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PubMed2006

Small, nonpeptide p75NTR ligands induce survival signaling and inhibit proNGF-induced death.

Studies showing that neurotrophin binding to p75NTR can promote cell survival in the absence of Trk (tropomyosin-related kinase) receptors, together with recent structural data indicating that NGF may bind to p75NTR in a monovalent manner, raise the possibility that small molecule p75NTR ligands that positively regulate survival might be found. A pharmacophore designed to capture selected structural and physical chemical features of a neurotrophin domain known to interact with p75NTR was applied to in silico screening of small molecule libraries. Small, nonpeptide, monomeric compounds were identified that interact with p75NTR. In cells showing trophic responses to neurotrophins, the compounds promoted survival signaling through p75NTR-dependent mechanisms. In cells susceptible to proneurotrophin-induced death, compounds did not induce apoptosis but inhibited proneurotrophin-mediated death. These studies identify a unique range of p75NTR behaviors that can result from isolated receptor liganding and establish several novel therapeutic leads.

Animals↗
PubMed1998

Domino reactions for library synthesis of small molecules in combinatorial chemistry.

Domino reactions are highly efficient processes that allow the synthesis of complex molecules starting from simple substrates, in a straightforward fashion. The transformations are extremely useful for the design of small-molecule libraries by combinatorial chemistry if multicomponent domino reactions are employed. The reactions can be performed in solution, as well as on solid support, and give access to highly diverse molecules; in addition, their use in automated synthesis is possible.

Chemistry, Organic↗
PubMed2003

A novel and rapid encoding method based on mass spectrometry for "one-bead-one-compound" small molecule combinatorial libraries.

A novel and efficient encoding method based on mass spectrometry for "one-bead-one-compound" small molecule combinatorial libraries has been developed. The topologically segregated bifunctional resin beads with orthogonal protecting groups in the outer and inner regions are first prepared according to our previously published procedure. Prior to library synthesis, the inner core of each bead is derivatized with 3-4 different coding blocks on a cleavable linker. Each functional group on the scaffold is encoded by an individual coding block containing a functional group with the same chemical reactivity. During the library synthesis, the same chemical reactions take place on the scaffold (outer layer of the bead) and coding blocks (inner core of the bead) concurrently. After screening, the coding tags in the positive beads are released, followed by molecular mass determination using matrix-assisted laser desorption ionization Fourier transform mass spectrometry. The chemical structure of library compounds can be readily identified according to the molecular masses of the coding tags. The feasibility and efficiency of this approach were demonstrated by the synthesis and screening of a model small molecule library containing 84 672 member compounds, with a model receptor, streptavidin. Streptavidin binding ligands with structural similarity (17) were identified. The decoding results were clear and unambiguous.

Combinatorial Chemistry Techniques↗
PubMed2002

A novel peptide-based encoding system for "one-bead one-compound" peptidomimetic and small molecule combinatorial libraries.

The "one-bead one-compound" (OBOC) combinatorial library method is highly efficient, especially when used with well-established on-bead binding or functional assays. Literally, millions of compounds can be screened concurrently within 1 to 2 days. However, structure determination of peptidomimetic and small molecule compounds on one single bead is not trivial. A novel, highly efficient, and robust peptide-based encoding system has been developed for OBOC peptidomimetic and small molecule combinatorial libraries. In this system, topologically segregated bifunctional beads, which are made by a simple biphasic solvent strategy, are employed for the preparation and screening of an OBOC combinatorial peptidomimetic and small molecule libraries. Testing molecules are on the outer layer, and the coding tags in the interior of the bead do not interfere with screening. The coding tag is a peptide containing a large number of unnatural alpha-amino acids derived from different building blocks used for generating the peptidomimetic or small molecule. By coupling common building blocks simultaneously to the scaffold of the testing compound and to the side chains of the alpha-amino acids on the coding peptide, extra synthetic steps are eliminated and the amount of undesirable side products is minimized. Positive bead decoding is easy and straightforward as there is no need for cleavage and retrieval of the coding tag, and positive beads can be sequenced directly with Edman degradation. To demonstrate the efficiency and simplicity of our encoding system, an encoded 158 400-member model peptidomimetic library has been generated and screened for ligands that bind to streptavidin. Potent and novel ligands with clear motifs have been identified.

