arXiv subjects

Youjun Xu

Publications and source records attributed to Youjun Xu.

6 recordsLinked to original sources

arXiv2025

PoseX: AI Defeats Physics Approaches on Protein-Ligand Cross Docking

Existing protein-ligand docking studies typically focus on the self-docking scenario, which is less practical in real applications. Moreover, some studies involve heavy frameworks requiring extensive training, posing challenges for convenient and efficient assessment of docking methods. To fill these gaps, we design PoseX, an open-source benchmark to evaluate both self-docking and cross-docking, enabling a practical and comprehensive assessment of algorithmic advances. Specifically, we curated a novel dataset comprising 718 entries for self-docking and 1,312 entries for cross-docking; second, we incorporated 23 docking methods in three methodological categories, including physics-based methods (e.g., Schr\"odinger Glide), AI docking methods (e.g., DiffDock) and AI co-folding methods (e.g., AlphaFold3); third, we developed a relaxation method for post-processing to minimize conformational energy and refine binding poses; fourth, we built a leaderboard to rank submitted models in real-time. We derived some key insights and conclusions from extensive experiments: (1) AI approaches have consistently outperformed physics-based methods in overall docking success rate. (2) Most intra- and intermolecular clashes of AI approaches can be greatly alleviated with relaxation, which means combining AI modeling with physics-based post-processing could achieve excellent performance. (3) AI co-folding methods exhibit ligand chirality issues, except for Boltz-1x, which introduced physics-inspired potentials to fix hallucinations, suggesting modeling on stereochemistry improves the structural plausibility markedly. (4) Specifying binding pockets significantly promotes docking performance, indicating that pocket information can be leveraged adequately, particularly for AI co-folding methods, in future modeling efforts. The code, dataset, and leaderboard are released at https://github.com/CataAI/PoseX.

cs.LG↗

arXiv2024

Accelerating Discovery of Novel and Bioactive Ligands With Pharmacophore-Informed Generative Models

Deep generative models have gained significant advancements to accelerate drug discovery by generating bioactive chemicals against desired targets. Nevertheless, most generated compounds that have been validated for potent bioactivity often exhibit structural novelty levels that fall short of satisfaction, thereby providing limited inspiration to human medicinal chemists. The challenge faced by generative models lies in their ability to produce compounds that are both bioactive and novel, rather than merely making minor modifications to known actives present in the training set. Recognizing the utility of pharmacophores in facilitating scaffold hopping, we developed TransPharmer, an innovative generative model that integrates ligand-based interpretable pharmacophore fingerprints with generative pre-training transformer (GPT) for de novo molecule generation. TransPharmer demonstrates superior performance across tasks involving unconditioned distribution learning, de novo generation and scaffold elaboration under pharmacophoric constraints. Its distinct exploration mode within the local chemical space renders it particularly useful for scaffold hopping, producing compounds that are structurally novel while pharmaceutically related. The efficacy of TransPharmer is validated through two case studies involving the dopamine receptor D2 (DRD2) and polo-like kinase 1 (PLK1). Notably in the case of PLK1, three out of four synthesized designed compounds exhibit submicromolar activities, with the most potent one, IIP0943, demonstrating a potency of 5.1 nM. Featuring a new scaffold of 4-(benzo[b]thiophen-7-yloxy)pyrimidine, IIP0943 also exhibits high selectivity for PLK1. It was demonstrated that TransPharmer is a powerful tool for discovery of novel and bioactive ligands.

q-bio.QM↗

arXiv2022

MolMiner: You only look once for chemical structure recognition

Molecular structures are always depicted as 2D printed form in scientific documents like journal papers and patents. However, these 2D depictions are not machine-readable. Due to a backlog of decades and an increasing amount of these printed literature, there is a high demand for the translation of printed depictions into machine-readable formats, which is known as Optical Chemical Structure Recognition (OCSR). Most OCSR systems developed over the last three decades follow a rule-based approach where the key step of vectorization of the depiction is based on the interpretation of vectors and nodes as bonds and atoms. Here, we present a practical software MolMiner, which is primarily built up using deep neural networks originally developed for semantic segmentation and object detection to recognize atom and bond elements from documents. These recognized elements can be easily connected as a molecular graph with distance-based construction algorithm. We carefully evaluate our software on four benchmark datasets with the state-of-the-art performance. Various real application scenarios are also tested, yielding satisfactory outcomes. The free download links of Mac and Windows versions are available: Mac: https://molminer-cdn.iipharma.cn/pharma-mind/artifact/latest/mac/PharmaMind-mac-latest-setup.dmg and Windows: https://molminer-cdn.iipharma.cn/pharma-mind/artifact/latest/win/PharmaMind-win-latest-setup.exe

