SynergyX: a multi-modality mutual attention network for interpretable drug synergy prediction.

Discovering effective anti-tumor drug combinations is crucial for advancing cancer therapy. Taking full account of intricate biological interactions is highly important in accurately predicting drug synergy. However, the extremely limited prior knowledge poses great challenges in developing current computational methods. To address this, we introduce SynergyX, a multi-modality mutual attention network to improve anti-tumor drug synergy prediction. It dynamically captures cross-modal interactions, allowing for the modeling of complex biological networks and drug interactions. A convolution-augmented attention structure is adopted to integrate multi-omic data in this framework effectively. Compared with other state-of-the-art models, SynergyX demonstrates superior predictive accuracy in both the General Test and Blind Test and cross-dataset validation. By exhaustively screening combinations of approved drugs, SynergyX reveals its ability to identify promising drug combination candidates for potential lung cancer treatment. Another notable advantage lies in its multidimensional interpretability. Taking Sorafenib and Vorinostat as an example, SynergyX serves as a powerful tool for uncovering drug-gene interactions and deciphering cell selectivity mechanisms. In summary, SynergyX provides an illuminating and interpretable framework, poised to catalyze the expedition of drug synergy discovery and deepen our comprehension of rational combination therapy.

Comprehensive assessment of protein loop modeling programs on large-scale datasets: prediction accuracy and efficiency.

Protein loops play a critical role in the dynamics of proteins and are essential for numerous biological functions, and various computational approaches to loop modeling have been proposed over the past decades. However, a comprehensive understanding of the strengths and weaknesses of each method is lacking. In this work, we constructed two high-quality datasets (i.e. the General dataset and the CASP dataset) and systematically evaluated the accuracy and efficiency of 13 commonly used loop modeling approaches from the perspective of loop lengths, protein classes and residue types. The results indicate that the knowledge-based method FREAD generally outperforms the other tested programs in most cases, but encountered challenges when predicting loops longer than 15 and 30 residues on the CASP and General datasets, respectively. The ab initio method Rosetta NGK demonstrated exceptional modeling accuracy for short loops with four to eight residues and achieved the highest success rate on the CASP dataset. The well-known AlphaFold2 and RoseTTAFold require more resources for better performance, but they exhibit promise for predicting loops longer than 16 and 30 residues in the CASP and General datasets. These observations can provide valuable insights for selecting suitable methods for specific loop modeling tasks and contribute to future advancements in the field.

Advancing Ligand Docking through Deep Learning: Challenges and Prospects in Virtual Screening.

Molecular docking, also termed ligand docking (LD), is a pivotal element of structure-based virtual screening (SBVS) used to predict the binding conformations and affinities of protein-ligand complexes. Traditional LD methodologies rely on a search and scoring framework, utilizing heuristic algorithms to explore binding conformations and scoring functions to evaluate binding strengths. However, to meet the efficiency demands of SBVS, these algorithms and functions are often simplified, prioritizing speed over accuracy.The emergence of deep learning (DL) has exerted a profound impact on diverse fields, ranging from natural language processing to computer vision and drug discovery. DeepMind's AlphaFold2 has impressively exhibited its ability to accurately predict protein structures solely from amino acid sequences, highlighting the remarkable potential of DL in conformation prediction. This groundbreaking advancement circumvents the traditional search-scoring frameworks in LD, enhancing both accuracy and processing speed and thereby catalyzing a broader adoption of DL algorithms in binding pose prediction. Nevertheless, a consensus on certain aspects remains elusive.In this Account, we delineate the current status of employing DL to augment LD within the VS paradigm, highlighting our contributions to this domain. Furthermore, we discuss the challenges and future prospects, drawing insights from our scholarly investigations. Initially, we present an overview of VS and LD, followed by an introduction to DL paradigms, which deviate significantly from traditional search-scoring frameworks. Subsequently, we delve into the challenges associated with the development of DL-based LD (DLLD), encompassing evaluation metrics, application scenarios, and physical plausibility of the predicted conformations. In the evaluation of LD algorithms, it is essential to recognize the multifaceted nature of the metrics. While the accuracy of binding pose prediction, often measured by the success rate, is a pivotal aspect, the scoring/screening power and computational speed of these algorithms are equally important given the pivotal role of LD tools in VS. Regarding application scenarios, early methods focused on blind docking, where the binding site is unknown. However, recent studies suggest a shift toward identifying binding sites rather than solely predicting binding poses within these models. In contrast, LD with a known pocket in VS has been shown to be more practical. Physical plausibility poses another significant challenge. Although DLLD models often achieve higher success rates compared to traditional methods, they may generate poses with implausible local structures, such as incorrect bond angles or lengths, which are disadvantageous for postprocessing tasks like visualization. Finally, we discuss the future perspectives for DLLD, emphasizing the need to improve generalization ability, strike a balance between speed and accuracy, account for protein conformation flexibility, and enhance physical plausibility. Additionally, we delve into the comparison between generative and regression algorithms in this context, exploring their respective strengths and potential.

