In silico pharmacology for drug discovery: applications to targets and beyond (original) (raw)
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In silico pharmacology for drug discovery: methods for virtual ligand screening and profiling
British Journal of Pharmacology, 2007
Pharmacology over the past 100 years has had a rich tradition of scientists with the ability to form qualitative or semiquantitative relations between molecular structure and activity in cerebro. To test these hypotheses they have consistently used traditional pharmacology tools such as in vivo and in vitro models. Increasingly over the last decade however we have seen that computational (in silico) methods have been developed and applied to pharmacology hypothesis development and testing. These in silico methods include databases, quantitative structure-activity relationships, pharmacophores, homology models and other molecular modeling approaches, machine learning, data mining, network analysis tools and data analysis tools that use a computer. In silico methods are primarily used alongside the generation of in vitro data both to create the model and to test it. Such models have seen frequent use in the discovery and optimization of novel molecules with affinity to a target, the clarification of absorption, distribution, metabolism, excretion and toxicity properties as well as physicochemical characterization. The aim of this review is to illustrate some of the in silico methods for pharmacology that are used in drug discovery. Further applications of these methods to specific targets and their limitations will be discussed in the second accompanying part of this review.
Recent Trends in In-Silico Drug Discovery
International Journal for Computational Biology
A Drug designing is a process in which new leads (potential drugs) are discovered which have therapeutic benefits in diseased condition. With development of various computational tools and availability of databases (having information about 3D structure of various molecules) discovery of drugs became comparatively, a faster process. The two major drug development methods are structure based drug designing and ligand based drug designing. Structure based methods try to make predictions based on three dimensional structure of the target molecules. The major approach of structure based drug designing is Molecular docking, a method based on several sampling algorithms and scoring functions. Docking can be performed in several ways depending upon whether ligand and receptors are rigid or flexible. Hotspot grafting, is another method of drug designing. It is preferred when the structure of a native binding protein and target protein complex is available and the hotspots on the interface are known. In absence of information of three Dimensional structure of target molecule, Ligand based methods are used. Two common methods used in ligand based drug designing are Pharmacophore modelling and QSAR. Pharmacophore modelling explains only essential features of an active ligand whereas QSAR model determines effect of certain property on activity of ligand. Fragment based drug designing is a de novo approach of building new lead compounds using fragments within the active site of the protein. All the candidate leads obtained by various drug designing method need to satisfy ADMET properties for its development as a drug. Insilico ADMET prediction tools have made ADMET profiling an easier and faster process. In this review, various softwares available for drug designing and ADMET property predictions have also been listed.
Drug Discovery and In Silico Techniques: A Mini-Review
Enzyme Engineering, 2014
Use of Computational (in silico) methods are widely applied in drug discovery. In drug discovery process, identification of the suitable drug target is the first and foremost task. These targets are biomolecules which mainly include DNA, RNA and proteins (such as receptors, transporters, enzymes and ion channels). Validation of such targets is necessary to exhibit a sufficient level of 'confidence' and to know their pharmacological relevance to the disease under investigation. The aim of this mini-review is to illustrate some of the in silico methods that are used in drug discovery, and to describe the applications of these computational methods.
Pharmacophore modeling: advances, limitations, and current utility in drug discovery
Journal of Receptor, Ligand and Channel Research, 2014
Pharmacophore modeling is a successful yet very diverse subfield of computer-aided drug design. The concept of the pharmacophore has been widely applied to the rational design of novel drugs. In this paper, we review the computational implementation of this concept and its common usage in the drug discovery process. Pharmacophores can be used to represent and identify molecules on a 2D or 3D level by schematically depicting the key elements of molecular recognition. The most common application of pharmacophores is virtual screening, and different strategies are possible depending on the prior knowledge. However, the pharmacophore concept is also useful for ADME-tox modeling, side effect, and off-target prediction as well as target identification. Furthermore, pharmacophores are often combined with molecular docking simulations to improve virtual screening. We conclude this review by summarizing the new areas where significant progress may be expected through the application of pharmacophore modeling; these include protein-protein interaction inhibitors and protein design.
Computational methods play a central role in modern drug discovery process. It includes the design and management of small molecule libraries, initial hit identification through virtual screening, optimization of the affinity as well as selectivity of hits and improving the physicochemical properties of the lead compounds. In this review article, computational drug designing approaches have been elucidated and discussed. The key considerations and guidelines for virtual chemical library design and whole drug discovery process. Traditional approach for discovery of a new drug is a costly and time consuming affair besides not being so productive. A number of potential reasons witness choosing the In-silico method of drug design to be a more wise and productive approach. There is a general perception that applied science has not kept pace with the advances of basic science. Therefore, there is a need for the use of alternative tools to get answers on efficacy and safety faster, with more certainty and at lower cost. In-silico drug design can play a significant role in all stages of drug development from the initial lead designing to final stage clinical development.
