PRO_SELECT:  Combining Structure-Based Drug Design and Array-Based Chemistry for Rapid Lead Discovery. 2. The Development of a Series of Highly Potent and Selective Factor Xa Inhibitors

Liebeschuetz, John W.; Jones, Stuart; Morgan, Philip J.; Murray, Christopher W.; Rimmer, Andrew D; Roscoe, Jonathan M.E; Waszkowycz, Bohdan; Welsh, Pauline M; Wylie, William A.; Young, Stephen; Martin, Harry; Mahler, Jacqui; Brady, Leo; Wilkinson, Kay

doi:10.1021/jm010944e

Cited by 91 publications

(43 citation statements)

References 29 publications

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“…Despite the numerous studies on human serine proteases, KLK inhibitors are still much sought-after (42)(43)(44)(45). As the KLK family comprises 15 different members, many of which contain structurally similar binding pockets, the discovery of either natural or synthetic subtype-selective KLK inhibitors is a challenging task.…”

Section: Introductionmentioning

confidence: 99%

A potent, proteolysis-resistant inhibitor of kallikrein-related peptidase 6 (KLK6) for cancer therapy, developed by combinatorial engineering

Sananes

Cohen

Shahar

et al. 2018

Journal of Biological Chemistry

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Section: Introductionmentioning

confidence: 99%

A potent, proteolysis-resistant inhibitor of kallikrein-related peptidase 6 (KLK6) for cancer therapy, developed by combinatorial engineering

Sananes

Cohen

Shahar

et al. 2018

Journal of Biological Chemistry

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“…The best benzamidine-based lead synthesized after virtual screening, 3a, obtained K i 16nM [177]. To improve the oral bioavailability and other pharmacokinetic properties, benzamidine moiety was replaced by indole, and it resulted in LY-517717, which achieved K i value at 5nM [226].…”

Section: From Existing Structuresmentioning

confidence: 99%

“…FBDD approach has been successfully utilized to guide pharmaceutical design inhibitors against a variety of targets, such as CDK4 [174], estrogen receptor [175,176], factor Xa [177], HIV protease [178], to name just a few [138]. Besides lead identification, FBDD also plays a significant role in lead optimization.…”

Section: Fragment-based Drug Design (Fbdd)mentioning

confidence: 99%

“…PRO_SELECT was implemented with template-substituent idea from combinatory chemistry when pre-docked seed and proposed fragment were linked. Of note, PRO_SELECT achieved great success in designing factor Xa protease inhibitor, LY-517717 by Eli Lilly [177]. Second, the binding mode of compound is not necessarily in a modular fashion as desired.…”

Section: Fragment-based Drug Design (Fbdd)mentioning

confidence: 99%

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From Laptop to Benchtop to Bedside: Structure-based Drug Design on Protein Targets

