Glide XP fragment docking and structurebased pharmacophores (original) (raw)
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Journal of Computer-Aided Molecular Design, 2009
We have developed a method that uses energetic analysis of structure-based fragment docking to elucidate key features for molecular recognition. This hybrid ligand-and structure-based methodology uses an atomic breakdown of the energy terms from the Glide XP scoring function to locate key pharmacophoric features from the docked fragments. First, we show that Glide accurately docks fragments, producing a root mean squared deviation (RMSD) of \1.0 Å for the top scoring pose to the native crystal structure. We then describe fragment-specific docking settings developed to generate poses that explore every pocket of a binding site while maintaining the docking accuracy of the top scoring pose. Next, we describe how the energy terms from the Glide XP scoring function are mapped onto pharmacophore sites from the docked fragments in order to rank their importance for binding. Using this energetic analysis we show that the most energetically favorable pharmacophore sites are consistent with features from known tight binding compounds. Finally, we describe a method to use the energetically selected sites from fragment docking to develop a pharmacophore hypothesis that can be used in virtual database screening to retrieve diverse compounds. We find that this method produces viable hypotheses that are consistent with known active compounds. In addition to retrieving diverse compounds that are not biased by the cocrystallized ligand, the method is able to recover known active compounds from a database screen, with an average enrichment of 8.1 in the top 1% of the database.
Docking, virtual high throughput screening and in silico fragment-based drug design
Journal of Cellular and Molecular Medicine, 2009
The drug discovery process has been profoundly changed recently by the adoption of computational methods helping the design of new drug candidates more rapidly and at lower costs. In silico drug design consists of a collection of tools helping to make rational decisions at the different steps of the drug discovery process, such as the identification of a biomolecular target of therapeutical interest, the selection or the design of new lead compounds and their modification to obtain better affinities, as well as pharmacokinetic and pharmacodynamic properties. Among the different tools available, a particular emphasis is placed in this review on molecular docking, virtual high-throughput screening and fragment-based ligand design.
Introduction to Fragment-Based Drug Discovery
Fragment-based drug discovery (FBDD) has emerged in the past decade as a powerful tool for discovering drug leads. The approach first identifies starting points: very small molecules (fragments) that are about half the size of typical drugs. These fragments are then expanded or linked together to generate drug leads. Although the origins of the technique date back some 30 years, it was only in the mid-1990s that experimental techniques became sufficiently sensitive and rapid for the concept to be become practical. Since that time, the field has exploded: FBDD has played a role in discovery of at least 18 drugs that have entered the clinic, and practitioners of FBDD can be found throughout the world in both academia and industry. Literally dozens of reviews have been published on various aspects of FBDD or on the field as a whole, as have three books (Jahnke and Erlanson, Fragment-based approaches in drug discovery, 2006; Zartler and Shapiro, Fragment-based drug discovery: a practical approach, 2008; Kuo, Fragment based drug design: tools, practical approaches, and examples, 2011). However, this chapter will assume that the reader is approaching the field with little prior knowledge. It will introduce some of the key concepts, set the stage for the chapters to follow, and demonstrate how X-ray crystallography plays a central role in fragment identification and advancement. Keywords Fragment-based drug discovery Á Fragment-based lead discovery Á Fragment-based screening Á Kinase Á Nuclear magnetic resonance spectroscopy Á Structure-based drug design Á X-ray crystallography
Journal of Chemical Information and Modeling, 2009
The use of QM/MM based methods to optimize and rescore GOLD derived cross-docked protein-ligand poses has been investigated using a range of fragment-like kinase inhibitors where experimental data have been reported. Particular emphasis has been placed on rationalizing the potential benefits of the method in the increasingly popular fragment based drug discovery area. The results of this cross-docking, rescoring study on 9 protein ligand complexes suggest that the hybrid QM/MM calculations could prove useful in kinase fragment based drug discovery (FBDD). B3LYP/6-31G**//UFF derived enthalphies allow us to identify the correct X-ray pose from a range of plausible decoys 77% of the time, almost a doubling of the retrieval rate compared to GOLD (44%). In addition, this method provides us with a means to rapidly and accurately generate virtual protein-ligand complexes that will allow a program team to probe the existing interactions between the ligand and protein and search for additional interactions.
