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Special Issue "Advances in Drug Design"

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A special issue of Pharmaceuticals (ISSN 1424-8247).

Deadline for manuscript submissions: closed (31 July 2012)

Special Issue Editor

Guest Editor
Dr. Arthur Gomtsyan

Abbvie Inc, Drug Discovery, 1 North Waukegan Road, Department ZR09, Bldg. AP10, North Chicago, IL 60064, USA
Interests: medicinal chemistry; synthetic organic chemistry; drug design in the area of pain and dermatology research

Special Issue Information

Dear Colleagues,

Productivity of the pharmaceutical industry measured in terms of a number of approved drugs has been in decline over the last several decades. New creative approaches in drug design have been put in place to reverse that trend. Structure-based drug design that relies on high resolution 3D structures of drug targets is being complimented with fragment-based drug design approach which utilizes NMR spectroscopy to shorten the time of lead generation. On the other hand, closer attention is drawn to a drug-likeness of molecules – molecular weight, solubility, lipophilicity, etc. Lipinski's rule of five or its modifications are gaining prominence in medicinal chemistry decision making. Cheminformatic tools are becoming part of arsenal for medicinal chemists. Drug design takes into account not only pharmacological properties, but also potential toxicological effects of the molecules. Potential for reactive metabolite formation and protein covalent binding now can be assessed with various successes in vitro to predict idiosyncratic toxicity in clinic. New procedures including in silico models can be implemented to predict pharmacokinetic properties of the compounds.
Prevailing dogma in drug discovery that values selective compounds the most is getting challenged with a concept of polypharmacology, which suggests that multitargeted drugs, compared with selective drugs, may display better efficacy in clinic. As far as the mechanism of drug action goes, concept of allosteric modulation is more widely employed in a number of therapeutic areas.

Dr. Arthur Gomtsyan
Guest Editor

Keywords

  • structure-based drug design
  • fragment-based drug design
  • drug-likeness, rule of five
  • cheminformatics
  • predictive methodologies for ADME and drug toxicity
  • polypharmacology
  • allosteric modulators

Published Papers (6 papers)

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Research

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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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Open AccessArticle Prediction of Positions of Active Compounds Makes It Possible To Increase Activity in Fragment-Based Drug Development
Pharmaceuticals 2011, 4(5), 758-769; doi:10.3390/ph4050758
Received: 28 March 2011 / Revised: 17 May 2011 / Accepted: 20 May 2011 / Published: 20 May 2011
PDF Full-text (238 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
We have developed a computational method that predicts the positions of active compounds, making it possible to increase activity as a fragment evolution strategy. We refer to the positions of these compounds as the active position. When an active fragment compound is [...] Read more.
We have developed a computational method that predicts the positions of active compounds, making it possible to increase activity as a fragment evolution strategy. We refer to the positions of these compounds as the active position. When an active fragment compound is found, the following lead generation process is performed, primarily to increase activity. In the current method, to predict the location of the active position, hydrogen atoms are replaced by small side chains, generating virtual compounds. These virtual compounds are docked to a target protein, and the docking scores (affinities) are examined. The hydrogen atom that gives the virtual compound with good affinity should correspond to the active position and it should be replaced to generate a lead compound. This method was found to work well, with the prediction of the active position being 2 times more efficient than random synthesis. In the current study, 15 examples of lead generation were examined. The probability of finding active positions among all hydrogen atoms was 26%, and the current method accurately predicted 60% of the active positions. Full article
(This article belongs to the Special Issue Advances in Drug Design)