Chen¹,

Morrow²,

Tran³

et al. 2012

curr drug metab

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As an important aspect of computer-aided drug design, structure-based drug design brought a new horizon to pharmaceutical development. This in silico method permeates all aspects of drug discovery today, including lead identification, lead optimization, ADMET prediction and drug repurposing. Structure-based drug design has resulted in fruitful successes drug discovery targeting protein-ligand and protein-protein interactions. Meanwhile, challenges, noted by low accuracy and combinatoric issues, may also cause failures. In this review, state-of-the-art techniques for protein modeling (e.g. structure prediction, modeling protein flexibility, etc.), hit identification/optimization (e.g. molecular docking, focused library design, fragment-based design, molecular dynamic, etc.), and polypharmacology design will be discussed. We will explore how structure-based techniques can facilitate the drug discovery process and interplay with other experimental approaches. KeywordsStructure-based drug design; protein modeling; focused library design; pharmacophore; flexible docking; high-throughput virtual screening; de novo design; protein-protein interaction; polypharmacology Modern computational-aided drug design established a novel platform by which researchers perform in-depth in silico simulation prior to labor-extensive wet-lab validation [1]. It comprises of two major parts corresponding to the information of molecular source it utilizes: structure-based (or receptor-based) drug design and ligand-based drug design. Structure-based drug design, which relies on the knowledge of biological target structures, aims to discover small molecules/peptides leads with desired chemistry properties, and orchestrate the following experimental validation and lead optimization. Structure-based approach provides mechanism-based basis, where potential ligands are excavated using receptor-dependent parameters, while ligand-based approaches bypass the consideration of complex biomolecular "black box" in a living cell. This in silico method permeates all aspects of drug discovery today [2], and we expect it will draw more attentions with the unprecedented advances of computational power and modeling accuracy in this decade.* Corresponding author: Shuxing Zhang, Ph.D., The University of Texas M. D. Anderson Cancer Center, Department of Experimental Therapeutics, Unit 1950, 1901 East Rd., Houston, TX 77054, Telephone: (713)-745-2958 794-5577, shuzhang@mdanderson.org. Conflict of interestThe authors declare that they do not have competing interests. NIH Public Access Author ManuscriptCurr Pharm Des. Author manuscript; available in PMC 2013 November 07.Published in final edited form as:Curr Pharm Des. 2012 ; 18(9): 1217-1239. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptIn this review, we will overview the state-of-the-art structure-based drug discovery techniques ranging from receptor modeling to lead identification and optimization. In each topic, we will also highlight the fruitful successes as well as ch...

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“…For the former, biophysical methods such as X-ray crystallography 26 , NMR spectroscopy 25, 27, 30 , and surface plasmon resonance 38 have been used to design and synthesize high-affinity ligands, based on fragments with good binding properties 25,31,32,[35][36][37] . Some compounds identified using fragment-based approaches have entered clinical trials 36 , and fragment based discovery can identify quality leads for targets where HTS has not succeeded 31, 32, 39 .…”

Section: Introductionmentioning

confidence: 99%

Novel inhibitors of anthrax edema factor

Chen

Misra

Sower

et al. 2008

Bioorganic & Medicinal Chemistry

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Several pathogenic bacteria produce adenylyl cyclase toxins, such as the edema factor (EF) of Bacillus anthracis. These disturb cellular metabolism by catalyzing production of excessive amounts of the regulatory molecule cAMP. Here, a structure-based method, where a 3D-pharmacophore that fit the active site of EF was constructed from fragments, was used to identify non-nucleotide inhibitors of EF. A library of small molecule fragments was docked to the EF-active site in existing crystal structures and those with the highest HINT scores were assembled into a 3D-pharmacophore. About 10,000 compounds, from over 2.7 million compounds in the ZINC database, had a similar molecular framework. These were ranked according to their docking scores, using methodology that was shown to achieve maximum accuracy (i.e., how well the docked position matched the experimentally determined site for ATP analogues in crystal structures of the complex). Finally, 19 diverse compounds with the best AutoDock binding/docking scores were assayed in a cell based assay for their ability to reduce cAMP secretion induced by EF. Four of the test compounds, from different structural groups, inhibited in the low micromolar range. One of these has a core structure common to phosphatase inhibitors previously identified by high-throughput assays of a diversity library. Thus, the fragment based pharmacophore identified a small number of diverse compounds for assay, and greatly enhanced the selection process of advanced lead compounds for combinatorial design.

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PRO_SELECT: Combining Structure-Based Drug Design and Array-Based Chemistry for Rapid Lead Discovery. 2. The Development of a Series of Highly Potent and Selective Factor Xa Inhibitors

Cited by 91 publications

References 29 publications

A potent, proteolysis-resistant inhibitor of kallikrein-related peptidase 6 (KLK6) for cancer therapy, developed by combinatorial engineering

A potent, proteolysis-resistant inhibitor of kallikrein-related peptidase 6 (KLK6) for cancer therapy, developed by combinatorial engineering

From Laptop to Benchtop to Bedside: Structure-based Drug Design on Protein Targets

Novel inhibitors of anthrax edema factor

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