SPLDExtraTrees: robust machine learning approach for predicting kinase inhibitor resistance.

Drug resistance is a major threat to the global health and a significant concern throughout the clinical treatment of diseases and drug development. The mutation in proteins that is related to drug binding is a common cause for adaptive drug resistance. Therefore, quantitative estimations of how mutations would affect the interaction between a drug and the target protein would be of vital significance for the drug development and the clinical practice. Computational methods that rely on molecular dynamics simulations, Rosetta protocols, as well as machine learning methods have been proven to be capable of predicting ligand affinity changes upon protein mutation. However, the severely limited sample size and heavy noise induced overfitting and generalization issues have impeded wide adoption of machine learning for studying drug resistance. In this paper, we propose a robust machine learning method, termed SPLDExtraTrees, which can accurately predict ligand binding affinity changes upon protein mutation and identify resistance-causing mutations. Especially, the proposed method ranks training data following a specific scheme that starts with easy-to-learn samples and gradually incorporates harder and diverse samples into the training, and then iterates between sample weight recalculations and model updates. In addition, we calculate additional physics-based structural features to provide the machine learning model with the valuable domain knowledge on proteins for these data-limited predictive tasks. The experiments substantiate the capability of the proposed method for predicting kinase inhibitor resistance under three scenarios and achieve predictive accuracy comparable with that of molecular dynamics and Rosetta methods with much less computational costs.

Knowledge-based BERT: a method to extract molecular features like computational chemists.

Molecular property prediction models based on machine learning algorithms have become important tools to triage unpromising lead molecules in the early stages of drug discovery. Compared with the mainstream descriptor- and graph-based methods for molecular property predictions, SMILES-based methods can directly extract molecular features from SMILES without human expert knowledge, but they require more powerful algorithms for feature extraction and a larger amount of data for training, which makes SMILES-based methods less popular. Here, we show the great potential of pre-training in promoting the predictions of important pharmaceutical properties. By utilizing three pre-training tasks based on atom feature prediction, molecular feature prediction and contrastive learning, a new pre-training method K-BERT, which can extract chemical information from SMILES like chemists, was developed. The calculation results on 15 pharmaceutical datasets show that K-BERT outperforms well-established descriptor-based (XGBoost) and graph-based (Attentive FP and HRGCN+) models. In addition, we found that the contrastive learning pre-training task enables K-BERT to 'understand' SMILES not limited to canonical SMILES. Moreover, the general fingerprints K-BERT-FP generated by K-BERT exhibit comparative predictive power to MACCS on 15 pharmaceutical datasets and can also capture molecular size and chirality information that traditional binary fingerprints cannot capture. Our results illustrate the great potential of K-BERT in the practical applications of molecular property predictions in drug discovery.

Out-of-the-box deep learning prediction of quantum-mechanical partial charges by graph representation and transfer learning.

