Repositioning or repurposing drugs account for a substantial part of entering approval pipeline drugs, which indicates that drug repositioning has huge market potential and value. Computational ...technologies such as machine learning methods have accelerated the process of drug repositioning in the last few decades years. The repositioning potential of type 2 diabetes mellitus (T2DM) drugs for various diseases such as cancer, neurodegenerative diseases, and cardiovascular diseases have been widely studied. Hence, the related summary about repurposing antidiabetic drugs is of great significance. In this review, we focus on the machine learning methods for the development of new T2DM drugs and give an overview of the repurposing potential of the existing antidiabetic agents.
Structure-based generative chemistry is essential in computer-aided drug discovery by exploring a vast chemical space to design ligands with high binding affinity for targets. However, traditional in ...silico methods are limited by computational inefficiency, while machine learning approaches face bottlenecks due to auto-regressive sampling. To address these concerns, we have developed a conditional deep generative model, PMDM, for 3D molecule generation fitting specified targets. PMDM consists of a conditional equivariant diffusion model with both local and global molecular dynamics, enabling PMDM to consider the conditioned protein information to generate molecules efficiently. The comprehensive experiments indicate that PMDM outperforms baseline models across multiple evaluation metrics. To evaluate the applications of PMDM under real drug design scenarios, we conduct lead compound optimization for SARS-CoV-2 main protease (M
) and Cyclin-dependent Kinase 2 (CDK2), respectively. The selected lead optimization molecules are synthesized and evaluated for their in-vitro activities against CDK2, displaying improved CDK2 activity.
Blood–brain barrier is a pivotal factor to be considered in the process of central nervous system (CNS) drug development, and it is of great significance to rapidly explore the blood–brain barrier ...permeability (BBBp) of compounds in silico in early drug discovery process. Here, we focus on whether and how uncertainty estimation methods improve in silico BBBp models. We briefly surveyed the current state of in silico BBBp prediction and uncertainty estimation methods of deep learning models, and curated an independent dataset to determine the reliability of the state-of-the-art algorithms. The results exhibit that, despite the comparable performance on BBBp prediction between graph neural networks-based deep learning models and conventional physicochemical-based machine learning models, the GROVER-BBBp model shows greatly improvement when using uncertainty estimations. In particular, the strategy combined Entropy and MC-dropout can increase the accuracy of distinguishing BBB + from BBB − to above 99% by extracting predictions with high confidence level (uncertainty score < 0.1). Case studies on preclinical/clinical drugs for Alzheimer’ s disease and marketed antitumor drugs that verified by literature proved the application value of uncertainty estimation enhanced BBBp prediction model, that may facilitate the drug discovery in the field of CNS diseases and metastatic brain tumors.
Artificial intelligence can train the related known drug data into deep learning models for drug design, while classical algorithms can design drugs through established and predefined procedures. ...Both deep learning and classical algorithms have their merits for drug design. Here, the webserver WADDAICA is built to employ the advantage of deep learning model and classical algorithms for drug design. The WADDAICA mainly contains two modules. In the first module, WADDAICA provides deep learning models for scaffold hopping of compounds to modify or design new novel drugs. The deep learning model which is used in WADDAICA shows a good scoring power based on the PDBbind database. In the second module, WADDAICA supplies functions for modifying or designing new novel drugs by classical algorithms. WADDAICA shows better Pearson and Spearman correlations of binding affinity than Autodock Vina that is considered to have the best scoring power. Besides, WADDAICA supplies a friendly and convenient web interface for users to submit drug design jobs. We believe that WADDAICA is a useful and effective tool to help researchers to modify or design novel drugs by deep learning models and classical algorithms. WADDAICA is free and accessible at https://bqflab.github.io or https://heisenberg.ucam.edu:5000.
We have developed a graph-based Variational Autoencoder with Gaussian Mixture hidden space (GraphGMVAE), a deep learning approach for controllable magnitude of scaffold hopping in generative ...chemistry. It can effectively and accurately generate molecules from a given reference compound, with excellent scaffold novelty against known molecules in the literature or patents (97.9% are novel scaffolds). Moreover, a pipeline for prioritizing the generated compounds was also proposed to narrow down our validation focus. In this work, GraphGMVAE was validated by rapidly hopping the scaffold from FDA-approved upadacitinib, which is an inhibitor of human Janus kinase 1 (JAK1), to generate more potent molecules with novel chemical scaffolds. Seven compounds were synthesized and tested to be active in biochemical assays. The most potent molecule has 5.0 nM activity against JAK1 kinase, which shows that the GraphGMVAE model can design molecules like how a human expert does but with high efficiency and accuracy.