Combined in silico and in vitro Approach to Drug Screening
The purpose of High Throughput Screening (HTS) in pharmaceutical industry is to identify, as soon as possible, compounds that are good starting points for successful new drug development process. Experts from this area study the chemical structures of so called »hit« compounds that have been found to interact with the target protein, interfere with proliferation of different types of cells or stop bacterial or fungal growth. Hypotheses to design related structures with improved biological properties are than builded. Each idea is then tested by the iterative synthesis and testing of novel compounds in various biological assays, searching for hits with better properties and defining useful and promising »lead« molecules. In parallel, molecular modeling and chemoinformatics experts can increase efficiency and decrease experimental costs by using different database filtering methods. In such a way, hits from HTS may be assessed before committing significant resource for chemical optimization. Joint efforts of these HTS experimental and modeling groups are the best way to speed up the process of finding a new useful hits and promising leads.
Current Medicinal Chemistry, 2004
A major goal in contemporary drug design is to develop new ligands with high affinity of binding toward a given protein receptor. Pharmacophore, which is the three-dimensional arrangement of essential features that enable a molecule to exert a particular biological effect, is a very useful model for achieving this goal. If the three-dimensional structure of the receptor is known, pharmacophore is a complementary tool to standard techniques, such as docking. However, frequently the structure of the receptor protein is unknown and only a set of ligands together with their measured binding affinities towards the receptor is available. In such a case, a pharmacophore-based strategy is one of the few applicable tools.
In Silico and In Vitro: Identifying New Drugs
Current Drug Targets, 2008
Drug development is a high cost and laborious process, requiring a number of tests until a drug is made available in the market. Therefore, the use of methods to screen large number of molecules with less cost is crucial for faster identification of hits and leads. One strategy to identify drug-like molecules is the search for molecules able to interfere with a protein function, since protein interactions control most biological processes. Ideally the use of in silico screenings would make drug development faster and less expensive. Currently, however, the confirmation of biological activity is still needed. Due to the complexity of the task of drug discovery, an integrated and multi-disciplinary approach is ultimately required. Here we discuss examples of drugs developed through a combination of in silico and in vitro strategies. The potential use of these methodologies for the identification of active compounds as well as for early toxicity and bioavailability is also reviewed.
Journal of Computer-Aided Molecular Design, 2007
In order to assess bioactivity profiles for small organic molecules we propose to use parallel pharmacophore-based virtual screening. Our aim is to provide a fast, reliable and scalable system that allows for rapid in silico activity profile prediction of virtual molecules. In this proof of principle study, carried out with the new structure-based pharmacophore modelling tool LigandScout and the high-performance database mining platform Catalyst, we present a model work for the application of parallel pharmacophore-based virtual screening on a set of 50 structure-based pharmacophore models built for various viral targets and 100 antiviral compounds. The latter were screened against all pharmacophore models in order to determine if their known biological targets could be correctly predicted via an enrichment of corresponding pharmaco-phores matching these ligands. The results demonstrate that the desired enrichment, i.e. a successful activity profiling, was achieved for approximately 90% of all input molecules. Additionally, we discuss descriptors for output validation, as well as various aspects influencing the analysis of the obtained activity profiles, and the effect of the searching mode utilized for screening. The results of the study presented here clearly indicate that pharmacophore-based parallel screening comprises a reliable in silico method to predict the potential biological activities of a compound or a compound library by screening it against a series of pharmacophore queries.
In-silico drug design: An approach which revolutionarised the drug discovery process
OA Drug Design and Delivery, 2013
Drug discovery and development is an intense, lengthy and an inter-disciplinary venture. Recently, a trend towards the use of in-silico chemistry and molecular modeling for computer-aided drug design has gained significant momentum. In-silico drug design skills are used in nanotechnology, molecular biology, biochemistry etc. The main benefit of the in-silico drug design is cost effective in research and development of drugs. There are wide ranges of software are used in in-silico drug design, Grid computing, window based general PBPK/PD modeling software, PKUDDS for structure based drug design, APIS, JAVA, Perl and Python, insilico drug design as well as software including software libraries. There are different techniques used in in-silico drug design visualization, homology, molecular dynamic, energy minimization molecular docking and QSAR etc. In-silico drug design can take part considerably in all stages of drug development from the preclinical discovery stage to late stage clinical development. Its exploitation in drug development helps in the selection of only a potent lead molecule and may thus thwart the late stage clinical failures; thereby a major diminution in cost can be achieved. This article gives an insight to all the aspects of in-silico drug design; its potential, drivers, current development and the future prospects.