Amino Acids↗
PubMed1997

Application of combinatorial library methods in cancer research and drug discovery.

Combinatorial chemistry is now considered as one of the most important recent advances in medicinal chemistry. There are five general approaches in combinatorial peptide library methods: biological libraries; spatially addressable parallel solid phase or solution phase libraries; synthetic library methods requiring deconvolution; the 'one-bead one-compound' library method; and synthetic library methods using affinity chromatography selection. Except for the biological library approach, which is limited to peptide libraries with eukaryotic amino acids, all the other four synthetic approaches are applicable to peptide, non-peptide oligomer or small molecule libraries. Although non-peptide or small molecule libraries are generally prepared by a synthetic approach, recent advances in biosynthetic methods using enzymes may enable one to prepare chemical libraries that are otherwise difficult to synthesize chemically. In the 'one-bead one-compound' library method every member of the library is screened in parallel, but the chemical structure of the positive compound-bead has to be determined either directly or via an encoding strategy. A reliable high-throughput biological assay is needed for a successful combinatorial library screen. Solid-phase binding or functional assays as well as solution phase assays have been used successfully in various library methods. There has been enormous progress in the technological advances of molecular biology and the fundamental understanding of the molecular basis of cancer in recent years. By applying combinatorial chemistry and computational chemistry to the many cancer targets that have recently been identified, it is hopeful that more potent, more specific and less toxic anti-cancer agents will be developed in the foreseeable future. In addition to being a great tool for drug discovery, combinatorial chemistry has also proven to be invaluable in basic research. A few specific examples of the applications of combinatorial chemistry in basic cancer research and drug discovery are described in this mini-review.

Antineoplastic Agents↗
PubMed2005

Identification of the F1F0 mitochondrial ATPase as a target for modulating skin pigmentation by screening a tagged triazine library in zebrafish.

A triazine-based combinatorial library of small molecules was screened in zebrafish to identify compounds that produced interesting phenotypes. One compound (of 1536 screened) induced a dramatic increase in the pigmentation of early stage zebrafish embryos. This compound, PPA, was also found to increase pigmentation in cultured mammalian melanocytes. The cellular target was identified as the mitochondrial F1F0-ATP synthase (ATPase) by affinity chromatography. Oligomycin, a small molecule known to inhibit the mitochondrial ATPase, competed with PPA for its cellular target in melanocytes. In addition, PPA was shown to alter the membrane potential of mitochondria, consistent with inhibition of the mitochondrial ATPase. Thus, PPA has been successfully used as a chemical probe in a forward chemical genetic approach to establish a link between the phenotype and the protein. The results attest to the power of screening small molecule libraries in zebrafish as a means of identifying mammalian targets and suggest the mitochondrial ATPase as a target for modulating pigmentation in both melanocytes and melanoma cells.

Amino Acid Sequence↗
PubMed2004

OBOC small-molecule combinatorial library encoded by halogenated mass-tags.

[reaction: see text] A bromine-/chlorine-containing mass-tag encoding strategy for a small-molecule OBOC combinatorial library is reported. The resulting MALDI FTMS isotope pattern of each tag clearly defines the component building blocks of each "hit" bead in an 1890-member demonstration library screened on-bead for binding against streptavidin via both enzyme-linked colorimetric and Quantum Dot/COPAS assays.

Journal Article↗
PubMedDate not supplied

Affinity ligand selection from a library of small molecules: assay development, screening, and application.

