197 research outputs found
Computer-Aided Multi-Objective Optimization in Small Molecule Discovery
Molecular discovery is a multi-objective optimization problem that requires
identifying a molecule or set of molecules that balance multiple, often
competing, properties. Multi-objective molecular design is commonly addressed
by combining properties of interest into a single objective function using
scalarization, which imposes assumptions about relative importance and uncovers
little about the trade-offs between objectives. In contrast to scalarization,
Pareto optimization does not require knowledge of relative importance and
reveals the trade-offs between objectives. However, it introduces additional
considerations in algorithm design. In this review, we describe pool-based and
de novo generative approaches to multi-objective molecular discovery with a
focus on Pareto optimization algorithms. We show how pool-based molecular
discovery is a relatively direct extension of multi-objective Bayesian
optimization and how the plethora of different generative models extend from
single-objective to multi-objective optimization in similar ways using
non-dominated sorting in the reward function (reinforcement learning) or to
select molecules for retraining (distribution learning) or propagation (genetic
algorithms). Finally, we discuss some remaining challenges and opportunities in
the field, emphasizing the opportunity to adopt Bayesian optimization
techniques into multi-objective de novo design
Advances in De Novo Drug Design : From Conventional to Machine Learning Methods
De novo drug design is a computational approach that generates novel molecular structures from atomic building blocks with no a priori relationships. Conventional methods include structure-based and ligand-based design, which depend on the properties of the active site of a biological target or its known active binders, respectively. Artificial intelligence, including ma-chine learning, is an emerging field that has positively impacted the drug discovery process. Deep reinforcement learning is a subdivision of machine learning that combines artificial neural networks with reinforcement-learning architectures. This method has successfully been em-ployed to develop novel de novo drug design approaches using a variety of artificial networks including recurrent neural networks, convolutional neural networks, generative adversarial networks, and autoencoders. This review article summarizes advances in de novo drug design, from conventional growth algorithms to advanced machine-learning methodologies and high-lights hot topics for further development.Peer reviewe
Evolutionary Computation and QSAR Research
[Abstract] The successful high throughput screening of molecule libraries for a specific biological property is one of the main improvements in drug discovery. The virtual molecular filtering and screening relies greatly on quantitative structure-activity relationship (QSAR) analysis, a mathematical model that correlates the activity of a molecule with molecular descriptors. QSAR models have the potential to reduce the costly failure of drug candidates in advanced (clinical) stages by filtering combinatorial libraries, eliminating candidates with a predicted toxic effect and poor pharmacokinetic profiles, and reducing the number of experiments. To obtain a predictive and reliable QSAR model, scientists use methods from various fields such as molecular modeling, pattern recognition, machine learning or artificial intelligence. QSAR modeling relies on three main steps: molecular structure codification into molecular descriptors, selection of relevant variables in the context of the analyzed activity, and search of the optimal mathematical model that correlates the molecular descriptors with a specific activity. Since a variety of techniques from statistics and artificial intelligence can aid variable selection and model building steps, this review focuses on the evolutionary computation methods supporting these tasks. Thus, this review explains the basic of the genetic algorithms and genetic programming as evolutionary computation approaches, the selection methods for high-dimensional data in QSAR, the methods to build QSAR models, the current evolutionary feature selection methods and applications in QSAR and the future trend on the joint or multi-task feature selection methods.Instituto de Salud Carlos III, PIO52048Instituto de Salud Carlos III, RD07/0067/0005Ministerio de Industria, Comercio y Turismo; TSI-020110-2009-53)Galicia. ConsellerĂa de EconomĂa e Industria; 10SIN105004P
Protein-Ligand Binding Affinity Directed Multi-Objective Drug Design Based on Fragment Representation Methods
Drug discovery is a challenging process with a vast molecular space to be explored and numerous pharmacological properties to be appropriately considered. Among various drug design protocols, fragment-based drug design is an effective way of constraining the search space and better utilizing biologically active compounds. Motivated by fragment-based drug search for a given protein target and the emergence of artificial intelligence (AI) approaches in this field, this work advances the field of in silico drug design by (1) integrating a graph fragmentation-based deep generative model with a deep evolutionary learning process for large-scale multi-objective molecular optimization, and (2) applying protein-ligand binding affinity scores together with other desired physicochemical properties as objectives. Our experiments show that the proposed method can generate novel molecules with improved property values and binding affinities