Review

Jump to: Research

Open AccessReview Advances in Drug Design Based on the Amino Acid Approach: Taurine Analogues for the Treatment of CNS Diseases
Pharmaceuticals 2012, 5(10), 1128-1146; doi:10.3390/ph5101128
Received: 31 July 2012 / Revised: 24 September 2012 / Accepted: 15 October 2012 / Published: 23 October 2012
Cited by 3 | PDF Full-text (337 KB) | HTML Full-text | XML Full-text
Abstract
Amino acids are well known to be an important class of compounds for the maintenance of body homeostasis and their deficit, even for the polar neuroactive aminoacids, can be controlled by supplementation. However, for the amino acid taurine (2-aminoethanesulfonic acid) this is [...] Read more.
Amino acids are well known to be an important class of compounds for the maintenance of body homeostasis and their deficit, even for the polar neuroactive aminoacids, can be controlled by supplementation. However, for the amino acid taurine (2-aminoethanesulfonic acid) this is not true. Due its special physicochemical properties, taurine is unable to cross the blood-brain barrier. In addition of injured taurine transport systems under pathological conditions, CNS supplementation of taurine is almost null. Taurine is a potent antioxidant and anti-inflammatory semi-essential amino acid extensively involved in neurological activities, acting as neurotrophic factor, binding to GABA A/glycine receptors and blocking the excitotoxicity glutamate-induced pathway leading to be a neuroprotective effect and neuromodulation. Taurine deficits have been implicated in several CNS diseases, such as Alzheimer’s, Parkinson’s, epilepsy and in the damage of retinal neurons. This review describes the CNS physiological functions of taurine and the development of new derivatives based on its structure useful in CNS disease treatment. Full article
(This article belongs to the Special Issue Advances in Drug Design)
Open AccessReview Anti-Inflammatory Drug Design Using a Molecular Hybridization Approach
Pharmaceuticals 2011, 4(11), 1450-1474; doi:10.3390/ph4111450
Received: 8 August 2011 / Revised: 20 October 2011 / Accepted: 20 October 2011 / Published: 27 October 2011
Cited by 16 | PDF Full-text (787 KB) | HTML Full-text | XML Full-text
Abstract
The design of new drugs with better physiochemical properties, adequate absorption, distribution, metabolism, and excretion, effective pharmacologic potency and lacking toxicity remains is a challenge. Inflammation is the initial trigger of several different diseases, such as Alzheimer’s disease, asthma, atherosclerosis, colitis, rheumatoid [...] Read more.
The design of new drugs with better physiochemical properties, adequate absorption, distribution, metabolism, and excretion, effective pharmacologic potency and lacking toxicity remains is a challenge. Inflammation is the initial trigger of several different diseases, such as Alzheimer’s disease, asthma, atherosclerosis, colitis, rheumatoid arthritis, depression, cancer; and disorders such as obesity and sexual dysfunction. Although inflammation is not the direct cause of these disorders, inflammatory processes often increase related pain and suffering. New anti-inflammatory drugs developed using molecular hybridization techniques to obtain multiple-ligand drugs can act at one or multiple targets, allowing for synergic action and minimizing toxicity. This work is a review of new anti-inflammatory drugs developed using the molecular modification approach. Full article
(This article belongs to the Special Issue Advances in Drug Design)
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Open AccessReview Targeting the Large Subunit of Human Ribonucleotide Reductase for Cancer Chemotherapy
Pharmaceuticals 2011, 4(10), 1328-1354; doi:10.3390/ph4101328
Received: 21 September 2011 / Revised: 27 September 2011 / Accepted: 30 September 2011 / Published: 13 October 2011
Cited by 5 | PDF Full-text (1239 KB) | HTML Full-text | XML Full-text
Abstract
Ribonucleotide reductase (RR) is a crucial enzyme in de novo DNA synthesis, where it catalyses the rate determining step of dNTP synthesis. RRs consist of a large subunit called RR1 (α), that contains two allosteric sites and one catalytic site, and a [...] Read more.
Ribonucleotide reductase (RR) is a crucial enzyme in de novo DNA synthesis, where it catalyses the rate determining step of dNTP synthesis. RRs consist of a large subunit called RR1 (α), that contains two allosteric sites and one catalytic site, and a small subunit called RR2 (β), which houses a tyrosyl free radical essential for initiating catalysis. The active form of mammalian RR is an anbm hetero oligomer. RR inhibitors are cytotoxic to proliferating cancer cells. In this brief review we will discuss the three classes of RR, the catalytic mechanism of RR, the regulation of the dNTP pool, the substrate selection, the allosteric activation, inactivation by ATP and dATP, and the nucleoside drugs that target RR. We will also discuss possible strategies for developing a new class of drugs that disrupts the RR assembly. Full article
(This article belongs to the Special Issue Advances in Drug Design)
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)

Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.


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