The Impact of Supervised Learning Methods in Ultralarge High-Throughput Docking.

Structure-based virtual screening methods are, nowadays, one of the key pillars of computational drug discovery. In recent years, a series of studies have reported docking-based virtual screening campaigns of large databases ranging from hundreds to thousands of millions compounds, further identifying novel hits after experimental validation. As these larg-scale efforts are not generally accessible, machine learning-based protocols have emerged to accelerate the identification of virtual hits within an ultralarge chemical space, reaching impressive reductions in computational time. Herein, we illustrate the motivation and the problem behind the screening of large databases, providing an overview of key concepts and essential applications of machine learning-accelerated protocols, specifically concerning supervised learning methods. We also discuss where the field stands with these novel developments, highlighting possible insights for future studies.

How good are AlphaFold models for docking-based virtual screening?

A crucial component in structure-based drug discovery is the availability of high-quality three-dimensional structures of the protein target. Whenever experimental structures were not available, homology modeling has been, so far, the method of choice. Recently, AlphaFold (AF), an artificial-intelligence-based protein structure prediction method, has shown impressive results in terms of model accuracy. This outstanding success prompted us to evaluate how accurate AF models are from the perspective of docking-based drug discovery. We compared the high-throughput docking (HTD) performance of AF models with their corresponding experimental PDB structures using a benchmark set of 22 targets. The AF models showed consistently worse performance using four docking programs and two consensus techniques. Although AlphaFold shows a remarkable ability to predict protein architecture, this might not be enough to guarantee that AF models can be reliably used for HTD, and post-modeling refinement strategies might be key to increase the chances of success.

Guided structure-based ligand identification and design via artificial intelligence modeling.

INTRODUCTION: The implementation of Artificial Intelligence (AI) methodologies to drug discovery (DD) are on the rise. Several applications have been developed for structure-based DD, where AI methods provide an alternative framework for the identification of ligands for validated therapeutic targets, as well as the de novo design of ligands through generative models. AREAS COVERED: Herein, the authors review the contributions between the 2019 to present period regarding the application of AI methods to structure-based virtual screening (SBVS) which encompasses mainly molecular docking applications - binding pose prediction and binary classification for ligand or hit identification-, as well as de novo drug design driven by machine learning (ML) generative models, and the validation of AI models in structure-based screening. Studies are reviewed in terms of their main objective, used databases, implemented methodology, input and output, and key results . EXPERT OPINION: More profound analyses regarding the validity and applicability of AI methods in DD have begun to appear. In the near future, we expect to see more structure-based generative models- which are scarce in comparison to ligand-based generative models-, the implementation of standard guidelines for validating the generated structures, and more analyses regarding the validation of AI methods in structure-based DD.

A Machine Learning Model to Predict Drug Transfer Across the Human Placenta Barrier.

The development of computational models for assessing the transfer of chemicals across the placental membrane would be of the utmost importance in drug discovery campaigns, in order to develop safe therapeutic options. We have developed a low-dimensional machine learning model capable of classifying compounds according to whether they can cross or not the placental barrier. To this aim, we compiled a database of 248 compounds with experimental information about their placental transfer, characterizing each compound with a set of ∼5.4 thousand descriptors, including physicochemical properties and structural features. We evaluated different machine learning classifiers and implemented a genetic algorithm, in a five cross validation scheme, to perform feature selection. The optimization was guided towards models displaying a low number of false positives (molecules that actually cross the placental barrier, but are predicted as not crossing it). A Linear Discriminant Analysis model trained with only four structural features resulted to be robust for this task, exhibiting only one false positive case across all testing folds. This model is expected to be useful in predicting placental drug transfer during pregnancy, and thus could be used as a filter for chemical libraries in virtual screening campaigns.

In silico Drug Repurposing for COVID-19: Targeting SARS-CoV-2 Proteins through Docking and Consensus Ranking.

In December 2019, an infectious disease caused by the coronavirus SARS-CoV-2 appeared in Wuhan, China. This disease (COVID-19) spread rapidly worldwide, and on March 2020 was declared a pandemic by the World Health Organization (WHO). Today, over 21 million people have been infected, with more than 750.000 casualties. Today, no vaccine or antiviral drug is available. While the development of a vaccine might take at least a year, and for a novel drug, even longer; finding a new use to an old drug (drug repurposing) could be the most effective strategy. We present a docking-based screening using a quantum mechanical scoring of a library built from approved drugs and compounds undergoing clinical trials, against three SARS-CoV-2 target proteins: the spike or S-protein, and two proteases, the main protease and the papain-like protease. The S-protein binds directly to the Angiotensin Converting Enzyme 2 receptor of the human host cell surface, while the two proteases process viral polyproteins. Following the analysis of our structure-based compound screening, we propose several structurally diverse compounds (either FDA-approved or in clinical trials) that could display antiviral activity against SARS-CoV-2. Clearly, these compounds should be further evaluated in experimental assays and clinical trials to confirm their actual activity against the disease. We hope that these findings may contribute to the rational drug design against COVID-19.

Artificial intelligence in the early stages of drug discovery.

Although the use of computational methods within the pharmaceutical industry is well established, there is an urgent need for new approaches that can improve and optimize the pipeline of drug discovery and development. In spite of the fact that there is no unique solution for this need for innovation, there has recently been a strong interest in the use of Artificial Intelligence for this purpose. As a matter of fact, not only there have been major contributions from the scientific community in this respect, but there has also been a growing partnership between the pharmaceutical industry and Artificial Intelligence companies. Beyond these contributions and efforts there is an underlying question, which we intend to discuss in this review: can the intrinsic difficulties within the drug discovery process be overcome with the implementation of Artificial Intelligence? While this is an open question, in this work we will focus on the advantages that these algorithms provide over the traditional methods in the context of early drug discovery.