A facile and cost-effective process for screening synthetic libraries for an affinity ligand is described. A high throughput 96-well plate filtration method was designed to screen both discrete compounds and mixtures of compounds attached to a solid support. Human serum albumin (HSA) was used as a target protein to demonstrate the proof of concept. Detection and quantitation by fluorescence was accomplished with the use of fluorescamine to conjugate the protein in the filtrate. It is found that mixtures demonstrating low average binding reflect an overall lower hit rate of the components, whereas deconvolution of mixtures with high protein binding consistently provides a high hit rate. This differs from many of the previous experiences screening solid-phase mixtures in which high false positive rates are noted to occur. A total of 100K compounds were tested: 25K as discrete samples and 75K as mixtures. An overall hit rate of 8% was observed. Secondary screening of compounds measured specificity, recovery, and dynamic binding capacity. The effectiveness of the method is illustrated using an affinity column made with a representative lead compound. A similar purity was achieved in a single-step purification of HSA from serum as compared to that obtained by two steps of ion-exchange chromatography. The process for primary screening of a large number of compounds is simple, inexpensive, and applicable to any soluble target protein of known or unknown function from crude mixtures and may have additional utility as a generic chemical affinity tool for the functional characterization of novel proteins emerging from proteomics work.

Chromatography, Affinity↗
PubMedDate not supplied

Alzheimer's therapeutics: neurotrophin small molecule mimetics.

A substantial portion of neuronal populations undergoing degeneration in Alzheimer's and other neurodegenerative disorders express neurotrophin receptors. Neurotrophin small molecule mimetics constitute candidate compounds that might be useful in preventing or delaying loss of neuronal function, neural networks or neuronal death in neurodegenerative states. We are testing the hypothesis that pharmacophores based on a combination of the crystal structures of neurotrophins and structure-activity relationships of active neurotrophin peptidomimetics can be used to screen small molecule libraries to identify non-peptide small molecules with neurotrophin agonist or antagonist activity. In preliminary screens using pharmacophores based on two nerve growth factor (NGF) loop domains, a number of small molecules have been identified that display neurotrophic activity using in vitro bioassays. Current studies are focused on determining whether these small molecules function via neurotrophin receptors and whether they activate neurotrophin signaling cascades. Assessment of structure-activity relationships between active and inactive small molecules will allow modification of pharmacophores and provide a basis for the iterative process if identifying compounds with increased potency and efficacy. A collection of such compounds will provide a basis for synthesis of compounds with targeted pharmacological properties.

Alzheimer Disease↗
PubMed1995

Libraries of non-polymeric organic molecules.

New technology is emerging that permits the chemical synthesis of large numbers of different compounds simultaneously. Combinatorial chemistry is heavily dependent upon the adaptation of organic synthesis to solid supports and has necessitated the development of appropriate analytical and chemical approaches to both monitor solid-phase reactions and release finished compounds into solution. Considerable progress has recently been made in all of these areas. Small-molecule libraries of medicinally important chemical classes, such as 1,4-benzodiazepines, mercaptopropionyl amino acids, and peptidyl phosphonates, have recently been reported. Encoded combinatorial libraries of dihydrobenzopyran-based and acylpiperidine-based pharmacophores have yielded potent inhibitors of carbonic anhydrase. Automated instrumentation is growing in importance for the synthesis of small-molecule libraries.

Journal Article↗
PubMed2004

Forward chemical genetics: library scaffold design.

With the unraveling of the entire human genome, it has become imperative to understand the function of the gene products, proteins. Within the past several years, chemical genetics has gained recognition as a powerful approach to study protein function by using small molecules as gene knock-out or knock-in mimics. Forward chemical genetics is a three-step process; the design and synthesis of a small molecule library represents the first step followed secondly by the search for novel phenotypes and then by isolation and identification of target protein(s). This review will focus on the first step, the design of the scaffold for small molecule libraries. It will also examine the connection between the choice of a scaffold and the propensity of that library to demonstrate enhanced biological activity when tested in certain cellular systems.

