Rational drug design often starts from specific scaffolds to which side chains/substituents are added or modified due to the large drug-like chemical space available to search for novel drug-like... Show moreRational drug design often starts from specific scaffolds to which side chains/substituents are added or modified due to the large drug-like chemical space available to search for novel drug-like molecules. With the rapid growth of deep learning in drug discovery, a variety of effective approaches have been developed for de novo drug design. In previous work we proposed a method named DrugEx, which can be applied in polypharmacology based on multi-objective deep reinforcement learning. However, the previous version is trained under fixed objectives and does not allow users to input any prior information (i.e. a desired scaffold). In order to improve the general applicability, we updated DrugEx to design drug molecules based on scaffolds which consist of multiple fragments provided by users. Here, a Transformer model was employed to generate molecular structures. The Transformer is a multi-head self-attention deep learning model containing an encoder to receive scaffolds as input and a decoder to generate molecules as output. In order to deal with the graph representation of molecules a novel positional encoding for each atom and bond based on an adjacency matrix was proposed, extending the architecture of the Transformer. The graph Transformer model contains growing and connecting procedures for molecule generation starting from a given scaffold based on fragments. Moreover, the generator was trained under a reinforcement learning framework to increase the number of desired ligands. As a proof of concept, the method was applied to design ligands for the adenosine A2A receptor (A2AAR) and compared with SMILES-based methods. The results show that 100% of the generated molecules are valid and most of them had a high predicted affinity value towards A2AAR with given scaffolds. Show less
Sbrollini, A.; Barocci, M.; Mancinelli, M.; Paris, M.; Raffaelli, S.; Marcantoni, I.; ... ; Burattini, L. 2023
Heart failure (HF) diagnosis, typically visually performed by serial electrocardiography, may be supported by machine-learning approaches. Repeated structuring & learning procedure (RS & LP... Show moreHeart failure (HF) diagnosis, typically visually performed by serial electrocardiography, may be supported by machine-learning approaches. Repeated structuring & learning procedure (RS & LP) is a constructive algorithm able to automatically create artificial neural networks (ANN); it relies on three parameters, namely maximal number of hidden layers (MNL), initializations (MNI) and confirmations (MNC), arbitrarily set by the user. The aim of this study is to evaluate RS & LP robustness to varying values of parameters and to identify an optimized combination of parameter values for HF diagnosis. To this aim, the Leiden University Medical Center HF data-base was used. The database is constituted by 129 serial ECG pairs acquired in patients who experienced myocardial infarction; 48 patients developed HF at follow-up (cases), while 81 remained clinically stable (controls). Overall, 15 ANNs were created by considering 13 serial ECG features as inputs (extracted from each serial ECG pair), 2 classes as outputs (cases/controls), and varying values of MNL (1, 2, 3, 4 and 10), MNI (50, 250, 500, 1000 and 1500) and MNC (2, 5, 10, 20 and 50). The area under the curve (AUC) of the receiver operating characteristic did not significantly vary with varying parameter values (P >= 0.09). The optimized combination of parameter values, identified as the one showing the highest AUC, was obtained for MNL = 3, MNI = 500 and MNC = 50 (AUC = 86 %; ANN structure: 3 hidden layers of 14, 14 and 13 neurons, respectively). Thus, RS & LP is robust, and the optimized ANN represents a potentially useful clinical tool for a reliable auto-matic HF diagnosis. Show less
Sicho, M.; Liu, X.; Svozil, D.; Westen, G.J.P. van 2021
Many contemporary cheminformatics methods, including computer-aided de novo drug design, hold promise to significantly accelerate and reduce the cost of drug discovery. Thanks to this attractive... Show moreMany contemporary cheminformatics methods, including computer-aided de novo drug design, hold promise to significantly accelerate and reduce the cost of drug discovery. Thanks to this attractive outlook, the field has thrived and in the past few years has seen an especially significant growth, mainly due to the emergence of novel methods based on deep neural networks. This growth is also apparent in the development of novel de novo drug design methods with many new generative algorithms now available. However, widespread adoption of new generative techniques in the fields like medicinal chemistry or chemical biology is still lagging behind the most recent developments. Upon taking a closer look, this fact is not surprising since in order to successfully integrate the most recent de novo drug design methods in existing processes and pipelines, a close collaboration between diverse groups of experimental and theoretical scientists needs to be established. Therefore, to accelerate the adoption of both modern and traditional de novo molecular generators, we developed Generator User Interface (GenUI), a software platform that makes it possible to integrate molecular generators within a feature-rich graphical user interface that is easy to use by experts of diverse backgrounds. GenUI is implemented as a web service and its interfaces offer access to cheminformatics tools for data preprocessing, model building, molecule generation, and interactive chemical space visualization. Moreover, the platform is easy to extend with customizable frontend React.js components and backend Python extensions. GenUI is open source and a recently developed de novo molecular generator, DrugEx, was integrated as a proof of principle. In this work, we present the architecture and implementation details of GenUI and discuss how it can facilitate collaboration in the disparate communities interested in de novo molecular generation and computer-aided drug discovery. Show less
