Library screening by fragment‐based docking

Huang, Danzhi; Caflisch, Amedeo

doi:10.1002/jmr.981

Cited by 41 publications

(34 citation statements)

References 123 publications

(134 reference statements)

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“…(3)-over the complete test set of 214 complexes with structurally diverse ligands and covering 62 different proteins-is also reasonable compared to the very good 1.0 kcal mol 21 and 0.6 values that have been obtained using the CHARMm force field in several distinct studies using the original LIECE equation. Indeed, in these studies, the LIECE equation was systematically refitted for each set of structurally related molecules binding only to b-secretase, 38,39 HIV-1 protease, 38 plasmepsin, 52 West Nile virus NS3 protease, 53 or different kinases, 40,54 as the subsequent applications were related only to one of these proteins. It is actually expected that, thanks to cancellation of errors, it is easier to find correlations applying only to one protein and a series of related ligands than for unrelated ligands of different proteins.…”

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confidence: 99%

SwissParam: A fast force field generation tool for small organic molecules

et al. 2011

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The drug discovery process has been deeply transformed recently by the use of computational ligand-based or structure-based methods, helping the lead compounds identification and optimization, and finally the delivery of new drug candidates more quickly and at lower cost. Structure-based computational methods for drug discovery mainly involve ligand-protein docking and rapid binding free energy estimation, both of which require force field parameterization for many drug candidates. Here, we present a fast force field generation tool, called SwissParam, able to generate, for arbitrary small organic molecule, topologies, and parameters based on the Merck molecular force field, but in a functional form that is compatible with the CHARMM force field. Output files can be used with CHARMM or GROMACS. The topologies and parameters generated by SwissParam are used by the docking software EADock2 and EADock DSS to describe the small molecules to be docked, whereas the protein is described by the CHARMM force field, and allow them to reach success rates ranging from 56 to 78%. We have also developed a rapid binding free energy estimation approach, using SwissParam for ligands and CHARMM22/27 for proteins, which requires only a short minimization to reproduce the experimental binding free energy of 214 ligand-protein complexes involving 62 different proteins, with a standard error of 2.0 kcal mol(-1), and a correlation coefficient of 0.74. Together, these results demonstrate the relevance of using SwissParam topologies and parameters to describe small organic molecules in computer-aided drug design applications, together with a CHARMM22/27 description of the target protein. SwissParam is available free of charge for academic users at www.swissparam.ch.

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confidence: 99%

SwissParam: A fast force field generation tool for small organic molecules

et al. 2011

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“…Huang and Caflisch recently reviewed their tools [102]. Their software suite includes three programs (DAIM, SEED and FFLD), each designed to perform one step of the process.…”

Section: Docking and Post-processing Strategiesmentioning

confidence: 99%

Fragment-Based Drug Design: Computational and Experimental State of the Art

Hoffer¹,

Renaud²,

Horvath

2011

CCHTS

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Fragment-based screening is an emerging technology which is used as an alternative to high-throughput screening (HTS), and often in parallel. Fragment screening focuses on very small compounds. Because of their small size and simplicity, fragments exhibit a low to medium binding affinity (mM to µM) and must therefore be screened at high concentration in order to detect binding events. Since some issues are associated with high-concentration screening in biochemical assays, biophysical methods are generally employed in fragment screening campaigns. Moreover, these techniques are very sensitive and some of them can give precise information about the binding mode of fragments, which facilitates the mandatory hit-to-lead optimization. One of the main advantages of fragment-based screening is that fragment hits generally exhibit a strong binding with respect to their size, and their subsequent optimization should lead to compounds with better pharmacokinetic properties compared to molecules evolved from HTS hits. In other words, fragments are interesting starting points for drug discovery projects. Besides, the chemical space of low-complexity compounds is very limited in comparison to that of drug-like molecules, and thus easier to explore with a screening library of limited size. Furthermore, the "combinatorial explosion" effect ensures that the resulting combinations of interlinked binding fragments may cover a significant part of "drug-like" chemical space. In parallel to experimental screening, virtual screening techniques, dedicated to fragments or wider compounds, are gaining momentum in order to further reduce the number of compounds to test. This article is a review of the latest news in both experimental and in silico virtual screening in the fragment-based discovery field. Given the specificity of this journal, special attention will be given to fragment library design.