cs.CV↗

arXiv2021

Deep Learning Model of Dock by Dock Process Significantly Accelerate the Process of Docking-based Virtual Screening

Docking-based virtual screening (VS process) selects ligands with potential pharmacological activities from millions of molecules using computational docking methods, which greatly could reduce the number of compounds for experimental screening, shorten the research period and save the research cost. Howerver, a majority of compouds with low docking scores could waste most of the computational resources. Herein, we report a novel and practical docking-based machine learning method called MLDDM (Machince Learning Docking-by-Docking Models). It is composed of a regression model and a classification model that simulates a classical docking by docking protocol ususally applied in many virtual screening projects. MLDDM could quickly eliminate compounds with low docking scores and the retained compounds with potential high docking scores would be examined for further real docking program. We demonstrated that MLDDM has a good ability to identify active compounds in the case studies for 10 specific protein targets. Compared to pure docking by docking based VS protocol, the VS process with MLDDM can achieve an over 120 times speed increment on average and the consistency rate with corresponding docking by docking VS protocol is above 0.8. Therefore, it would be promising to be used for examing ultra-large compound libraries in the current big data era.

q-bio.QM↗

arXiv2019

Automatic Retrosynthetic Pathway Planning Using Template-free Models

We present an attention-based Transformer model for automatic retrosynthesis route planning. Our approach starts from reactants prediction of single-step organic reactions for given products, followed by Monte Carlo tree search-based automatic retrosynthetic pathway prediction. Trained on two datasets from the United States patent literature, our models achieved a top-1 prediction accuracy of over 54.6% and 63.0% with more than 95% and 99.6% validity rate of SMILES, respectively, which is the best up to now to our knowledge. We also demonstrate the application potential of our model by successfully performing multi-step retrosynthetic route planning for four case products, i.e., antiseizure drug Rufinamide, a novel allosteric activator, an inhibitor of human acute-myeloid-leukemia cells and a complex intermediate of drug candidate. Further, by using heuristics Monte Carlo tree search, we achieved automatic retrosynthetic pathway searching and successfully reproduced published synthesis pathways. In summary, our model has achieved the state-of-the-art performance on single-step retrosynthetic prediction and provides a novel strategy for automatic retrosynthetic pathway planning.

q-bio.QM↗

arXiv2017

Deep Learning Based Regression and Multi-class Models for Acute Oral Toxicity Prediction with Automatic Chemical Feature Extraction

For quantitative structure-property relationship (QSPR) studies in chemoinformatics, it is important to get interpretable relationship between chemical properties and chemical features. However, the predictive power and interpretability of QSPR models are usually two different objectives that are difficult to achieve simultaneously. A deep learning architecture using molecular graph encoding convolutional neural networks (MGE-CNN) provided a universal strategy to construct interpretable QSPR models with high predictive power. Instead of using application-specific preset molecular descriptors or fingerprints, the models can be resolved using raw and pertinent features without manual intervention or selection. In this study, we developed acute oral toxicity (AOT) models of compounds using the MGE-CNN architecture as a case study. Three types of high-level predictive models: regression model (deepAOT-R), multi-classification model (deepAOT-C) and multi-task model (deepAOT-CR) for AOT evaluation were constructed. These models highly outperformed previously reported models. For the two external datasets containing 1673 (test set I) and 375 (test set II) compounds, the R2 and mean absolute error (MAE) of deepAOT-R on the test set I were 0.864 and 0.195, and the prediction accuracy of deepAOT-C was 95.5% and 96.3% on the test set I and II, respectively. The two external prediction accuracy of deepAOT-CR is 95.0% and 94.1%, while the R2 and MAE are 0.861 and 0.204 for test set I, respectively.

stat.ML↗