Advances and applications in high-dimensional heuristic optimization
“Applicable to most real-world decision scenarios, multiobjective optimization is an area of multicriteria decision-making that seeks to simultaneously optimize two or more conflicting objectives. In contrast to single-objective scenarios, nontrivial multiobjective optimization problems are characterized by a set of Pareto optimal solutions wherein no solution unanimously optimizes all objectives. Evolutionary algorithms have emerged as a standard approach to determine a set of these Pareto optimal solutions, from which a decision-maker can select a vetted alternative. While easy to implement and having demonstrated great efficacy, these evolutionary approaches have been criticized for their runtime complexity when dealing with many alternatives or a high number of objectives, effectively limiting the range of scenarios to which they may be applied. This research introduces mechanisms to improve the runtime complexity of many multiobjective evolutionary algorithms, achieving state-of-the-art performance, as compared to many prominent methods from the literature. Further, the investigations here presented demonstrate the capability of multiobjective evolutionary algorithms in a complex, large-scale optimization scenario. Showcasing the approach’s ability to intelligently generate well-performing solutions to a meaningful optimization problem.
These investigations advance the concept of multiobjective evolutionary algorithms by addressing a key limitation and demonstrating their efficacy in a challenging real-world scenario. Through enhanced computational efficiency and exhibited specialized application, the utility of this powerful heuristic strategy is made more robust and evident”--Abstract, page iv
Multi-and many-objective optimization: present and future in de novo drug design
de novo Drug Design (dnDD) aims to create new molecules that satisfy multiple conflicting objectives. Since several desired properties can be considered in the optimization process, dnDD is naturally categorized as a many-objective optimization problem (ManyOOP), where more than three objectives must be simultaneously optimized. However, a large number of objectives typically pose several challenges that affect the choice and the design of optimization methodologies. Herein, we cover the application of multi- and many-objective optimization methods, particularly those based on Evolutionary Computation and Machine Learning techniques, to enlighten their potential application in dnDD. Additionally, we comprehensively analyze how molecular properties used in the optimization process are applied as either objectives or constraints to the problem. Finally, we discuss future research in many-objective optimization for dnDD, highlighting two important possible impacts: i) its integration with the development of multi-target approaches to accelerate the discovery of innovative and more efficacious drug therapies and ii) its role as a catalyst for new developments in more fundamental and general methodological frameworks in the field
Sample-efficient Multi-objective Molecular Optimization with GFlowNets
Many crucial scientific problems involve designing novel molecules with
desired properties, which can be formulated as a black-box optimization problem
over the discrete chemical space. In practice, multiple conflicting objectives
and costly evaluations (e.g., wet-lab experiments) make the diversity of
candidates paramount. Computational methods have achieved initial success but
still struggle with considering diversity in both objective and search space.
To fill this gap, we propose a multi-objective Bayesian optimization (MOBO)
algorithm leveraging the hypernetwork-based GFlowNets (HN-GFN) as an
acquisition function optimizer, with the purpose of sampling a diverse batch of
candidate molecular graphs from an approximate Pareto front. Using a single
preference-conditioned hypernetwork, HN-GFN learns to explore various
trade-offs between objectives. We further propose a hindsight-like off-policy
strategy to share high-performing molecules among different preferences in
order to speed up learning for HN-GFN. We empirically illustrate that HN-GFN
has adequate capacity to generalize over preferences. Moreover, experiments in
various real-world MOBO settings demonstrate that our framework predominantly
outperforms existing methods in terms of candidate quality and sample
efficiency. The code is available at https://github.com/violet-sto/HN-GFN.Comment: NeurIPS 202
Using multiobjective optimization and energy minimization to design an isoform-selective ligand of the 14-3-3 Protein
Medicinal ChemistryAnimal sciencesComputer Systems, Imagery and Medi
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