Frontiers Section Editor (Bioinformatics and Biophysics) for the Current Drug Targets ISSN: 1873-5592


Section Editor (Bioinformatics in Drug Design and Discovery) for the Current Medicinal Chemistry ISSN: 1875-533X


Section Editor (Combinatorial/Medicinal Chemistry) for the Combinatorial Chemistry & High Throughput Screening ISSN: 1875-5402


Member of the Editorial Board for the Current Bioinformatics ISSN: 2212-392X (Online) ISSN: 1574-8936 (Print)


Member of the Editorial Board for the Organic & Medicinal Chemistry International Journal ISSN: 2474-7610


Section Editor in Chief (Bioinformatics) for Bioengineering International. ISSN 2668-7119




Protein-Ligand Interacions


Molecular Docking


Bioinspired Computing


Computational Systems Biology


Recent Publications


da Silva AD et al. J Comput Chem. 2020; 41(1): 69-73.


Volkart PA et al. Curr Drug Targets. 2019;20(7):716-726


Russo S, De Azevedo WF. Curr Med Chem 2019. 26(10):1908-1919

Discovery and Development of Drugs in Silico 

By Prof. Walter F. de Azevedo, Jr., PhD 


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Title: How Docking Programs Work


Protein-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. These structures gave further support for the development and validation of in silico approaches to address the binding of small molecules to proteins. As a result, we have now dozens of open source programs and web servers to carry out molecular docking simulations. The development of the docking programs and the success of such simulations called the attention of a broad spectrum of researchers not necessarily familiar with computer simulations. In this scenario, it is essential for those involved in experimental studies of protein-ligand interactions and biophysical techniques to have a glimpse of the basics of the protein-ligand docking simulations. Applications of protein-ligand docking simulations to drug development and discovery were able to identify hits, inhibitors, and even drugs. In the present chapter, we cover the fundamental ideas behind protein-ligand docking programs for non-specialists, which may benefit from such knowledge when studying molecular recognition mechanism.

Keywords: Docking; Drug design; Ligand; Molecular recognition; Protein.

Title: SAnDReS: A Computational Tool for Docking


Since 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. Considering these developments, we have a favorable scenario for the creation of a computational tool that integrates into one workflow all steps involved in molecular docking simulations. We had these goals in mind when we developed the program SAnDReS. This program allows the integration of all computational features related to modern docking studies into one workflow. SAnDReS not only carries out docking simulations but also evaluates several docking protocols allowing the selection of the best approach for a given protein system. SAnDReS is a free and open-source (GNU General Public License) computational environment for running docking simulations. Here, we describe the combination of SAnDReS and AutoDock4 for protein-ligand docking simulations. AutoDock4 is a free program that has been applied to over a thousand receptor-ligand docking simulations. The dataset described in this chapter is available for downloading at

Keywords: AutoDock4; Binding affinity; Docking; Drug design; Molecular recognition; SAnDReS.

Title: Electrostatic Energy in Protein–Ligand Complexes


Computational 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. Most of the scoring functions consider electrostatic interactions involving the protein and the ligand. In this chapter, we present the main physics concepts necessary to understand electrostatics interactions relevant to molecular recognition of a ligand by the binding pocket of a protein target. Moreover, we analyze the electrostatic potential energy for an ensemble of structures to highlight the main features related to the importance of this interaction for binding affinity.

Keywords: Binding affinity; Drug design; Electrostatic interactions; Molecular recognition; Shikimate pathway.

Title: Van der Waals Potential in Protein Complexes


Van 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. In this chapter, we present the main concepts necessary to understand van der Waals interactions relevant to molecular recognition of a ligand by the binding pocket of a protein target. We describe the Lennard-Jones potential and its application to calculate potential energy for an ensemble of structures to highlight the main features related to the importance of this interaction for binding affinity.

Keywords: Binding affinity; Drug design; Lennard-Jones potential; Shikimate pathway; van der Waals interactions.

Title: Hydrogen Bonds in Protein-Ligand Complexes


Fast 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. We described here the 12-10 potential and applied it to evaluate the binding affinity for an ensemble of crystallographic structures for which experimental data about binding affinity are available.

Keywords:: Binding affinity; Drug design; Hydrogen bond interactions; Molecular recognition; Shikimate pathway.

Title: Molecular Dynamics Simulations with NAMD2


X-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. In this chapter, we describe in detail a tutorial to carry out molecular dynamics simulations using the program NAMD2. We chose as a molecular system to simulate the structure of human cyclin-dependent kinase 2.

Keywords: Cyclin-dependent kinase 2; Drug design; Force fields; Molecular dynamics; Molecular recognition; NAMD2.

Title: Docking with AutoDock4


AutoDock 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. It has been used not only for protein-ligand docking simulation but also for the prediction of binding affinity with good correlation with experimental binding affinity for several protein systems. The latest version makes use of a semi-empirical force field to evaluate protein-ligand binding affinity and for selecting the lowest energy pose in docking simulation. AutoDock4.2.6 has an arsenal of four search algorithms to carry out docking simulation including simulated annealing, genetic algorithm, and Lamarckian algorithm. In this chapter, we describe a tutorial about how to perform docking with AutoDock4. We focus our simulations on the protein target cyclin-dependent kinase 2.