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“…During 2004-2008, our suite of programs for fragment-based docking [68,71,72] has been employed in eight in silico screening campaigns on six different enzymes that play a key role in a variety of diseases (Table 17.1) [94]. Four of these enzymes are proteases of three different classes (aspartic, serine, and cysteine proteases), while the remaining two are a tyrosine kinase and a Ser/Thr kinase.…”

Section: In Silico Screening Campaignsmentioning

confidence: 99%

“…The 2D structures of the most potent inhibitors discovered in the eight high-throughput docking campaigns are shown in Figure 17.2. Here we present the results obtained on two of the six enzymes, West Nile virus NS3 protease and EphB4 tyrosine kinase, while more details can be found in a recent review [94] The pathogenic members of the flavivirus family, for example, West Nile virus and the closely related dengue virus, are transmitted by mosquito bites. Although an estimated 2.5 billion people are potential victims of encephalitis and other fatal maladies caused by flaviviruses [100], these diseases have received much less attention than other tropical diseases such as avian influenza.…”

Section: In Silico Screening Campaignsmentioning

confidence: 99%

Fragment‐Based Approaches in Virtual Screening

Huang

Caflisch

2011

Methods and Principles in Medicinal Chemistry

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IntroductionFragment-based screening (FBS) as a method to identify starting points for smallmolecule drug discovery has become increasingly popular in recent years [1]. As a complementary and alternative approach to the traditional high-throughput screening (HTS), FBS starts from molecules whose molecular weights typically range from 150 to 250 Da. This approach is more routinely undertaken in therapeutic areas such as infectious disease, for which conventional screening has usually resulted in low hit rates [2]. The theoretical basis regarding the benefits of the fragment linking approach has already been reported about 30 years ago [3]. Interestingly, the importance of molecular fragments has been first recognized and exploited by computational approaches [4][5][6], which share similar aspects with experimental techniques that have been developed afterward, such as structure-activity relationship by nuclear magnetic resonance (NMR) [7]. More recently, fragment-based drug discovery strategies have been developed using X-ray crystallography [8], NMR spectroscopy [9], surface plasmon resonance [10], mass spectrometry [11,12], substrate activity screening (where the fragments are substrates later converted into inhibitors [13-15]), and tethering [16,17]. Experimental techniques for fragmentbased drug discovery have been discussed in previous reviews that contain a large number of applications [1,[18][19][20][21][22]. Successful in vitro screening campaigns have been reported for several targets, and a nonexhaustive list includes b-secretase [10,18,23,24], several protein kinases [25][26][27][28][29], DNA gyrase [30], caspase [31, 32], anthrax lethal factor [33], and phosphodiesterase [34]. The advantages of FBS over HTS have been reported [1], the main benefit being that a larger degree of chemical space can be explored using fragment libraries. HTS handles compounds up to millions but this amount only covers a tiny amount of the chemical space accessible to the small druglike molecules, which is estimated in the range of 10 60 -10 100 [35,36]. Fragment-based approaches, however, allow sampling of a much larger amount of chemical diversity using a much smaller number of starting molecules. It has been estimated that the number of stable and synthetically Virtual Screening. Edited by C. Sotriffer

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Library screening by fragment‐based docking

Cited by 41 publications

References 123 publications

SwissParam: A fast force field generation tool for small organic molecules

SwissParam: A fast force field generation tool for small organic molecules

Fragment-Based Drug Design: Computational and Experimental State of the Art

Fragment‐Based Approaches in Virtual Screening

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