Fragment Docking to Proteins with the Multi‐copy Simultaneous Search Methodology

Stultz, Collin M.; Karplus, Martin

doi:10.1002/3527608761.ch7

Cited by 4 publications

(2 citation statements)

References 30 publications

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“…A library of 26 frameworks and 29 side chains (Figures 7.2 and 7.3 in ref ; see also Figures S3 and S4 of the Supporting Information) was extracted from common features of commercially available drugs. , These have been docked independently to determine maps of favorable binding modes. In each generation of the evolutionary algorithm, 10% of the population of 500 binding modes was renewed.…”

Section: Methodsmentioning

confidence: 99%

Rational Design of Indoleamine 2,3-Dioxygenase Inhibitors

et al. 2010

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Indoleamine 2,3-dioxygenase (IDO) is an important therapeutic target for the treatment of diseases such as cancer that involve pathological immune escape. We have used the evolutionary docking algorithm EADock to design new inhibitors of this enzyme. First, we investigated the modes of binding of all known IDO inhibitors. On the basis of the observed docked conformations, we developed a pharmacophore model, which was then used to devise new compounds to be tested for IDO inhibition. We also used a fragment-based approach to design and to optimize small organic molecule inhibitors. Both approaches yielded several new low-molecular weight inhibitor scaffolds, the most active being of nanomolar potency in an enzymatic assay. Cellular assays confirmed the potential biological relevance of four different scaffolds.

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Section: Methodsmentioning

confidence: 99%

Rational Design of Indoleamine 2,3-Dioxygenase Inhibitors

et al. 2010

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“…This approach is largely complementary to HTS as a technique that aids the hit-to-lead or lead discovery processes [3]. The technologies that have played a major role in driving the development of fragment discovery are NMR spectroscopy [4][5][6], X-ray crystallography [7][8][9][10][11], mass spectrometry [12] as well as in silico approaches like virtual screening [13][14][15][16], and more recently ITC experiments [17]. These methods are also sometimes used in a synergistic approach, for example combining NMR-based screening with X-ray structure determination *Address correspondence to this author at the Pfizer Global Research and Development, Sandwich Laboratories, Ramsgate Road, Sandwich, Kent CT13 9NJ, United Kingdom; E-mail: alexander.alex@pfizer.com [18].…”

Section: Introductionmentioning

confidence: 99%

Fragment-Based Drug Discovery: What has it Achieved so Far?

Alex

Flocco

2007

CTMC

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Fragment-based drug discovery has proved to be a very useful approach particularly in the hit-to-lead process, providing a complementary tool to traditional high-throughput screening. Although often synonymous with fragment screening, fragment-based drug discovery is a far wider area covering high-throughput screening, fragment screening and virtual screening efforts. The unifying feature of fragment-based drug discovery is the low molecular weight of the hit rather than the approach it originates from. Over the last ten years, fragment-based drug discovery has provided in excess of 50 examples of small molecule hits that have been successfully advanced to leads and therefore resulted in useful substrate for drug discovery programs. To our knowledge, there are currently no marketed drugs that can be attributed to these efforts. However, due to the time scales of drug discovery and development it is likely that over the next few years the number of such examples will increase significantly.

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CHARMM: The biomolecular simulation program

et al. 2009

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CHARMM (Chemistry at HARvard Molecular Mechanics) is a highly versatile and widely used molecular simulation program. It has been developed over the last three decades with a primary focus on molecules of biological interest, including proteins, peptides, lipids, nucleic acids, carbohydrates and small molecule ligands, as they occur in solution, crystals, and membrane environments. For the study of such systems, the program provides a large suite of computational tools that include numerous conformational and path sampling methods, free energy estimators, molecular minimization, dynamics, and analysis techniques, and model-building capabilities. In addition, the CHARMM program is applicable to problems involving a much broader class of many-particle systems. Calculations with CHARMM can be performed using a number of different energy functions and models, from mixed quantum mechanical-molecular mechanical force fields, to all-atom classical potential energy functions with explicit solvent and various boundary conditions, to implicit solvent and membrane models. The program has been ported to numerous platforms in both serial and parallel architectures. This paper provides an overview of the program as it exists today with an emphasis on developments since the publication of the original CHARMM paper in 1983.

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Fragment Docking to Proteins with the Multi‐copy Simultaneous Search Methodology

Cited by 4 publications

References 30 publications

Rational Design of Indoleamine 2,3-Dioxygenase Inhibitors

Rational Design of Indoleamine 2,3-Dioxygenase Inhibitors

Fragment-Based Drug Discovery: What has it Achieved so Far?

CHARMM: The biomolecular simulation program

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