Animals↗
PubMed2001

Solid phase synthesis of mixture-based acyclic and heterocyclic small molecule combinatorial libraries from resin-bound polyamides.

The development of soluble mixture-based heterocyclic combinatorial libraries derived from amino acids and peptides is described. Starting with a "toolbox" of various chemical transformations, including alkylations, reductions, acylations, and the use of a variety of bifunctional reagents, the "libraries from libraries" concept has been expanded to encompass the development of more than fifty positional scanning combinatorial libraries each composed of tens of thousands of low molecular weight acyclic and heterocyclic compounds.

Combinatorial Chemistry Techniques↗
PubMed2003

Ketenes in polymer-assisted synthesis.

Since its inception, ketene chemistry has developed into a unique and well-established source of useful transformations for conventional synthetic organic chemistry. It is, therefore, not surprising that soon after their movement from the realm of peptide and peptoid libraries to that of small molecules, combinatorial chemists have sought the benefits of ketene chemistry to satisfy their own synthetic needs. The ability of these versatile molecules to undergo reactions with nucleophiles, and to participate in cycloadditions and cyclocondensations, has been utilized for the preparation of diverse heterocyclic compounds, and has added to the advantages of polymer-assisted synthesis for rapid purification. Different types of ketenes and different methods for their generation have been involved, which illustrates the potential diversity of the chemistry. There is now a better grasp of the effect of the fragility of these sometimes transient molecules on the reactions involving solid supports, and this augurs well for the application of some of the more recent developments in ketene chemistry to the generation of small-molecule libraries.

Journal Article↗
PubMed2004

High-throughput characterization and quality control of small-molecule combinatorial libraries.

To fully realize the potential of combinatorial synthesis and high-throughput screening for increasing the efficiency of the drug discovery and development process, issues related to compound purity must be addressed. Impurities, often present after synthesis, can lead to ambiguous screening results and inhibit the development of quality structure-activity relationships. The demand for high-throughput analytical characterization of combinatorial libraries has prompted the development of more rapid methods to keep pace with compound production. Recent progress has focused upon the development of parallel separation methods, multiplexed detector interfaces, and synergistic combinations of different detectors possessing complementary selectivities.

Combinatorial Chemistry Techniques↗
PubMed2001

Novel strategies for solid-phase construction of small-molecule combinatorial libraries.

During the past decade we witnessed a rapid advance in the new field of chemical science, combinatorial chemistry. The pharmaceutical industries invested heavily in accelerating the development of this new technology. As a result, it has become an extremely important tool in lead identification and optimization in current pharmaceutical research. It also quickly crossed the boundaries of the original chemical discipline and demonstrated great potential in many other important areas, such as searching for novel and highly efficient catalysts and superconductive material. Researchers from both academic and industrial laboratories have directed great effort towards the development of novel strategies for combinatorial synthesis.

Journal Article↗
PubMed2006

Chemical screening methods to identify ligands that promote protein stability, protein crystallization, and structure determination.

The 3D structures of human therapeutic targets are enabling for drug discovery. However, their purification and crystallization remain rate determining. In individual cases, ligands have been used to increase the success rate of protein purification and crystallization, but the broad applicability of this approach is unknown. We implemented two screening platforms, based on either fluorimetry or static light scattering, to measure the increase in protein thermal stability upon binding of a ligand without the need to monitor enzyme activity. In total, 221 different proteins from humans and human parasites were screened against one or both of two sorts of small-molecule libraries. The first library comprised different salts, pH conditions, and commonly found small molecules and was applicable to all proteins. The second comprised compounds specific for protein families of particular interest (e.g., protein kinases). In 20 cases, including nine unique human protein kinases, a small molecule was identified that stabilized the proteins and promoted structure determination. The methods are cost-effective, can be implemented in any laboratory, promise to increase the success rates of purifying and crystallizing human proteins significantly, and identify new ligands for these proteins.

Animals↗