Applications of Molecular Docking

Computational tools have extended their reach into different realms of scientific research. Often coupled with molecular dynamics simulation, docking provides comprehensive insight into molecular mechanisms of biological processes. Influence of molecular docking is highly experienced in the field of structure based drug discovery, wherein docking is vital in validating novel lead compounds. The significance of molecular docking is also understood in several environmental and industrial research, in order to untangle the interactions among macromolecules of non-medical interest. Various processes such as bioremediation (REMEDIDOCK), nanomaterial interactions (NANODOCK), nutraceutical interactions (NUTRADOCK), fatty acid biosynthesis (FADOCK), and antifoulers interactions (FOULDOCK) find the application of molecular docking. This chapter emphasizes the involvement of computational techniques in the aforementioned fields to expand our knowledge on macromolecular interacting mechanisms.

Protein-Protein Interactions (PPIs) as an Alternative to Targeting the ATP Binding Site of Kinase

Most of the developed kinase inhibitor drugs are ATP competitive and suffer from drawbacks such as off-target kinase activity, development of resistance due to mutation in the ATP binding pocket and unfavorable intellectual property situations. Besides the ATP binding pocket, protein kinases have binding sites that are involved in Protein-Protein Interactions (PPIs); these PPIs directly or indirectly regulate the protein kinase activity. Of recent, small molecule inhibitors of PPIs are emerging as an alternative to ATP competitive agents. Rational design of inhibitors for kinase PPIs could be carried out using molecular modeling techniques. In silico tools available for the prediction of hot spot residues and cavities at the PPI sites and the means to utilize this information for the identification of inhibitors are discussed. Moreover, in silico studies to target the Aurora B-INCENP PPI sites are discussed in context. Overall, this chapter provides detailed in silico strategies that are available to the researchers for carrying out structure-based drug design of PPI inhibitors.

In Silico Perspective into Interactions and Mutations in Human TLR4 and Ebola Glycoprotein

Toll-Like Receptor-4 (TLR4) senses life-threatening Ebola virus Glycoprotein (GP) and produces pro-inflammatory cytokines, resulting in lethal Ebola virus infections. GP2-subunit of Ebola promotes viral entry via membrane fusion. The present study models, optimizes and demonstrates the 3D monomer of the responsible human protein. The essential residue (studied from wet-laboratory research) was observed to be functionally conserved from multiple-sequence alignment. Thus, after performing point-mutation, the mutant protein was satisfactorily re-modelled; keeping its functionality preserved. Comparable residual participation in GP2 and each of the proteins was examined, individually. Stability of the proteins and protein-GP2 complexes on mutation; were discerned via energy calculations, solvent-accessibility area and conformational switching, with supportive statistical significances. Therefore, this probe paves a pathway to examine the weaker interaction of the stable mutated human protein with Ebola GP2 protein, thereby defending the Ebola viral entry.

Role of Molecular Docking in Computer-Aided Drug Design and Development

Molecular Docking is widely used in CADD (Computer-Aided Drug Designing), SBDD (Structure-Based Drug Designing) and LBDD (Ligand-Based Drug Designing). It is a method used to predict the binding orientation of one molecule with the other and used for any kind of molecule based on the interaction like, small drug molecule with its protein target, protein – protein binding or a DNA – protein binding. Docking is very much popular technique due to its reliable prediction properties. This book chapter will provide an overview of diverse docking methodologies present that are used in drug design and development. There will be discussion on several case studies, pertaining to each method, followed by advantages and disadvantages of the discussed methodology. It will typically aim professionals in the field of cheminformatics and bioinformatics, both in academia and in industry and aspiring scientists and students who want to take up this as a profession in the near future. We will conclude with our opinion on the effectiveness of this technology in the future of pharmaceutical industry.

Molecular Modelling, Dynamics, and Docking of Membrane Proteins

Computational tools and techniques are now most popular and promising to progress the research at rapid rate. Molecular modelling studies contribute their maximum role in wide variety of disciplines especially in proteomics and drug discovery strategies. Molecular dynamics and molecular docking algorithms are now became an essential part in daily research activities of every laboratory throughout the world. These strategies are now well established and standardised to study any specific protein of interest and drug molecule. But still there exist considerable drawbacks in a special concern with membrane proteins as the presently available tools and methods cannot be applied directly to them. Modelling, dynamics and docking studies of membrane proteins need a special care and attention as several challenges are to be crossed with an intensive care to produce a reliable result. This chapter is aimed to discuss such challenges and solutions to handle membrane proteins.