Accurate prediction of atomic partial charges with high-level quantum mechanics (QM) methods suffers from high computational cost. Numerous feature-engineered machine learning (ML)-based predictors with favorable computability and reliability have been developed as alternatives. However, extensive expertise effort was needed for feature engineering of atom chemical environment, which may consequently introduce domain bias. In this study, SuperAtomicCharge, a data-driven deep graph learning framework, was proposed to predict three important types of partial charges (i.e. RESP, DDEC4 and DDEC78) derived from high-level QM calculations based on the structures of molecules. SuperAtomicCharge was designed to simultaneously exploit the 2D and 3D structural information of molecules, which was proved to be an effective way to improve the prediction accuracy of the model. Moreover, a simple transfer learning strategy and a multitask learning strategy based on self-supervised descriptors were also employed to further improve the prediction accuracy of the proposed model. Compared with the latest baselines, including one GNN-based predictor and two ML-based predictors, SuperAtomicCharge showed better performance on all the three external test sets and had better usability and portability. Furthermore, the QM partial charges of new molecules predicted by SuperAtomicCharge can be efficiently used in drug design applications such as structure-based virtual screening, where the predicted RESP and DDEC4 charges of new molecules showed more robust scoring and screening power than the commonly used partial charges. Finally, two tools including an online server (http://cadd.zju.edu.cn/deepchargepredictor) and the source code command lines (https://github.com/zjujdj/SuperAtomicCharge) were developed for the easy access of the SuperAtomicCharge services.

Acquired diffuse palmoplantar erythema with keratoderma in Chinese patients with pustular psoriasis: A predictor for IL36 receptor antagonist c.115+6T>C mutation?

Several studies have suggested that mutation of the interleukin 36 receptor antagonist gene (IL36RN) is related to generalized pustular psoriasis (GPP), and the presence of IL36RN mutation may affect the clinical manifestations and treatment responses. However, genetic testing is not routinely available in clinical practice for the diagnosis of GPP. Previously, GPP patients with acrodermatitis continua of Hallopeau (ACH) were found to have a high percentage of carrying IL36RN mutation. In this study, we reported six patients with pustular psoriasis presenting as diffuse palmoplantar erythema with keratoderma among 60 patients who carried IL36RN mutation. ACH was present in five patients and five patients had acute flare of GPP. This unique presentation may serve as a predictor for IL36RN mutation in patients with pustular psoriasis, similar to ACH.

Genetic Algorithm-Based Receptor Ligand: A Genetic Algorithm-Guided Generative Model to Boost the Novelty and Drug-Likeness of Molecules in a Sampling Chemical Space.

Deep learning-based de novo molecular design has recently gained significant attention. While numerous DL-based generative models have been successfully developed for designing novel compounds, the majority of the generated molecules lack sufficiently novel scaffolds or high drug-like profiles. The aforementioned issues may not be fully captured by commonly used metrics for the assessment of molecular generative models, such as novelty, diversity, and quantitative estimation of the drug-likeness score. To address these limitations, we proposed a genetic algorithm-guided generative model called GARel (genetic algorithm-based receptor-ligand interaction generator), a novel framework for training a DL-based generative model to produce drug-like molecules with novel scaffolds. To efficiently train the GARel model, we utilized dense net to update the parameters based on molecules with novel scaffolds and drug-like features. To demonstrate the capability of the GARel model, we used it to design inhibitors for three targets: AA2AR, EGFR, and SARS-Cov2. The results indicate that GARel-generated molecules feature more diverse and novel scaffolds and possess more desirable physicochemical properties and favorable docking scores. Compared with other generative models, GARel makes significant progress in balancing novelty and drug-likeness, providing a promising direction for the further development of DL-based de novo design methodology with potential impacts on drug discovery.

DrugFlow: An AI-Driven One-Stop Platform for Innovative Drug Discovery.

Artificial intelligence (AI)-aided drug design has demonstrated unprecedented effects on modern drug discovery, but there is still an urgent need for user-friendly interfaces that bridge the gap between these sophisticated tools and scientists, particularly those who are less computer savvy. Herein, we present DrugFlow, an AI-driven one-stop platform that offers a clean, convenient, and cloud-based interface to streamline early drug discovery workflows. By seamlessly integrating a range of innovative AI algorithms, covering molecular docking, quantitative structure-activity relationship modeling, molecular generation, ADMET (absorption, distribution, metabolism, excretion and toxicity) prediction, and virtual screening, DrugFlow can offer effective AI solutions for almost all crucial stages in early drug discovery, including hit identification and hit/lead optimization. We hope that the platform can provide sufficiently valuable guidance to aid real-word drug design and discovery. The platform is available at https://drugflow.com.

