Protein docking refinement by convex underestimation in the low-dimensional subspace of encounter complexes

We propose a novel stochastic global optimization algorithm with applications to the refinement stage of protein docking prediction methods. Our approach can process conformations sampled from multiple clusters, each roughly corresponding to a different binding energy funnel. These clusters are obtained using a density-based clustering method. In each cluster, we identify a smooth “permissive” subspace which avoids high-energy barriers and then underestimate the binding energy function using general convex polynomials in this subspace. We use the underestimator to bias sampling towards its global minimum. Sampling and subspace underestimation are repeated several times and the conformations sampled at the last iteration form a refined ensemble. We report computational results on a comprehensive benchmark of 224 protein complexes, establishing that our refined ensemble significantly improves the quality of the conformations of the original set given to the algorithm. We also devise a method to enhance the ensemble from which near-native models are selected.Published versio

Generation of new inhibitors of selected cytochrome P450 subtypes- "In silico" study

Physicochemical and pharmacokinetic compound profile has crucial impact on compound potency to become a future drug. Ligands with desired activity profile cannot be used for treatment if they are characterized by unfavourable physicochemical or ADMET properties. In the study, we consider metabolic stability and focus on selected subtypes of cytochrome P450 - proteins, which take part in the first phase of compound transformations in the organism. We develop a protocol for generation of new potential inhibitors of selected cytochrome isoforms. Its subsequent stages are composed of generation and assessment of new derivatives of known cytochrome inhibitors, docking and evaluation of the compound possible inhibition on the basis of the obtained ligand-protein complexes. Besides the library of new potential agents inhibiting particular cytochrome subtypes, we also prepare a graph neural network that predicts the change in activity for all modifications of the starting molecule. In addition, we perform a systematic statistical study on the influence of particular substitutions on the potential inhibition properties of generated compounds (both mono- and di-substitutions are considered), provide explanations of the inhibitory predictions and prepare an on-line visualization platform enabling manual inspection of the results. The developed methodology can greatly support the design of new cytochrome P450 inhibitors with the overarching goal of generation of new metabolically stable compounds. It enables instant evaluation of possible compound-cytochrome interactions and selection of ligands with the highest potential of possessing desired biological activity

Generating Focussed Molecule Libraries for Drug Discovery with Recurrent Neural Networks

In de novo drug design, computational strategies are used to generate novel molecules with good affinity to the desired biological target. In this work, we show that recurrent neural networks can be trained as generative models for molecular structures, similar to statistical language models in natural language processing. We demonstrate that the properties of the generated molecules correlate very well with the properties of the molecules used to train the model. In order to enrich libraries with molecules active towards a given biological target, we propose to fine-tune the model with small sets of molecules, which are known to be active against that target. Against Staphylococcus aureus, the model reproduced 14% of 6051 hold-out test molecules that medicinal chemists designed, whereas against Plasmodium falciparum (Malaria) it reproduced 28% of 1240 test molecules. When coupled with a scoring function, our model can perform the complete de novo drug design cycle to generate large sets of novel molecules for drug discovery.Comment: 17 pages, 17 figure

A computational view on nanomaterial intrinsic and extrinsic features for nanosafety and sustainability

In recent years, an increasing number of diverse Engineered Nano-Materials (ENMs), such as nanoparticles and nanotubes, have been included in many technological applications and consumer products. The desirable and unique properties of ENMs are accompanied by potential hazards whose impacts are difficult to predict either qualitatively or in a quantitative and predictive manner. Alongside established methods for experimental and computational characterisation, physics-based modelling tools like molecular dynamics are increasingly considered in Safe and Sustainability-by-design (SSbD) strategies that put user health and environmental impact at the centre of the design and development of new products. Hence, the further development of such tools can support safe and sustainable innovation and its regulation. This paper stems from a community effort and presents the outcome of a four-year-long discussion on the benefits, capabilities and limitations of adopting physics-based modelling for computing suitable features of nanomaterials that can be used for toxicity assessment of nanomaterials in combination with data-based models and experimental assessment of toxicity endpoints. We review modern multiscale physics-based models that generate advanced system-dependent (intrinsic) or timeand environment-dependent (extrinsic) descriptors/features of ENMs (primarily, but not limited to nanoparticles, NPs), with the former being related to the bare NPs and the latter to their dynamic fingerprinting upon entering biological media. The focus is on (i) effectively representing all nanoparticle attributes for multicomponent nanomaterials, (ii) generation and inclusion of intrinsic nanoform properties, (iii) inclusion of selected extrinsic properties, (iv) the necessity of considering distributions of structural advanced features rather than only averages. This review enables us to identify and highlight a number of key challenges associated with ENMs’ data generation, curation, representation and use within machine learning or other advanced data-driven models to ultimately enhance toxicity assessment. Finally, the set up of dedicated databases as well as the development of grouping and read-across strategies based on the mode of action of ENMs using omics methods are identified as emerging methodologies for safety assessment and reduction of animal testing

A review on machine learning approaches and trends in drug discovery

Abstract: Drug discovery aims at finding new compounds with specific chemical properties for the treatment of diseases. In the last years, the approach used in this search presents an important component in computer science with the skyrocketing of machine learning techniques due to its democratization. With the objectives set by the Precision Medicine initiative and the new challenges generated, it is necessary to establish robust, standard and reproducible computational methodologies to achieve the objectives set. Currently, predictive models based on Machine Learning have gained great importance in the step prior to preclinical studies. This stage manages to drastically reduce costs and research times in the discovery of new drugs. This review article focuses on how these new methodologies are being used in recent years of research. Analyzing the state of the art in this field will give us an idea of where cheminformatics will be developed in the short term, the limitations it presents and the positive results it has achieved. This review will focus mainly on the methods used to model the molecular data, as well as the biological problems addressed and the Machine Learning algorithms used for drug discovery in recent years.Instituto de Salud Carlos III; PI17/01826Instituto de Salud Carlos III; PI17/01561Xunta de Galicia; Ref. ED431D 2017/16Xunta de Galicia; Ref. ED431D 2017/23Xunta de Galicia; Ref. ED431C 2018/4