Identification of Non-Phosphate-Containing Small Molecular Weight Inhibitors of the Tyrosine Kinase p56 Lck SH2 Domain via in Silico Screening against the pY + 3 Binding Site

Huang, Niu; Nagarsekar, Ashish; Xia, Guanjun; Hayashi, Jun; MacKerell, Alexander D.

doi:10.1021/jm030470e

Cited by 54 publications

(77 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…1A) for the initial CADD screen. A database of 1.5 million commercially available, low molecular weight chemicals was subjected to an in silico screen for molecules that may bind within the DNA-binding pocket using the program DOCK (6)(7)(8)(9)(10). From this virtual screen, a total of 233 compounds were selected for biochemical and biological assays.…”

Section: Resultsmentioning

confidence: 99%

Rational Design of Human DNA Ligase Inhibitors that Target Cellular DNA Replication and Repair

Chen¹,

et al. 2008

Self Cite

View full text Add to dashboard Cite

Based on the crystal structure of human DNA ligase I complexed with nicked DNA, computer-aided drug design was used to identify compounds in a database of 1.5 million commercially available low molecular weight chemicals that were predicted to bind to a DNA-binding pocket within the DNA-binding domain of DNA ligase I, thereby inhibiting DNA joining. Ten of 192 candidates specifically inhibited purified human DNA ligase I. Notably, a subset of these compounds was also active against the other human DNA ligases. Three compounds that differed in their specificity for the three human DNA ligases were analyzed further. L82 inhibited DNA ligase I, L67 inhibited DNA ligases I and III, and L189 inhibited DNA ligases I, III, and IV in DNA joining assays with purified proteins and in cell extract assays of DNA replication, base excision repair, and nonhomologous end-joining. L67 and L189 are simple competitive inhibitors with respect to nicked DNA, whereas L82 is an uncompetitive inhibitor that stabilized complex formation between DNA ligase I and nicked DNA. In cell culture assays, L82 was cytostatic whereas L67 and L189 were cytotoxic. Concordant with their ability to inhibit DNA repair in vitro, subtoxic concentrations of L67 and L189 significantly increased the cytotoxicity of DNA-damaging agents. Interestingly, the ligase inhibitors specifically sensitized cancer cells to DNA damage. Thus, these novel human DNA ligase inhibitors will not only provide insights into the cellular function of these enzymes but also serve as lead compounds for the development of anticancer agents. [Cancer Res 2008;68(9):3169-77]

show abstract

Section: Resultsmentioning

confidence: 99%

Rational Design of Human DNA Ligase Inhibitors that Target Cellular DNA Replication and Repair

Chen¹,

et al. 2008

Self Cite

View full text Add to dashboard Cite

show abstract

“…Although molecular docking screens of chemical databases are widely used for ligand discovery, [1][2][3][4][5][6][7] the method retains important weaknesses. [8][9][10][11][12][13] A testament to these is the criterion by which docking screens are evaluated: the enrichment of annotated ligands from among a large database of presumed non-binding, "decoy" molecules.…”

Section: Introductionmentioning

confidence: 99%

Benchmarking Sets for Molecular Docking

2006

Self Cite

View full text Add to dashboard Cite

Ligand enrichment among top-ranking hits is a key metric of molecular docking. To avoid bias, decoys should resemble ligands physically, so that enrichment is not simply a separation of gross features, yet be chemically distinct from them, so that they are unlikely to be binders. We have assembled a directory of useful decoys (DUD), with 2950 ligands for 40 different targets. Every ligand has 36 decoy molecules that are physically similar but topologically distinct, leading to a database of 98,266 compounds. For most targets, enrichment was at least half a log better with uncorrected databases such as the MDDR than with DUD, evidence of bias in the former. These calculations also allowed forty-by-forty cross docking, where the enrichments of each ligand set could be compared for all 40 targets, enabling a specificity metric for the docking screens. DUD is freely available online as a benchmarking set for docking at http://blaster.docking.org/dud/.

show abstract

“…Over the past few years, a high number of case studies has been reported using a variety of SBVS methods, demonstrating its broad applicability and the level of interest in this drug design strategy. Some important applications include, besides the examples abovementioned, the identification of antagonists of the thyroid hormone receptor, the discovery of inhibitors of tyrosine kinase p56 Lck, the selection of epidermal growth factor receptor (EGFR) inhibitors, as well as the discovery of inhibitors of the Bcl-2 protein [54][55][56][57]. The strategy for identification of ellagic acid, a natural compound, as nanomolar competitive inhibitor of casein kinase 2 (CK2), is depicted in Fig.…”

Section: Structure-based Virtual Screeningmentioning

confidence: 99%

Structure-Based Drug Design Strategies in Medicinal Chemistry

Andricopulo¹,

Salum²,

Abraham

2009

CTMC

139

View full text Add to dashboard Cite

A broad variety of medicinal chemistry approaches can be used for the identification of hits, generation of leads, as well as to accelerate the development of high quality drug candidates. Structure-based drug design (SBDD) methods are becoming increasingly powerful, versatile and more widely used. This review summarizes current developments in structure-based virtual screening and receptor-based pharmacophores, highlighting achievements as well as challenges, along with the value of structure-based lead optimization, with emphasis on recent examples of successful applications for the identification of novel active compounds.Keywords: Structure-based drug design, medicinal chemistry, virtual screening, QSAR, pharmacophores. STRUCTURE-BASED DRUG DESIGNThe performance of biochemical processes and cell mechanisms are dependent upon complex and multiple noncovalent intermolecular interactions between proteins and small-molecule modulators. The understanding of the structural and chemical binding properties of important drug targets in biologically relevant pathways allows the design of small molecules capable of regulating or modulating specific target functions in the body that are closely linked to human diseases and disorders, through multiple intermolecular interactions within a well-defined binding pocket [1][2][3][4]. In general, the identification of promising hits for further optimization is a major challenge faced by the both pharmaceutical and academic laboratories. Although the trial-anderror nature is inherent in drug research, rational concepts and modern computational methods have become widely employed for lead selection and optimization.The use of three-dimensional (3D) protein structure information in the development of new biologically active molecules, which is termed Structure-Based Drug Design (SBDD), is a well-established, successful and highly attarctive strategy used by academic and pharmaceutical research laboratories worldwide [3][4][5][6][7][8]. As a creative and knowledgedriven approach, an essential requirement for structure-based studies is a substantial understanding of the spatial and energetic aspects that affect the binding affinities of proteinligand complexes. Considering that the shape and chemical nature of the binding site of a specific target protein are known, and the possible intermolecular interactions between ligands and the protein within its active site have been identified, this qualified information can be directly employed for the identification of new ligands and the optimization of lead compounds. This opens new possibilities to boost the search for lead molecules and to limit the number of compounds that need to be evaluated experimentally.Hits can be identified through the docking of smallmolecule ligands (selected from databases of chemical structures) into protein active sites or by using receptorbased pharmacophore models. Furthermore, drug candidates can be designed de novo by improving the complementary binding properties of lead compounds and the r...

show abstract

Identification of Non-Phosphate-Containing Small Molecular Weight Inhibitors of the Tyrosine Kinase p56 Lck SH2 Domain via in Silico Screening against the pY + 3 Binding Site

Cited by 54 publications

References 39 publications

Rational Design of Human DNA Ligase Inhibitors that Target Cellular DNA Replication and Repair

Rational Design of Human DNA Ligase Inhibitors that Target Cellular DNA Replication and Repair

Benchmarking Sets for Molecular Docking

Structure-Based Drug Design Strategies in Medicinal Chemistry

Contact Info

Product

Resources

About