction models on most benchmark datasets.ConclusionsWe confirmed that an attention mechanism can capture the binding sites in a protein-ligand complex to improve prediction performance. Our code is available at https://github.com/Blue1993/BAPA .
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