Keywords: AutoDock; Cyclin-dependent kinase 2; Drug design; Molecular docking; Protein-ligand interactions.

Title: Molegro Virtual Docker for Docking


Molegro 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. Considering that we may have water molecules or not in the docking simulations, we have a total of 32 docking protocols. The integration of the programs SAnDReS ( ) and MVD opens the possibility to carry out a detailed statistical analysis of docking results, which adds to the native capabilities of the program MVD. In this chapter, we describe a tutorial to carry out docking simulations with MVD and how to perform a statistical analysis of the docking results with the program SAnDReS. To illustrate the integration of both programs, we describe the redocking simulation focused the cyclin-dependent kinase 2 in complex with a competitive inhibitor.

Keywords: Cyclin-dependent kinase 2; Drug design; MolDock; Molecular docking; Molegro Virtual Docker; Protein-ligand interactions.

Title: Docking with GemDock


GEMDOCK 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. GEMDOCK has been applied to a wide range of protein systems with docking accuracy similar to other docking programs such as Molegro Virtual Docker, AutoDock4, and AutoDock Vina. In this chapter, we explain how to carry out protein-ligand docking simulations with GEMDOCK. We focus this tutorial on the protein target cyclin-dependent kinase 2.

Keywords: Cyclin-dependent kinase 2; Drug design; GEMDOCK; Molecular docking; Protein-ligand interactions.

Title: Docking with SwissDock


Protein-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. SwissDock is based on the protein-ligand docking program EADock DSS and has a simple and integrated interface. The SwissDock allows the user to upload structure files for a protein and a ligand, and returns the results by e-mail. To facilitate the upload of the protein and ligand files, we can prepare these input files using the program UCSF Chimera. In this chapter, we describe how to use UCSF Chimera and SwissDock to perform protein-ligand docking simulations. To illustrate the process, we describe the molecular docking of the competitive inhibitor roscovitine against the structure of human cyclin-dependent kinase 2.

Keywords: Cyclin-dependent kinase 2; Drug design; Molecular docking; Protein-ligand interactions; SwissDock.

Title: Molecular Docking Simulations with ArgusLab


Molecular 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 ( ) for protein-ligand docking simulation. This easy-to-use computational tool makes use of a genetic algorithm as a search algorithm and a fast scoring function that allows users with minimal experience in the simulations of protein-ligand simulations to carry out docking simulations. In this chapter, we present a detailed tutorial to perform docking simulations using ArgusLab.

Keywords: ArgusLab; Cyclin-dependent kinase 2; Drug design; Molecular docking; Molecular recognition; Protein-ligand interactions.

Title: Homology Modeling of Protein Targets with MODELLER


Homology 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. Our goal in this chapter is to explain how to perform homology modeling of protein targets for drug development. We choose as a homology modeling tool the program MODELLER. To illustrate its use, we describe how to model the structure of human cyclin-dependent kinase 3 using MODELLER. We explain the modeling procedure of CDK3 apoenzyme and the structure of this enzyme in complex with roscovitine.

Keywords: Cyclin-dependent kinase 3; Drug design; Homology modeling; MODELLER; Molecular recognition.

Title: Machine Learning to Predict Binding Affinity


Recent 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. The essential aspect of these machine-learning approaches is to train a new computational model by using technologies such as supervised machine-learning techniques, convolutional neural network, and random forest to mention the most commonly applied methods. In this chapter, we focus on supervised machine-learning techniques and their applications in the development of protein-targeted scoring functions for the prediction of binding affinity. We discuss the development of the program SAnDReS and its application to the creation of machine-learning models to predict inhibition of cyclin-dependent kinase and HIV-1 protease. Moreover, we describe the scoring function space, and how to use it to explain the development of targeted scoring functions.

Keywords: Binding affinity; Cyclin-dependent kinase; HIV-1 protease; Machine learning; Regression; SAnDReS; Scoring function space.

Title: Exploring the Scoring Function Space


In 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. New abstractions are required to guide the conceptual analysis of the molecular recognition problem. Using a systems approach, we proposed to address protein-ligand scoring functions using the modern idea of the scoring function space. In this chapter, we describe the fundamental concept behind the scoring function space and how it has been applied to develop the new generation of targeted-scoring functions.

Keywords: Binding affinity; Chemical space; Machine learning; Protein space; SAnDReS; Scoring function; Scoring function space.

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Template for Writing a Review Paper

Current Medicinal Chemistry


Here, we have the course Discovery and Development of Drugs in Silico. This course focuses on protein structures and their interactions with drugs. The main technique used to assess protein-ligand interactions is the protein crystallography as described in this video on the right. 

Prof. Walter F. de Azevedo Jr., PhD.

Crystallization of protein in a microgravity environment (video in Portuguese). Experiments carried out on the Discovery space shuttle STS-95 on October 29, 1998.

Video about protein crystallography (Dr. José Henrique Pereira, Molecular Biophysics & Integrated Bioimaging, LBNL, Berkeley, CA, USA).

Pereira JH, de Oliveira JS, Canduri F, Dias MV, Palma MS, Basso LA, Santos DS, de Azevedo WF Jr. Structure of shikimate kinase from Mycobacterium tuberculosis reveals the binding of shikimic acid. Acta Crystallogr D Biol Crystallogr. 2004; 60(Pt 12 Pt 2): 2310-9.

PubMed  PDB