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Pharmaceuticals, Volume 4, Issue 9 (September 2011), Pages 1196-1280

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Research

Jump to: Review

Open AccessArticle Target Profile Prediction and Practical Evaluation of a Biginelli-Type Dihydropyrimidine Compound Library
Pharmaceuticals 2011, 4(9), 1236-1247; doi:10.3390/ph4091236
Received: 26 August 2011 / Revised: 13 September 2011 / Accepted: 16 September 2011 / Published: 20 September 2011
Cited by 5 | PDF Full-text (549 KB) | HTML Full-text | XML Full-text
Abstract
We present a self-organizing map (SOM) approach to predicting macromolecular targets for combinatorial compound libraries. The aim was to study the usefulness of the SOM in combination with a topological pharmacophore representation (CATS) for selecting biologically active compounds from a virtual combinatorial [...] Read more.
We present a self-organizing map (SOM) approach to predicting macromolecular targets for combinatorial compound libraries. The aim was to study the usefulness of the SOM in combination with a topological pharmacophore representation (CATS) for selecting biologically active compounds from a virtual combinatorial compound collection, taking the multi-component Biginelli dihydropyrimidine reaction as an example. We synthesized a candidate compound from this library, for which the SOM model suggested inhibitory activity against cyclin-dependent kinase 2 (CDK2) and other kinases. The prediction was confirmed in an in vitro panel assay comprising 48 human kinases. We conclude that the computational technique may be used for ligand-based in silico pharmacology studies, off-target prediction, and drug re-purposing, thereby complementing receptor-based approaches. Full article
(This article belongs to the Special Issue Advances in Drug Design)
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Review

Jump to: Research

Open AccessReview In Silico Veritas: The Pitfalls and Challenges of Predicting GPCR-Ligand Interactions
Pharmaceuticals 2011, 4(9), 1196-1215; doi:10.3390/ph4091196
Received: 5 August 2011 / Revised: 23 August 2011 / Accepted: 29 August 2011 / Published: 1 September 2011
Cited by 14 | PDF Full-text (2144 KB) | HTML Full-text | XML Full-text
Abstract
Recently the first community-wide assessments of the prediction of the structures of complexes between proteins and small molecule ligands have been reported in the so-called GPCR Dock 2008 and 2010 assessments. In the current review we discuss the different steps along the [...] Read more.
Recently the first community-wide assessments of the prediction of the structures of complexes between proteins and small molecule ligands have been reported in the so-called GPCR Dock 2008 and 2010 assessments. In the current review we discuss the different steps along the protein-ligand modeling workflow by critically analyzing the modeling strategies we used to predict the structures of protein-ligand complexes we submitted to the recent GPCR Dock 2010 challenge. These representative test cases, focusing on the pharmaceutically relevant G Protein-Coupled Receptors, are used to demonstrate the strengths and challenges of the different modeling methods. Our analysis indicates that the proper performance of the sequence alignment, introduction of structural adjustments guided by experimental data, and the usage of experimental data to identify protein-ligand interactions are critical steps in the protein-ligand modeling protocol. Full article
(This article belongs to the Special Issue Advances in Drug Design)
Open AccessReview Methods To Identify Aptamers against Cell Surface Biomarkers
Pharmaceuticals 2011, 4(9), 1216-1235; doi:10.3390/ph4091216
Received: 1 August 2011 / Revised: 2 September 2011 / Accepted: 9 September 2011 / Published: 20 September 2011
Cited by 23 | PDF Full-text (805 KB) | HTML Full-text | XML Full-text
Abstract
Aptamers are nucleic acid-based ligands identified through a process of molecular evolution named SELEX (Systematic Evolution of Ligands by Exponential enrichment). During the last 10-15 years, numerous aptamers have been developed specifically against targets present on or associated with the surface of [...] Read more.
Aptamers are nucleic acid-based ligands identified through a process of molecular evolution named SELEX (Systematic Evolution of Ligands by Exponential enrichment). During the last 10-15 years, numerous aptamers have been developed specifically against targets present on or associated with the surface of human cells or infectious pathogens such as viruses, bacteria, fungi or parasites. Several of the aptamers have been described as potent probes, rivalling antibodies, for use in flow cytometry or microscopy. Some have also been used as drugs by inhibiting or activating functions of their targets in a manner similar to neutralizing or agonistic antibodies. Additionally, it is straightforward to conjugate aptamers to other agents without losing their affinity and they have successfully been used in vitro and in vivo to deliver drugs, siRNA, nanoparticles or contrast agents to target cells. Hence, aptamers identified against cell surface biomarkers represent a promising class of ligands. This review presents the different strategies of SELEX that have been developed to identify aptamers for cell surface-associated proteins as well as some of the methods that are used to study their binding on living cells. Full article
(This article belongs to the Special Issue Aptamer-Based Therapeutics)
Open AccessReview RFamide Peptides: Structure, Function, Mechanisms and Pharmaceutical Potential
Pharmaceuticals 2011, 4(9), 1248-1280; doi:10.3390/ph4091248
Received: 29 August 2011 / Revised: 9 September 2011 / Accepted: 15 September 2011 / Published: 21 September 2011
Cited by 17 | PDF Full-text (601 KB) | HTML Full-text | XML Full-text
Abstract
Different neuropeptides, all containing a common carboxy-terminal RFamide sequence, have been characterized as ligands of the RFamide peptide receptor family. Currently, five subgroups have been characterized with respect to their N-terminal sequence and hence cover a wide pattern of biological functions, like [...] Read more.
Different neuropeptides, all containing a common carboxy-terminal RFamide sequence, have been characterized as ligands of the RFamide peptide receptor family. Currently, five subgroups have been characterized with respect to their N-terminal sequence and hence cover a wide pattern of biological functions, like important neuroendocrine, behavioral, sensory and automatic functions. The RFamide peptide receptor family represents a multiligand/multireceptor system, as many ligands are recognized by several GPCR subtypes within one family. Multireceptor systems are often susceptible to cross-reactions, as their numerous ligands are frequently closely related. In this review we focus on recent results in the field of structure-activity studies as well as mutational exploration of crucial positions within this GPCR system. The review summarizes the reported peptide analogs and recently developed small molecule ligands (agonists and antagonists) to highlight the current understanding of the pharmacophoric elements, required for affinity and activity at the receptor family. Furthermore, we address the biological functions of the ligands and give an overview on their involvement in physiological processes. We provide insights in the knowledge for the design of highly selective ligands for single receptor subtypes to minimize cross-talk and to eliminate effects from interactions within the GPCR system. This will support the drug development of members of the RFamide family. Full article
(This article belongs to the Special Issue Peptidomimetics)

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