Molecular-Docking-Based Drug Design and Discovery

Currently 30-50% of drug targets are G Protein-Coupled Receptors (GPCRs). However, the clinical useful drugs for targeting GPCR have been limited by the lack of subtype selectivity or efficacy, leading to undesirable side effects. To develop subtype-selective GPCR ligands with desired molecular properties, better understanding is needed of the pharmacophore elements and of the binding mechanism required for subtype selectivity. To illustrate these issues, we describe here three successful applications to understand the binding mechanism associated with subtype selectivity: 5-HT2B (5-Hydroxytryptamine, 5-HT) serotonin receptor (HT2BR), H3 histamine receptor (H3HR) and A3 adenosine receptor (A3AR). The understanding of structure-function relationships among individual types and subtypes of GPCRs gained from such computational predictions combined with experimental validation and testing is expected the development of new highly selective and effective ligands to address such diseases while minimizing side-effects.

Application of Docking Methodologies in QSAR-Based Studies

The computational strategies permeate all aspects of drug discovery such as virtual screening techniques. Virtual screening can be classified into ligand based and structure based methods. The ligand based method such as Quantitative Structure Activity Relationship (QSAR) is used when a set of active ligand compounds is recognized and slight or no structural information is available for the receptors. In structure based drug design, the most widespread method is molecular docking. It is widely accepted that drug activity is obtained through the molecular binding of one ligand to receptor. In their binding conformations, the molecules exhibit geometric and chemical complementarity, both of which are essential for successful drug activity. The molecular docking approach can be used to model the interaction between a small drug molecule and a protein, which allow us to characterize the performance of small molecules in the binding site of target proteins as well as to clarify fundamental biochemical processes.

Molecular-Docking-Based Anti-Allergic Drug Design

Allergens are foreign proteins that when come in contact of part(s) of human body stimulate the production of immunoglobulin types of proteins (antibodies). These allergens react with antibodies (immunoglobulin type E or IgE) produces allergic reactions, also known as immediate-type hypersensitivity reactions. As much as 20% of the general population may be affected by grass pollen as a major cause of allergic disease. EXPB class of proteins are known in the immunological literature as group-1 grass pollen allergens Molecular docking method can be used to identify the predicated the interaction of pollen allergen EXPB1 (Zea m 1), a beta-expansin and group-1 pollen allergen from maize with IgE molecules of human. The World Health Organization recognised allergen immunotherapy, as therapeutics for allergic diseases. RNA Interference (RNAi) is a biological process in which RNA molecules e.g. Small Interfering RNAs (siRNAs) inhibit gene expression, by cleavage and destruction of specific mRNA molecules. Use of Small Interfering RNA (siRNA) is a novel method in the induction of RNA Interference (RNAi), which is a potent method for therapeutics of allergic reactions. Due to various effects of STAT 6 proteins during hypersensitivity reactions caused by pollen allergens, mRNA of STAT6 gene is selected as target gene for allergy therapeutics via Post-Transcriptional Gene Silencing (PTGS). Using molecular docking study a specific sense siRNA is identified as anti allergic drug to treat allergic asthma during immediate type of hypersensitivity reaction, caused by Zea m 1 pollen allergen.

Molecular Docking of Biologically Active Substances to Double Helical Nucleic Acids

Molecular docking of ligands to DNA-targets is of great importance for the design of new anticancer drugs. Unfortunately, most docking programs were developed for protein-ligand docking which raises a question about their applicability for the DNA-ligand docking. In this study, the popular docking programs AutoDock Vina, AutoDock4 and AutoDock3 were compared for a test set of 50 DNA-ligand complexes taken from the Nucleic Acid Database. It was shown that the version 3.05 of the AutoDock program was the most successful in reproducing the structures of intercalation and minor-groove complexes. The program AutoDock4 was able to re-dock to within 2 Å RMSD most of the intercalation complexes of the test set, but showed poor performance for minor groove binders. While Vina, on the contrary, failed to construct six intercalation complexes of the test set, but showed satisfactory results for DNA-ligand minor-groove complexes when small search space was used.

Application of Molecular Docking in Studies on the Binding Mechanism of Three Enzymes with Natural Products

Enzymes play an important role in many biologically relevant processes and are some attractive targets in the therapy and pharmaceutical research. The interaction between drugs and enzymes in vitro might account for a variety of biological processes and has attracted scientists' great interest for several decades. Investigation of the interaction can explore their mechanism of biological activities and provide useful knowledge for optimizing molecular structure of drug, prescriptions and route of administration and it can also provide the information for their bioavailability and bioactivity. In this chapter, the bindings of natural products (including flavionoids and coumarins) with three enzymes, including pepsin, hyaluronidase and acetylcholinesterase, were investigated by fluorescence spectroscopy and molecular docking. The present studies provide direct evidence at a molecular level to understand the mechanism of inhibitory effect of natural products against enzymes.