As data acquisition technologies advance, longitudinal analysis is facing challenges of exploring complex feature patterns from high-dimensional data and modeling potential temporally lagged effects ...of features on a response. We propose a tensor-based model to analyze multidimensional data. It simultaneously discovers patterns in features and reveals whether features observed at past time points have impact on current outcomes. The model coefficient, a k-mode tensor, is decomposed into a summation of k tensors of the same dimension. We introduce a so-called latent F-1 norm that can be applied to the coefficient tensor to performed structured selection of features. Specifically, features will be selected along each mode of the tensor. The proposed model takes into account within-subject correlations by employing a tensor-based quadratic inference function. An asymptotic analysis shows that our model can identify true support when the sample size approaches to infinity. To solve the corresponding optimization problem, we develop a linearized block coordinate descent algorithm and prove its convergence for a fixed sample size. Computational results on synthetic datasets and real-life fMRI and EEG datasets demonstrate the superior performance of the proposed approach over existing techniques.
Abstract Deep learning is an important branch of artificial intelligence that has been successfully applied into medicine and two-dimensional ligand design. The three-dimensional (3D) ligand ...generation in the 3D pocket of protein target is an interesting and challenging issue for drug design by deep learning. Here, the MolAICal software is introduced to supply a way for generating 3D drugs in the 3D pocket of protein targets by combining with merits of deep learning model and classical algorithm. The MolAICal software mainly contains two modules for 3D drug design. In the first module of MolAICal, it employs the genetic algorithm, deep learning model trained by FDA-approved drug fragments and Vinardo score fitting on the basis of PDBbind database for drug design. In the second module, it uses deep learning generative model trained by drug-like molecules of ZINC database and molecular docking invoked by Autodock Vina automatically. Besides, the Lipinski’s rule of five, Pan-assay interference compounds (PAINS), synthetic accessibility (SA) and other user-defined rules are introduced for filtering out unwanted ligands in MolAICal. To show the drug design modules of MolAICal, the membrane protein glucagon receptor and non-membrane protein SARS-CoV-2 main protease are chosen as the investigative drug targets. The results show MolAICal can generate the various and novel ligands with good binding scores and appropriate XLOGP values. We believe that MolAICal can use the advantages of deep learning model and classical programming for designing 3D drugs in protein pocket. MolAICal is freely for any nonprofit purpose and accessible at https://molaical.github.io.
Unsupervised domain adaptation (UDA) transfers knowledge from a label-rich source domain to a fully-unlabeled target domain. To tackle this task, recent approaches resort to discriminative domain ...transfer in virtue of pseudo-labels to enforce the class-level distribution alignment across the source and target domains. These methods, however, are vulnerable to the error accumulation and thus incapable of preserving cross-domain category consistency, as the pseudo-labeling accuracy is not guaranteed explicitly. In this paper, we propose the Progressive Feature Alignment Network (PFAN) to align the discriminative features across domains progressively and effectively, via exploiting the intra-class variation in the target domain. To be specific, we first develop an Easy-to-Hard Transfer Strategy (EHTS) and an Adaptive Prototype Alignment (APA) step to train our model iteratively and alternatively. Moreover, upon observing that a good domain adaptation usually requires a non-saturated source classifier, we consider a simple yet efficient way to retard the convergence speed of the source classification loss by further involving a temperature variate into the soft-max function. The extensive experimental results reveal that the proposed PFAN exceeds the state-of-the-art performance on three UDA datasets.
•Small modifications in molecule structures potentially lead to drastic increasing of properties.•Graph alignment can discover the similarity of molecule pairs.•Two-level generation improves the ...performance of constrained molecule optimization.•Variational evidence lower bound facilitates the constrained molecule optimization with structure similarity.
The goal of molecule optimization is to optimize molecular properties by modifying molecule structures. Conditional generative models provide a promising way to transfer the input molecules to the ones with better property. However, molecular properties are highly sensitive to small changes in molecular structures. This leads to an interesting thought that we can improve the property of molecules with limited modification in structure. In this paper, we propose a structure-aware conditional Variational Auto-Encoder, namely SCVAE, which exploits the topology of molecules as structure condition and optimizes the molecular properties with constrained structural modification. SCVAE leverages graph alignment of two-level molecule structures in an unsupervised manner to bind the structure conditions between two molecules. Then, this structure condition facilitates the molecule optimization with limited structural modification, namely, constrained molecule optimization, under a novel variational auto-encoder framework. Extensive experimental evaluations demonstrate that structure-aware CVAE generates new molecules with high similarity to the original ones and better molecular properties.
Generative Models for De Novo Drug Design Tong, Xiaochu; Liu, Xiaohong; Tan, Xiaoqin ...
Journal of medicinal chemistry,
10/2021, Letnik:
64, Številka:
19
Journal Article
Recenzirano
Artificial intelligence (AI) is booming. Among various AI approaches, generative models have received much attention in recent years. Inspired by these successes, researchers are now applying ...generative model techniques to de novo drug design, which has been considered as the “holy grail” of drug discovery. In this Perspective, we first focus on describing models such as recurrent neural network, autoencoder, generative adversarial network, transformer, and hybrid models with reinforcement learning. Next, we summarize the applications of generative models to drug design, including generating various compounds to expand the compound library and designing compounds with specific properties, and we also list a few publicly available molecular design tools based on generative models which can be used directly to generate molecules. In addition, we also introduce current benchmarks and metrics frequently used for generative models. Finally, we discuss the challenges and prospects of using generative models to aid drug design.
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