Molecular-Docking-Guided Design, Synthesis, and Biologic Evaluation of Radioiodinated Quinazolinone Prodrugs

Chen, Kai; Aowad, Ayman F. Al; Adelstein, S. James; Kassis, Amin I.

doi:10.1021/jm060944k

Cited by 35 publications

(38 citation statements)

References 38 publications

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“…LSGraph version 1.5 (Life Science Graph, 4 IT.Omics, Lille, France) and Ingenuity Pathways Analysis (IPA) version 2.0 (Ingenuity Systems, 5 Mountain View, CA; Fig. 1).…”

Section: Methodsmentioning

confidence: 99%

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Computational Modeling and Experimental Evaluation of a Novel Prodrug for Targeting the Extracellular Space of Prostate Tumors

et al. 2007

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We are developing a noninvasive approach for targeting imaging and therapeutic radionuclides to prostate cancer. Our method, Enzyme-Mediated Cancer Imaging and Therapy (EMCIT), aims to use enzyme-dependent, site-specific, in vivo precipitation of a radioactive molecule within the extracellular space of solid tumors. Advanced methods for data mining of the literature, protein databases, and knowledge bases (IT.Omics LSGraph and Ingenuity Systems) identified prostatic acid phosphatase (PAP) as an enzyme overexpressed in prostate cancer and secreted in the extracellular space. Using AutoDock 3.0 software, the prodrug ammonium 2-(2 ¶-phosphoryloxyphenyl)-6-iodo-4-(3H)-quinazolinone (IQ 2-P ) was docked in silico into the X-ray structure of PAP. The data indicate that IQ 2-P docked into the PAP active site with a calculated inhibition constant (K i ) more favorable than that of the PAP inhibitor A-benzylaminobenzylphosphonic acid. When 125 IQ 2-P , the radioiodinated form of the water-soluble prodrug, was incubated with PAP, rapid hydrolysis of the compound was observed as exemplified by formation of the water-insoluble 2-(2 ¶-hydroxyphenyl)-6-[125 I]iodo-4-(3H)-quinazolinone ( 125 IQ 2-OH ). Similarly, the incubation of IQ 2-P with human LNCaP, PC-3, and 22Rv1 prostate tumor cells resulted in the formation of large fluorescent IQ 2-OH crystals. No hydrolysis was seen in the presence of normal human cells. Autoradiography of tumor cells incubated with 125 IQ 2-P showed accumulation of radioactive grains ( 125 IQ 2-OH ) around the cells. We anticipate that the EMCIT approach will enable the active in vivo entrapment of radioimaging and radiotherapeutic compounds within the extracellular spaces of primary prostate tumors and their metastases. [Cancer Res 2007;67(5):2197-205]

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“…LSGraph version 1.5 (Life Science Graph, 4 IT.Omics, Lille, France) and Ingenuity Pathways Analysis (IPA) version 2.0 (Ingenuity Systems, 5 Mountain View, CA; Fig. 1).…”

Section: Methodsmentioning

confidence: 99%

“…Toward these objectives, we present a novel approach, Enzyme-Mediated Cancer Imaging and Therapy (EMCIT; refs. [1][2][3][4][5], which potentially enables the active entrapment of a radioisotopically labeled compound within the extracellular spaces of primary prostate tumors and their metastases (Fig. 1).…”

Section: Introductionmentioning

confidence: 99%

Computational Modeling and Experimental Evaluation of a Novel Prodrug for Targeting the Extracellular Space of Prostate Tumors

et al. 2007

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“…The radioiodinated quinazolinone derivative, ammonium 2-(2′-phosphoryloxyphenyl)-6-iodo-4-(3H)-quinazolinone has been developed as a new antitumor radiopharmaceutical (Ho et al, 2002;Chen et al, 2006;Chen et al, 2007;Pospisil et al, 2007;Wang et al, 2007). This is a water-soluble compound that is hydrolyzed by various phosphatases (overexpressed extracellularly by tumor cells) to a water-insoluble compound, 2-(2′-hydroxyphenyl)-6-iodo-4-(3H)-quinazolinone, which is trapped within the extracellular spaces of solid tumors.…”

Section: Synthesis Of Radiolabeled ( 123 I/ 125 I/ 131 I) Ammonium 2-mentioning

confidence: 99%

DMSO increases radioiodination yield of radiopharmaceuticals

Wang

Adelstein

Kassis

2008

Applied Radiation and Isotopes

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A high-yield radioiodination method for various types of molecules is described. The approach employs DMSO as precursor solvent, a reaction ratio of 2-5 precursor molecules per iodine atom, 5-10 μg oxidant, and a 10-25-μl reaction volume. The solution is vortexed at room temperature for 1-5 min and progress of the reaction is assessed by HPLC. Radioiodinated products are obtained in ≥95% yield and meet the requirements for radiotracer imaging, biodistribution studies, and molecular and cellular biology research.

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“…AutoDock4 is acknowledged to be one of the most reliable and broadly used molecular docking tool [5], with several examples of accurate docking predictions already published [6,7]. AutoDock4 uses genetic algorithms and the results are given as estimates of free-energy change (ΔG) upon ligand binding and as a prediction of the ligand-receptor complex three-dimensional conformation.…”

Section: Introductionmentioning

confidence: 99%

MOLA: a bootable, self-configuring system for virtual screening using AutoDock4/Vina on computer clusters

et al. 2010

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BackgroundVirtual screening of small molecules using molecular docking has become an important tool in drug discovery. However, large scale virtual screening is time demanding and usually requires dedicated computer clusters. There are a number of software tools that perform virtual screening using AutoDock4 but they require access to dedicated Linux computer clusters. Also no software is available for performing virtual screening with Vina using computer clusters. In this paper we present MOLA, an easy-to-use graphical user interface tool that automates parallel virtual screening using AutoDock4 and/or Vina in bootable non-dedicated computer clusters.ImplementationMOLA automates several tasks including: ligand preparation, parallel AutoDock4/Vina jobs distribution and result analysis. When the virtual screening project finishes, an open-office spreadsheet file opens with the ligands ranked by binding energy and distance to the active site. All results files can automatically be recorded on an USB-flash drive or on the hard-disk drive using VirtualBox. MOLA works inside a customized Live CD GNU/Linux operating system, developed by us, that bypass the original operating system installed on the computers used in the cluster. This operating system boots from a CD on the master node and then clusters other computers as slave nodes via ethernet connections.ConclusionMOLA is an ideal virtual screening tool for non-experienced users, with a limited number of multi-platform heterogeneous computers available and no access to dedicated Linux computer clusters. When a virtual screening project finishes, the computers can just be restarted to their original operating system. The originality of MOLA lies on the fact that, any platform-independent computer available can he added to the cluster, without ever using the computer hard-disk drive and without interfering with the installed operating system. With a cluster of 10 processors, and a potential maximum speed-up of 10x, the parallel algorithm of MOLA performed with a speed-up of 8,64× using AutoDock4 and 8,60× using Vina.

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Molecular-Docking-Guided Design, Synthesis, and Biologic Evaluation of Radioiodinated Quinazolinone Prodrugs

Cited by 35 publications

References 38 publications

Computational Modeling and Experimental Evaluation of a Novel Prodrug for Targeting the Extracellular Space of Prostate Tumors

Computational Modeling and Experimental Evaluation of a Novel Prodrug for Targeting the Extracellular Space of Prostate Tumors

DMSO increases radioiodination yield of radiopharmaceuticals

MOLA: a bootable, self-configuring system for virtual screening using AutoDock4/Vina on computer clusters

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