Assessing the performance of MM/PBSA and MM/GBSA methods. 10. Prediction reliability of binding affinities and binding poses for RNA-ligand complexes.

Ribonucleic acid (RNA)-ligand interactions play a pivotal role in a wide spectrum of biological processes, ranging from protein biosynthesis to cellular reproduction. This recognition has prompted the broader acceptance of RNA as a viable candidate for drug targets. Delving into the atomic-scale understanding of RNA-ligand interactions holds paramount importance in unraveling intricate molecular mechanisms and further contributing to RNA-based drug discovery. Computational approaches, particularly molecular docking, offer an efficient way of predicting the interactions between RNA and small molecules. However, the accuracy and reliability of these predictions heavily depend on the performance of scoring functions (SFs). In contrast to the majority of SFs used in RNA-ligand docking, the end-point binding free energy calculation methods, such as molecular mechanics/generalized Born surface area (MM/GBSA) and molecular mechanics/Poisson Boltzmann surface area (MM/PBSA), stand as theoretically more rigorous approaches. Yet, the evaluation of their effectiveness in predicting both binding affinities and binding poses within RNA-ligand systems remains unexplored. This study first reported the performance of MM/PBSA and MM/GBSA with diverse solvation models, interior dielectric constants (εin) and force fields in the context of binding affinity prediction for 29 RNA-ligand complexes. MM/GBSA is based on short (5 ns) molecular dynamics (MD) simulations in an explicit solvent with the YIL force field; the GBGBn2 model with higher interior dielectric constant (εin = 12, 16 or 20) yields the best correlation (Rp = -0.513), which outperforms the best correlation (Rp = -0.317, rDock) offered by various docking programs. Then, the efficacy of MM/GBSA in identifying the near-native binding poses from the decoys was assessed based on 56 RNA-ligand complexes. However, it is evident that MM/GBSA has limitations in accurately predicting binding poses for RNA-ligand systems, particularly compared with notably proficient docking programs like rDock and PLANTS. The best top-1 success rate achieved by MM/GBSA rescoring is 39.3%, which falls below the best results given by docking programs (50%, PLNATS). This study represents the first evaluation of MM/PBSA and MM/GBSA for RNA-ligand systems and is expected to provide valuable insights into their successful application to RNA targets.

TrimNet: learning molecular representation from triplet messages for biomedicine.

MOTIVATION: Computational methods accelerate drug discovery and play an important role in biomedicine, such as molecular property prediction and compound-protein interaction (CPI) identification. A key challenge is to learn useful molecular representation. In the early years, molecular properties are mainly calculated by quantum mechanics or predicted by traditional machine learning methods, which requires expert knowledge and is often labor-intensive. Nowadays, graph neural networks have received significant attention because of the powerful ability to learn representation from graph data. Nevertheless, current graph-based methods have some limitations that need to be addressed, such as large-scale parameters and insufficient bond information extraction. RESULTS: In this study, we proposed a graph-based approach and employed a novel triplet message mechanism to learn molecular representation efficiently, named triplet message networks (TrimNet). We show that TrimNet can accurately complete multiple molecular representation learning tasks with significant parameter reduction, including the quantum properties, bioactivity, physiology and CPI prediction. In the experiments, TrimNet outperforms the previous state-of-the-art method by a significant margin on various datasets. Besides the few parameters and high prediction accuracy, TrimNet could focus on the atoms essential to the target properties, providing a clear interpretation of the prediction tasks. These advantages have established TrimNet as a powerful and useful computational tool in solving the challenging problem of molecular representation learning. AVAILABILITY: The quantum and drug datasets are available on the website of MoleculeNet: http://moleculenet.ai. The source code is available in GitHub: https://github.com/yvquanli/trimnet. CONTACT: xjyao@lzu.edu.cn, songsen@tsinghua.edu.cn.

