Classical scoring functions may exhibit low accuracy in determining ligand binding affinity for proteins. The availability of both protein-ligand structures and affinity data make it possible to develop machine-learning models focused on specific protein systems with superior predictive performance. Here, we report a new methodology named SAnDReS that combines AutoDock Vina 1.
View Article and Find Full Text PDFBackground: The idea of scoring function space established a systems-level approach to address the development of models to predict the affinity of drug molecules by those interested in drug discovery.
Objective: Our goal here is to review the concept of scoring function space and how to explore it to develop machine learning models to address protein-ligand binding affinity.
Methods: We searched the articles available in PubMed related to the scoring function space.
Background: The main protease of SARS-CoV-2 (M) is one of the targets identified in SARS-CoV-2, the causative agent of COVID-19. The application of X-ray diffraction crystallography made available the three-dimensional structure of this protein target in complex with ligands, which paved the way for docking studies.
Objective: Our goal here is to review recent efforts in the application of docking simulations to identify inhibitors of the M using the program AutoDock4.
Background: Electrostatic interactions are one of the forces guiding the binding of molecules to proteins. The assessment of this interaction through computational approaches makes it possible to evaluate the energy of protein-drug complexes.
Objective: Our purpose here is to review some of the methods used to calculate the electrostatic energy of protein-drug complexes and explore the capacity of these approaches for the generation of new computational tools for drug discovery using the abstraction of scoring function space.
Background: Analysis of atomic coordinates of protein-ligand complexes can provide three-dimensional data to generate computational models to evaluate binding affinity and thermodynamic state functions. Application of machine learning techniques can create models to assess protein-ligand potential energy and binding affinity. These methods show superior predictive performance when compared with classical scoring functions available in docking programs.
View Article and Find Full Text PDFBackground: The elucidation of the structure of cyclin-dependent kinase 2 (CDK2) made it possible to develop targeted scoring functions for virtual screening aimed to identify new inhibitors for this enzyme. CDK2 is a protein target for the development of drugs intended to modulate cellcycle progression and control. Such drugs have potential anticancer activities.
View Article and Find Full Text PDFIn the analysis of protein-ligand interactions, two abstractions have been widely employed to build a systematic approach to analyze these complexes: protein and chemical spaces. The pioneering idea of the protein space dates back to 1970, and the chemical space is newer, later 1990s. With the progress of computational methodologies to create machine-learning models to predict the ligand-binding affinity, clearly there is a need for novel approaches to the problem of protein-ligand interactions.
View Article and Find Full Text PDFRecent progress in the development of scientific libraries with machine-learning techniques paved the way for the implementation of integrated computational tools to predict ligand-binding affinity. The prediction of binding affinity uses the atomic coordinates of protein-ligand complexes. These new computational tools made application of a broad spectrum of machine-learning techniques to study protein-ligand interactions possible.
View Article and Find Full Text PDFHomology modeling is a computational approach to generate three-dimensional structures of protein targets when experimental data about similar proteins are available. Although experimental methods such as X-ray crystallography and nuclear magnetic resonance spectroscopy successfully solved the structures of nearly 150,000 macromolecules, there is still a gap in our structural knowledge. We can fulfill this gap with computational methodologies.
View Article and Find Full Text PDFMolecular docking is the major computational technique employed in the early stages of computer-aided drug discovery. The availability of free software to carry out docking simulations of protein-ligand systems has allowed for an increasing number of studies using this technique. Among the available free docking programs, we discuss the use of ArgusLab ( http://www.
View Article and Find Full Text PDFProtein-ligand docking simulation is central in drug design and development. Therefore, the development of web servers intended to docking simulations is of pivotal importance. SwissDock is a web server dedicated to carrying out protein-ligand docking simulation intuitively and elegantly.
View Article and Find Full Text PDFGEMDOCK is a protein-ligand docking software that makes use of an elegant biologically inspired computational methodology based on the differential evolution algorithm. As any docking program, GEMDOCK has two major features to predict the binding of a small-molecule ligand to the binding site of a protein target: the search algorithm and the scoring function to evaluate the generated poses. The GEMDOCK scoring function uses a piecewise potential energy function integrated into the differential evolutionary algorithm.
View Article and Find Full Text PDFMolegro Virtual Docker is a protein-ligand docking simulation program that allows us to carry out docking simulations in a fully integrated computational package. MVD has been successfully applied to hundreds of different proteins, with docking performance similar to other docking programs such as AutoDock4 and AutoDock Vina. The program MVD has four search algorithms and four native scoring functions.
View Article and Find Full Text PDFAutoDock is one of the most popular receptor-ligand docking simulation programs. It was first released in the early 1990s and is in continuous development and adapted to specific protein targets. AutoDock has been applied to a wide range of biological systems.