Structural biology in fragment-based drug design
Current Opinion in Structural Biology, 2010
Fragment-based ligand screening is now established as an emerging paradigm for drug discovery. Here we examine the recent literature looking at how structural biology has been used in a variety of successful fragment-screening applications. We argue that the determination of experimental binding modes has proved to be one of the mainstays of successful fragment-based approaches and that this reflects the difficulty in optimising a fragment to a lead molecule in the absence of structural information. We focus on antimicrobial research where fragment-based drug discovery allows control of the physical properties of the emerging lead molecule.
The multiple roles of computational chemistry in fragment-based drug design
Journal of Computer-Aided Molecular Design, 2009
Fragment-based drug discovery (FBDD) represents a change in strategy from the screening of molecules with higher molecular weights and physical properties more akin to fully drug-like compounds, to the screening of smaller, less complex molecules. This is because it has been recognised that fragment hit molecules can be efficiently grown and optimised into leads, particularly after the binding mode to the target protein has been first determined by 3D structural elucidation, e.g. by NMR or X-ray crystallography. Several studies have shown that medicinal chemistry optimisation of an already drug-like hit or lead compound can result in a final compound with too high molecular weight and lipophilicity. The evolution of a lower molecular weight fragment hit therefore represents an attractive alternative approach to optimisation as it allows better control of compound properties. Computational chemistry can play an important role both prior to a fragment screen, in producing a target focussed fragment library, and post-screening in the evolution of a drug-like molecule from a fragment hit, both with and without the available fragment-target co-complex structure. We will review many of the current developments in the area and illustrate with some recent examples from successful FBDD discovery projects that we have conducted.
Structure-Based Drug Design: Docking and Scoring
This review gives an introduction into ligand -receptor docking and illustrates the basic underlying concepts. An overview of different approaches and algorithms is provided. Although the application of docking and scoring has led to some remarkable successes, there are still some major challenges ahead, which are outlined here as well. Approaches to address some of these challenges and the latest developments in the area are presented. Some aspects of the assessment of docking program performance are discussed. A number of successful applications of structure-based virtual screening are described.
Steering Target Selectivity and Potency by Fragment-Based De Novo Drug Design
Angewandte Chemie International Edition, 2013
Computer-aided approaches help to mitigate attrition rates of drug candidates and suggest new chemical entities for sustained drug discovery. In this study we followed a dual strategy of ligand-based de novo design and fragment grafting for generating innovative and readily synthesizable compounds, which we morphed into a highly potent and selective kinase inhibitor. We disclose the discovery of a ligand-efficient (ligand efficiency (LE) = 0.35) inhibitor presenting an IC 50 value of 64 nm against vascular endothelial growth factor receptor-2 (VEGFR-2) kinase. This lead compound exhibits the highest kinase selectivity profile known to date among VEGFR-2 kinase inhibitors (Gini index = 0.87), with the essential selectivity feature having been generated by de novo design. Further profiling fully corroborated VEGFR-2-selective effects on a cellular level. Our findings validate fragment-based de novo design as a premier method for rapid leadstructure prototyping, thereby offering a compelling solution to finding tailored bioactive compounds for chemical biology and drug discovery.
Pharmacophore-based molecular docking to account for ligand flexibility
Proteins: Structure, Function, and Genetics, 2003
Rapid computational mining of large 3D molecular databases is central to generating new drug leads. Accurate virtual screening of large 3D molecular databases requires consideration of the conformational flexibility of the ligand molecules. Ligand flexibility can be included without prohibitively increasing the search time by docking ensembles of precomputed conformers from a conformationally expanded database. A pharmacophore-based docking method whereby conformers of the same or different molecules are overlaid by their largest 3D pharmacophore and simultaneously docked by partial matches to that pharmacophore is presented. The method is implemented in DOCK 4.0. Proteins 2003;51:172-188.