Hyperbolic relational graph convolution networks plus: a simple but highly efficient QSAR-modeling method.

Accurate predictions of druggability and bioactivities of compounds are desirable to reduce the high cost and time of drug discovery. After more than five decades of continuing developments, quantitative structure-activity relationship (QSAR) methods have been established as indispensable tools that facilitate fast, reliable and affordable assessments of physicochemical and biological properties of compounds in drug-discovery programs. Currently, there are mainly two types of QSAR methods, descriptor-based methods and graph-based methods. The former is developed based on predefined molecular descriptors, whereas the latter is developed based on simple atomic and bond information. In this study, we presented a simple but highly efficient modeling method by combining molecular graphs and molecular descriptors as the input of a modified graph neural network, called hyperbolic relational graph convolution network plus (HRGCN+). The evaluation results show that HRGCN+ achieves state-of-the-art performance on 11 drug-discovery-related datasets. We also explored the impact of the addition of traditional molecular descriptors on the predictions of graph-based methods, and found that the addition of molecular descriptors can indeed boost the predictive power of graph-based methods. The results also highlight the strong anti-noise capability of our method. In addition, our method provides a way to interpret models at both the atom and descriptor levels, which can help medicinal chemists extract hidden information from complex datasets. We also offer an HRGCN+'s online prediction service at https://quantum.tencent.com/hrgcn/.

MG-BERT: leveraging unsupervised atomic representation learning for molecular property prediction.

MOTIVATION: Accurate and efficient prediction of molecular properties is one of the fundamental issues in drug design and discovery pipelines. Traditional feature engineering-based approaches require extensive expertise in the feature design and selection process. With the development of artificial intelligence (AI) technologies, data-driven methods exhibit unparalleled advantages over the feature engineering-based methods in various domains. Nevertheless, when applied to molecular property prediction, AI models usually suffer from the scarcity of labeled data and show poor generalization ability. RESULTS: In this study, we proposed molecular graph BERT (MG-BERT), which integrates the local message passing mechanism of graph neural networks (GNNs) into the powerful BERT model to facilitate learning from molecular graphs. Furthermore, an effective self-supervised learning strategy named masked atoms prediction was proposed to pretrain the MG-BERT model on a large amount of unlabeled data to mine context information in molecules. We found the MG-BERT model can generate context-sensitive atomic representations after pretraining and transfer the learned knowledge to the prediction of a variety of molecular properties. The experimental results show that the pretrained MG-BERT model with a little extra fine-tuning can consistently outperform the state-of-the-art methods on all 11 ADMET datasets. Moreover, the MG-BERT model leverages attention mechanisms to focus on atomic features essential to the target property, providing excellent interpretability for the trained model. The MG-BERT model does not require any hand-crafted feature as input and is more reliable due to its excellent interpretability, providing a novel framework to develop state-of-the-art models for a wide range of drug discovery tasks.

Deficiency of interleukin-36 receptor antagonist (DITRA): An analysis of 58 Chinese patients in a tertiary hospital in Taiwan.

DITRA, acronym for deficiency of interleukin-36 receptor antagonist (IL36RN), leads to unopposed pro-inflammatory signalling which typically manifests as pustular psoriasis. In Asian patients, c.115 + 6 T > C mutation is the most common and important single-nucleotide variant in DITRA. We present the largest case series consisting of 58 DITRA patients carrying heterozygous or homozygous c.115 + 6 T > C mutation. The mean age of onset (±SD) was 20.74 (±20.86), and the median age of onset was 13 years old. Twelve patients (20.7%) had disease onset before the age of two. Twenty-two patients (37.9%) had disease onset between the ages of 2-18. Main clinical phenotype was generalized pustular psoriasis (GPP) with systemic symptoms (33 patients, 56.9%), followed by acrodermatitis continua of Hallopeau (ACH) (16 patients, 27.6%). Nearly half of our patients (27 patients, 46.6%) ever had ACH, and only three of them are free of ACH currently, which indicates that the development of ACH is relatively persistent and irreversible. Thirty-four patients (58.6%) had recurrent GPP and 29 patients (50%) have been admitted due to GPP flare. Compared to those with heterozygous (C/T) mutation, more patients carrying homozygous mutation (C/C) have recurrent episodes of GPP (C/T vs. C/C: 25.53 vs. 76.47%, p = 0.0367). Two patients with squamous cell carcinomas arising from the pustular psoriasis skin lesions were noted. Two patients had elevated serum IgG4 levels.

