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Register a new userCASTELO: Clustered Atom Subtypes aidEd Lead Optimization -- a combined machine learning and molecular modeling method
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Drug discovery is a multi-stage process that comprises two costly major steps: pre-clinical research and clinical trials. Among its stages, lead optimization easily consumes more than half of the pre-clinical budget. We propose a combined machine learning and molecular modeling approach that automates lead optimization workflow textit{in silico}. The initial data collection is achieved with physics-based molecular dynamics (MD) simulation. Contact matrices are calculated as the preliminary features extracted from the simulations. To take advantage of the temporal information from the simulations, we enhanced contact matrices data with temporal dynamism representation, which are then modeled with unsupervised convolutional variational autoencoder (CVAE). Finally, conventional clustering method and CVAE-based clustering method are compared with metrics to rank the submolecular structures and propose potential candidates for lead optimization. With no need for extensive structure-activity relationship database, our method provides new hints for drug modification hotspots which can be used to improve drug efficacy. Our workflow can potentially reduce the lead optimization turnaround time from months/years to days compared with the conventional labor-intensive process and thus can potentially become a valuable tool for medical researchers.
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Molecular machine learning has been maturing rapidly over the last few years. Improved methods and the presence of larger datasets have enabled machine learning algorithms to make increasingly accurate predictions about molecular properties. However, algorithmic progress has been limited due to the lack of a standard benchmark to compare the efficacy of proposed methods; most new algorithms are benchmarked on different datasets making it challenging to gauge the quality of proposed methods. This work introduces MoleculeNet, a large scale benchmark for molecular machine learning. MoleculeNet curates multiple public datasets, establishes metrics for evaluation, and offers high quality open-source implementations of multiple previously proposed molecular featurization and learning algorithms (released as part of the DeepChem open source library). MoleculeNet benchmarks demonstrate that learnable representations are powerful tools for molecular machine learning and broadly offer the best performance. However, this result comes with caveats. Learnable representations still struggle to deal with complex tasks under data scarcity and highly imbalanced classification. For quantum mechanical and biophysical datasets, the use of physics-aware featurizations can be more important than choice of particular learning algorithm.
The pipeline optimization problem in machine learning requires simultaneous optimization of pipeline structures and parameter adaptation of their elements. Having an elegant way to express these structures can help lessen the complexity in the management and analysis of their performances together with the different choices of optimization strategies. With these issues in mind, we created the AutoMLPipeline (AMLP) toolkit which facilitates the creation and evaluation of complex machine learning pipeline structures using simple expressions. We use AMLP to find optimal pipeline signatures, datamine them, and use these datamined features to speed-up learning and prediction. We formulated a two-stage pipeline optimization with surrogate modeling in AMLP which outperforms other AutoML approaches with a 4-hour time budget in less than 5 minutes of AMLP computation time.
Chemistry research has both high material and computational costs to conduct experiments. Institutions thus consider chemical data to be valuable and there have been few efforts to construct large public datasets for machine learning. Another challenge is that different intuitions are interested in different classes of molecules, creating heterogeneous data that cannot be easily joined by conventional distributed training. In this work, we introduce federated heterogeneous molecular learning to address these challenges. Federated learning allows end-users to build a global model collaboratively while preserving the training data distributed over isolated clients. Due to the lack of related research, we first simulate a federated heterogeneous benchmark called FedChem. FedChem is constructed by jointly performing scaffold splitting and Latent Dirichlet Allocation on existing datasets. Our results on FedChem show that significant learning challenges arise when working with heterogeneous molecules. We then propose a method to alleviate the problem, namely Federated Learning by Instance reweighTing (FLIT). FLIT can align the local training across heterogeneous clients by improving the performance for uncertain samples. Comprehensive experiments conducted on our new benchmark FedChem validate the advantages of this method over other federated learning schemes. FedChem should enable a new type of collaboration for improving AI in chemistry that mitigates concerns about valuable chemical data.
In view of training increasingly complex learning architectures, we establish a nonsmooth implicit function theorem with an operational calculus. Our result applies to most practical problems (i.e., definable problems) provided that a nonsmooth form of the classical invertibility condition is fulfilled. This approach allows for formal subdifferentiation: for instance, replacing derivatives by Clarke Jacobians in the usual differentiation formulas is fully justified for a wide class of nonsmooth problems. Moreover this calculus is entirely compatible with algorithmic differentiation (e.g., backpropagation). We provide several applications such as training deep equilibrium networks, training neural nets with conic optimization layers, or hyperparameter-tuning for nonsmooth Lasso-type models. To show the sharpness of our assumptions, we present numerical experiments showcasing the extremely pathological gradient dynamics one can encounter when applying implicit algorithmic differentiation without any hypothesis.
Computer-aided design (CAD) programs are essential to engineering as they allow for better designs through low-cost iterations. While CAD programs are typically taught to undergraduate students as a job skill, such software can also help students learn engineering concepts. A current limitation of CAD programs (even those that are specifically designed for educational purposes) is that they are not capable of providing automated real-time help to students. To encourage CAD programs to build in assistance to students, we used data generated from students using a free, open source CAD software called Aladdin to demonstrate how student data combined with machine learning techniques can predict how well a particular student will perform in a design task. We challenged students to design a house that consumed zero net energy as part of an introductory engineering technology undergraduate course. Using data from 128 students, along with the scikit-learn Python machine learning library, we tested our models using both total counts of design actions and sequences of design actions as inputs. We found that our models using early design sequence actions are particularly valuable for prediction. Our logistic regression model achieved a >60% chance of predicting if a student would succeed in designing a zero net energy house. Our results suggest that it would be feasible for Aladdin to provide useful feedback to students when they are approximately halfway through their design. Further improvements to these models could lead to earlier predictions and thus provide students feedback sooner to enhance their learning.
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