View Article and Find Full Text PDFX-ray diffraction crystallography is the primary technique to determine the three-dimensional structures of biomolecules. Although a robust method, X-ray crystallography is not able to access the dynamical behavior of macromolecules. To do so, we have to carry out molecular dynamics simulations taking as an initial system the three-dimensional structure obtained from experimental techniques or generated using homology modeling.
View Article and Find Full Text PDFFast and reliable evaluation of the hydrogen bond potential energy has a significant impact in the drug design and development since it allows the assessment of large databases of organic molecules in virtual screening projects focused on a protein of interest. Semi-empirical force fields implemented in molecular docking programs make it possible the evaluation of protein-ligand binding affinity where the hydrogen bond potential is a common term used in the calculation. In this chapter, we describe the concepts behind the programs used to predict hydrogen bond potential energy employing semi-empirical force fields as the ones available in the programs AMBER, AutoDock4, TreeDock, and ReplicOpter.
View Article and Find Full Text PDFVan der Waals forces are determinants of the formation of protein-ligand complexes. Physical models based on the Lennard-Jones potential can estimate van der Waals interactions with considerable accuracy and with a computational complexity that allows its application to molecular docking simulations and virtual screening of large databases of small organic molecules. Several empirical scoring functions used to evaluate protein-ligand interactions approximate van der Waals interactions with the Lennard-Jones potential.
View Article and Find Full Text PDFComputational analysis of protein-ligand interactions is of pivotal importance for drug design. Assessment of ligand binding energy allows us to have a glimpse of the potential of a small organic molecule as a ligand to the binding site of a protein target. Considering scoring functions available in docking programs such as AutoDock4, AutoDock Vina, and Molegro Virtual Docker, we could say that they all rely on equations that sum each type of protein-ligand interactions to model the binding affinity.
View Article and Find Full Text PDFSince the early 1980s, we have witnessed considerable progress in the development and application of docking programs to assess protein-ligand interactions. Most of these applications had as a goal the identification of potential new binders to protein targets. Another remarkable progress is taking place in the determination of the structures of protein-ligand complexes, mostly using X-ray diffraction crystallography.
View Article and Find Full Text PDFProtein-ligand docking simulations are of central interest for computer-aided drug design. Docking is also of pivotal importance to understand the structural basis for protein-ligand binding affinity. In the last decades, we have seen an explosion in the number of three-dimensional structures of protein-ligand complexes available at the Protein Data Bank.
View Article and Find Full Text PDFEvaluation of ligand-binding affinity using the atomic coordinates of a protein-ligand complex is a challenge from the computational point of view. The availability of crystallographic structures of complexes with binding affinity data opens the possibility to create machine-learning models targeted to a specific protein system. Here, we describe a new methodology that combines a mass-spring system approach with supervised machine-learning techniques to predict the binding affinity of protein-ligand complexes.
View Article and Find Full Text PDFBackground: The enzyme trans-enoyl-[acyl carrier protein] reductase (InhA) is a central protein for the development of antitubercular drugs. This enzyme is the target for the pro-drug isoniazid, which is catalyzed by the enzyme catalase-peroxidase (KatG) to become active.
Objective: Our goal here is to review the studies on InhA, starting with general aspects and focusing on the recent structural studies, with emphasis on the crystallographic structures of complexes involving InhA and inhibitors.
Background: Cyclin-dependent kinase 2 (CDK2) has been studied due to its role in the cell-cycle progression. The elucidation of the CDK2 structure paved the way to investigate the molecular basis for inhibition of this enzyme, with the coordinated efforts combining crystallography with functional studies.
Objective: Our goal here is to review recent functional and structural studies directed to understanding the role of CDK2 in cancer and senescence.
The possibility of using the atomic coordinates of protein-ligand complexes to assess binding affinity has a beneficial impact in the early stages of drug development and design. From the computational view, the creation of reliable scoring functions is still an open problem in the simulation of biological systems, and the development of a new generation machine-learning model is an active research field. In this work, we propose a novel scoring function to predict Gibbs free energy of binding (ΔG) based on the crystallographic structure of complexes involving a protein and an active ligand.
View Article and Find Full Text PDFCyclin-dependent kinase (CDK) is an interesting biological macromolecule due to its role in cell cycle progression, transcription control, and neuronal development, to mention the most studied biological activities. Furthermore, the availability of hundreds of structural studies focused on the intermolecular interactions of CDK with competitive inhibitors makes possible to develop computational models to predict binding affinity, where the atomic coordinates of binary complexes involving CDK and ligands can be used to train a machine learning model. The present work is focused on the development of new machine learning models to predict binding affinity for CDK.
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