Discrete Time Crystal Enabled by Stark Many-Body Localization.

Discrete time crystals (DTCs) have recently attracted increasing attention, but most DTC models and their properties are only revealed after disorder average. In this Letter, we propose a simple disorder-free periodically driven model that exhibits nontrivial DTC order stabilized by Stark many-body localization (MBL). We demonstrate the existence of the DTC phase by analytical analysis from perturbation theory and convincing numerical evidence from observable dynamics. The new DTC model paves a new promising way for further experiments and deepens our understanding of DTCs. Since the DTC order does not require special quantum state preparation and the strong disorder average, it can be naturally realized on the noisy intermediate-scale quantum hardware with much fewer resources and repetitions. Moreover, in addition to the robust subharmonic response, there are other novel robust beating oscillations in the Stark-MBL DTC phase that are absent in random or quasiperiodic MBL DTCs.

Predictors for the effectiveness of 75 mg risankizumab in treating psoriasis-A real-word evidence from a 52-week retrospective study.

In the registration trial of risankizumab for patients with moderate-to-severe psoriasis in Japan, similar Psoriasis Area Severity Index (PASI) responses were observed for 75 mg or 150 mg risankizumab at most time points up to 52 weeks, except for PASI 100 at week 16. The use of 75 mg risankizumab offers an attractive option considering the high cost of risankizumab. However, it is unknown whether patients with mild-to-moderate psoriasis respond similarly, and the efficacy data of non-Japanese patients is also lacking. We retrospectively included 30 consecutive Chinese patients receiving half-dose (75 mg) risankizumab as scheduled up to 52 weeks. Compared with biologic-experienced group, biologic-naive group had a significantly higher PASI 50/75/90/100 achievement (p = 0.0098/0.0039/0.0016/0.0054) at week 52. PASI 50/75/90/100 curves in biologic-naive group (p = 0.0117/0.0239/0.0143/0.0269) were also significantly higher when analysed generalized estimating equations (GEE) model. Though there was no statistically significant difference in terms of PASI 50/75/90/100 responses at any time points between those with body weight ≦ 65 kg and those >65 kg, a tendency of secondary failure was noted in those >65 kg from week 40 onwards. Patients who were both biologic-naive and weighed ≦ 65 kg achieved sustained PASI 50/75/90 responses from week 16/28/40 onwards, respectively, indicating that they could be considered as potential candidates for 75 mg risankizumab. Though PASI 75 curve in patients without diabetes mellitus (DM) surpassed that in patient without DM, curves of other parameters did not reach significance when analysed by GEE model. There was no HBV, HCV or TB reactivation, nor other new safety signals during the 52-week observational period. Providing risankizumab with flexible dosing options is beneficial in clinical practice considering the high cost of this medication.

Deep Generation Model Guided by the Docking Score for Active Molecular Design.

A deep generation model, as a novel drug design and discovery tool, shows obvious advantages in generating compounds with novel backbones and has been applied successfully in the field of drug discovery. However, it is still a challenge to generate molecules with expected properties, especially high activity. Here, to obtain compounds both with novelty and high activity to a target, we proposed a conditional molecular generation model COMG by considering the docking score and 3D pharmacophore matching during molecular generation. The proposed model was based on the conditional variational autoencoder architecture constrained by the pharmacophore matching score. During Bayesian optimization, the docking score was applied to enhance the target relevance of generated compounds. Furthermore, to overcome the problem of high structural similarity caused by Bayesian optimization, the idea of the scaffold memory unit was also introduced. The evaluation results of COMG show that our model not only can improve the structural diversity of generated molecules but also can effectively improve the proportion of target-related drug-active molecules. The obtained results indicate that our proposed model COMG is a useful drug design tool.

