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MedGAN: optimized generative adversarial network with graph convolutional networks for novel molecule design.

ABSTRACT: Generative Artificial Intelligence can be an important asset in the drug discovery process to meet the demand for novel medicines. This work outlines the optimization and fine-tuning steps of MedGAN, a deep learning model based on Wasserstein Generative Adversarial Networks and Graph Convolutional Networks, developed to generate new quinoline-scaffold molecules from complex molecular graphs, including hyperparameter adjustments and evaluations of drug-likeness attributes such as pharmacokinetics, toxicity, and synthetic accessibility. The best model was capable of generating 25% valid molecules, 62% fully connected, from which 92% were quinolines, 93% were novel, and 95% unique, preserving chirality, atom charge, and favorable drug-like properties while generating 4831 novel quinolines. These results provide valuable insights into how activation functions, optimizers, learning rates, neuron units, molecule size and constitution, and scaffold structure affect the performance of generative models and their potential to create new molecular structures, enhancing deep learning applications in computational drug design.

SUBMITTER: Macedo B

PROVIDER: S-EPMC10786821 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature

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MedGAN: optimized generative adversarial network with graph convolutional networks for novel molecule design.

Macedo Bruno B Ribeiro Vaz Inês I Taveira Gomes Tiago T

Scientific reports 20240112 1

Generative Artificial Intelligence can be an important asset in the drug discovery process to meet the demand for novel medicines. This work outlines the optimization and fine-tuning steps of MedGAN, a deep learning model based on Wasserstein Generative Adversarial Networks and Graph Convolutional Networks, developed to generate new quinoline-scaffold molecules from complex molecular graphs, including hyperparameter adjustments and evaluations of drug-likeness attributes such as pharmacokinetics ...[more]

PMID: 38216614

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Project description:Drug design is an important area of study for pharmaceutical businesses. However, low efficacy, off-target delivery, time consumption, and high cost are challenges and can create barriers that impact this process. Deep Learning models are emerging as a promising solution to perform de novo drug design, i.e., to generate drug-like molecules tailored to specific needs. However, stereochemistry was not explicitly considered in the generated molecules, which is inevitable in targeted-oriented molecules. This paper proposes a framework based on Feedback Generative Adversarial Network (GAN) that includes optimization strategy by incorporating Encoder-Decoder, GAN, and Predictor deep models interconnected with a feedback loop. The Encoder-Decoder converts the string notations of molecules into latent space vectors, effectively creating a new type of molecular representation. At the same time, the GAN can learn and replicate the training data distribution and, therefore, generate new compounds. The feedback loop is designed to incorporate and evaluate the generated molecules according to the multiobjective desired property at every epoch of training to ensure a steady shift of the generated distribution towards the space of the targeted properties. Moreover, to develop a more precise set of molecules, we also incorporate a multiobjective optimization selection technique based on a non-dominated sorting genetic algorithm. The results demonstrate that the proposed framework can generate realistic, novel molecules that span the chemical space. The proposed Encoder-Decoder model correctly reconstructs 99% of the datasets, including stereochemical information. The model's ability to find uncharted regions of the chemical space was successfully shown by optimizing the unbiased GAN to generate molecules with a high binding affinity to the Kappa Opioid and Adenosine [Formula: see text] receptor. Furthermore, the generated compounds exhibit high internal and external diversity levels 0.88 and 0.94, respectively, and uniqueness.

Project description:Although massive data is quickly accumulating on protein sequence and structure, there is a small and limited number of protein architectural types (or structural folds). This study is addressing the following question: how well could one reveal underlying sequence-structure relationships and design protein sequences for an arbitrary, potentially novel, structural fold? In response to the question, we have developed novel deep generative models, namely, semisupervised gcWGAN (guided, conditional, Wasserstein Generative Adversarial Networks). To overcome training difficulties and improve design qualities, we build our models on conditional Wasserstein GAN (WGAN) that uses Wasserstein distance in the loss function. Our major contributions include (1) constructing a low-dimensional and generalizable representation of the fold space for the conditional input, (2) developing an ultrafast sequence-to-fold predictor (or oracle) and incorporating its feedback into WGAN as a loss to guide model training, and (3) exploiting sequence data with and without paired structures to enable a semisupervised training strategy. Assessed by the oracle over 100 novel folds not in the training set, gcWGAN generates more successful designs and covers 3.5 times more target folds compared to a competing data-driven method (cVAE). Assessed by sequence- and structure-based predictors, gcWGAN designs are physically and biologically sound. Assessed by a structure predictor over representative novel folds, including one not even part of basis folds, gcWGAN designs have comparable or better fold accuracy yet much more sequence diversity and novelty than cVAE. The ultrafast data-driven model is further shown to boost the success of a principle-driven de novo method (RosettaDesign), through generating design seeds and tailoring design space. In conclusion, gcWGAN explores uncharted sequence space to design proteins by learning generalizable principles from current sequence-structure data. Data, source codes, and trained models are available at https://github.com/Shen-Lab/gcWGAN.

Project description:BackgroundThe efficient and accurate diagnosis of pulmonary adenocarcinoma before surgery is of considerable significance to clinicians. Although computed tomography (CT) examinations are widely used in practice, it is still challenging and time-consuming for radiologists to distinguish between different types of subcentimeter pulmonary nodules. Although there have been many deep learning algorithms proposed, their performance largely depends on vast amounts of data, which is difficult to collect in the medical imaging area. Therefore, we propose an automatic classification system for subcentimeter pulmonary adenocarcinoma, combining a convolutional neural network (CNN) and a generative adversarial network (GAN) to optimize clinical decision-making and to provide small dataset algorithm design ideas.MethodsA total of 206 nodules with postoperative pathological labels were analyzed. Among them were 30 adenocarcinomas in situ (AISs), 119 minimally invasive adenocarcinomas (MIAs), and 57 invasive adenocarcinomas (IACs). Our system consisted of two parts, a GAN-based image synthesis, and a CNN classification. First, several popular existing GAN techniques were employed to augment the datasets, and comprehensive experiments were conducted to evaluate the quality of the GAN synthesis. Additionally, our classification system processes were based on two-dimensional (2D) nodule-centered CT patches without the need of manual labeling information.ResultsFor GAN-based image synthesis, the visual Turing test showed that even radiologists could not tell the GAN-synthesized from the raw images (accuracy: primary radiologist 56%, senior radiologist 65%). For CNN classification, our progressive growing wGAN improved the performance of CNN most effectively (area under the curve =0.83). The experiments indicated that the proposed GAN augmentation method improved the classification accuracy by 23.5% (from 37.0% to 60.5%) and 7.3% (from 53.2% to 60.5%) in comparison with training methods using raw and common augmented images respectively. The performance of this combined GAN and CNN method (accuracy: 60.5%±2.6%) was comparable to the state-of-the-art methods, and our CNN was also more lightweight.ConclusionsThe experiments revealed that GAN synthesis techniques could effectively alleviate the problem of insufficient data in medical imaging. The proposed GAN plus CNN framework can be generalized for use in building other computer-aided detection (CADx) algorithms and thus assist in diagnosis.

Dataset Information

MedGAN: optimized generative adversarial network with graph convolutional networks for novel molecule design.

Publications

MedGAN: optimized generative adversarial network with graph convolutional networks for novel molecule design.

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