From Black Boxes to Actionable Insights: A Perspective on Explainable Artificial Intelligence for Scientific Discovery.

The application of Explainable Artificial Intelligence (XAI) in the field of chemistry has garnered growing interest for its potential to justify the prediction of black-box machine learning models and provide actionable insights. We first survey a range of XAI techniques adapted for chemical applications and categorize them based on the technical details of each methodology. We then present a few case studies to illustrate the practical utility of XAI, such as identifying carcinogenic molecules and guiding molecular optimizations, in order to provide chemists with concrete examples of ways to take full advantage of XAI-augmented machine learning for chemistry. Despite the initial success of XAI in chemistry, we still face the challenges of developing more reliable explanations, assuring robustness against adversarial actions, and customizing the explanation for different applications and needs of the diverse scientific community. Finally, we discuss the emerging role of large language models like GPT in generating natural language explanations and discusses the specific challenges associated with them. We advocate that addressing the aforementioned challenges and actively embracing new techniques may contribute to establishing machine learning as an indispensable technique for chemistry in this digital era.

Molecular Generation with Reduced Labeling through Constraint Architecture.

In the past few years, a number of machine learning (ML)-based molecular generative models have been proposed for generating molecules with desirable properties, but they all require a large amount of label data of pharmacological and physicochemical properties. However, experimental determination of these labels, especially bioactivity labels, is very expensive. In this study, we analyze the dependence of various multi-property molecule generation models on biological activity label data and propose Frag-G/M, a fragment-based multi-constraint molecular generation framework based on conditional transformer, recurrent neural networks (RNNs), and reinforcement learning (RL). The experimental results illustrate that, using the same number of labels, Frag-G/M can generate more desired molecules than the baselines (several times more than the baselines). Moreover, compared with the known active compounds, the molecules generated by Frag-G/M exhibit higher scaffold diversity than those generated by the baselines, thus making it more promising to be used in real-world drug discovery scenarios.

Improved GNNs for Log D7.4 Prediction by Transferring Knowledge from Low-Fidelity Data.

The n-octanol/buffer solution distribution coefficient at pH = 7.4 (log D7.4) is an indicator of lipophilicity, and it influences a wide variety of absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties and druggability of compounds. In log D7.4 prediction, graph neural networks (GNNs) can uncover subtle structure-property relationships (SPRs) by automatically extracting features from molecular graphs that facilitate the learning of SPRs, but their performances are often limited by the small size of available datasets. Herein, we present a transfer learning strategy called pretraining on computational data and then fine-tuning on experimental data (PCFE) to fully exploit the predictive potential of GNNs. PCFE works by pretraining a GNN model on 1.71 million computational log D data (low-fidelity data) and then fine-tuning it on 19,155 experimental log D7.4 data (high-fidelity data). The experiments for three GNN architectures (graph convolutional network (GCN), graph attention network (GAT), and Attentive FP) demonstrated the effectiveness of PCFE in improving GNNs for log D7.4 predictions. Moreover, the optimal PCFE-trained GNN model (cx-Attentive FP, Rtest2 = 0.909) outperformed four excellent descriptor-based models (random forest (RF), gradient boosting (GB), support vector machine (SVM), and extreme gradient boosting (XGBoost)). The robustness of the cx-Attentive FP model was also confirmed by evaluating the models with different training data sizes and dataset splitting strategies. Therefore, we developed a webserver and defined the applicability domain for this model. The webserver (http://tools.scbdd.com/chemlogd/) provides free log D7.4 prediction services. In addition, the important descriptors for log D7.4 were detected by the Shapley additive explanations (SHAP) method, and the most relevant substructures of log D7.4 were identified by the attention mechanism. Finally, the matched molecular pair analysis (MMPA) was performed to summarize the contributions of common chemical substituents to log D7.4, including a variety of hydrocarbon groups, halogen groups, heteroatoms, and polar groups. In conclusion, we believe that the cx-Attentive FP model can serve as a reliable tool to predict log D7.4 and hope that pretraining on low-fidelity data can help GNNs make accurate predictions of other endpoints in drug discovery.