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10 pages, 181 KiB

Open AccessArticle

Synthesis and Biological Activity of trans-Tiliroside Derivatives as Potent Anti-Diabetic Agents

by Yujin Zhu, Yanjun Zhang, Yi Liu, Hongwan Chu and Hongquan Duan

Molecules 2010, 15(12), 9174-9183; https://doi.org/10.3390/molecules15129174 - 10 Dec 2010

Cited by 34 | Viewed by 10579

Abstract

A set of novel trans-tiliroside derivatives were synthesized. The structures of the derivatives were identified by their IR, ¹H-NMR, and MS spectra analysis. Their anti-diabetic activities were evaluated on the insulin resistant (IR) HepG2 cell model. As a result, compounds 7a [...] Read more.

A set of novel trans-tiliroside derivatives were synthesized. The structures of the derivatives were identified by their IR, ¹H-NMR, and MS spectra analysis. Their anti-diabetic activities were evaluated on the insulin resistant (IR) HepG2 cell model. As a result, compounds 7a, 7c, 7h, and trans-tiliroside exhibited significant glucose consumption-enhancing effects in IR-HepG2 cells compared with the positive control (metformin). This research provides useful clues for further design and discovery of anti-diabetic agents. Full article

(This article belongs to the Special Issue Structure-Based Drug Design)

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19 pages, 1576 KiB

Open AccessArticle

Lead Generation and Optimization Based on Protein-Ligand Complementarity

by Koji Ogata, Tetsu Isomura, Shinji Kawata, Hiroshi Yamashita, Hideo Kubodera and Shoshana J. Wodak

Molecules 2010, 15(6), 4382-4400; https://doi.org/10.3390/molecules15064382 - 17 Jun 2010

Cited by 10 | Viewed by 9419

Abstract

This work proposes a computational procedure for structure-based lead generation and optimization, which relies on the complementarity of the protein-ligand interactions. This procedure takes as input the known structure of a protein-ligand complex. Retaining the positions of the ligand heavy atoms in the [...] Read more.

This work proposes a computational procedure for structure-based lead generation and optimization, which relies on the complementarity of the protein-ligand interactions. This procedure takes as input the known structure of a protein-ligand complex. Retaining the positions of the ligand heavy atoms in the protein binding site it designs structurally similar compounds considering all possible combinations of atomic species (N, C, O, CH_3, NH,etc). Compounds are ranked based on a score which incorporates energetic contributions evaluated using molecular mechanics force fields. This procedure was used to design new inhibitor molecules for three serine/threonine protein kinases (p38 MAP kinase, p42 MAP kinase (ERK2), and c-Jun N-terminal kinase 3 (JNK3)). For each enzyme, the calculations produce a set of potential inhibitors whose scores are in agreement with IC50 data and Ki values. Furthermore, the native ligands for each protein target, scored within the five top-ranking compounds predicted by our method, one of the top-ranking compounds predicted to inhibit JNK3 was synthesized and his inhibitory activity confirmed against ATP hydrolysis. Our computational procedure is therefore deemed to be a useful tool for generating chemically diverse molecules active against known target proteins. Full article

(This article belongs to the Special Issue Structure-Based Drug Design)

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35 pages, 3759 KiB

Open AccessArticle

Design, Synthesis and Structure-activity Studies of Rhodanine Derivatives as HIV-1 Integrase Inhibitors

by Kavya Ramkumar, Vladimir N. Yarovenko, Alexandra S. Nikitina, Igor V. Zavarzin, Mikhail M. Krayushkin, Leonid V. Kovalenko, Adrian Esqueda, Srinivas Odde and Nouri Neamati

Molecules 2010, 15(6), 3958-3992; https://doi.org/10.3390/molecules15063958 - 1 Jun 2010

Cited by 44 | Viewed by 12394

Abstract

Raltegravir was the first HIV-1 integrase inhibitor that gained FDA approval for use in the treatment of HIV-1 infection. Because of the emergence of IN inhibitor-resistant viral strains, there is a need to identify innovative second-generation IN inhibitors. Previously, we identified 2-thioxo-4-thiazolidinone (rhodanine)-containing [...] Read more.

Raltegravir was the first HIV-1 integrase inhibitor that gained FDA approval for use in the treatment of HIV-1 infection. Because of the emergence of IN inhibitor-resistant viral strains, there is a need to identify innovative second-generation IN inhibitors. Previously, we identified 2-thioxo-4-thiazolidinone (rhodanine)-containing compounds as IN inhibitors. Herein, we report the design, synthesis and docking studies of a series of novel rhodanine derivatives as IN inhibitors. All these compounds were further tested against human apurinic/apyrimidinic endonuclease 1 (APE1) to determine their selectivity. Two compounds showed significant cytotoxicity in a panel of human cancer cell lines. Taken together, our results show that rhodanines are a promising class of compounds for developing drugs with antiviral and anticancer properties. Full article

(This article belongs to the Special Issue Structure-Based Drug Design)

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16 pages, 285 KiB

Open AccessArticle

Novel Indole-Based Analogs of Melatonin: Synthesis and in Vitro Antioxidant Activity Studies

by Hanif Shirinzadeh, Burcu Eren, Hande Gurer-Orhan, Sibel Suzen and Seçkin Özden

Molecules 2010, 15(4), 2187-2202; https://doi.org/10.3390/molecules15042187 - 29 Mar 2010

Cited by 75 | Viewed by 11200

Abstract

The aim of this study was to synthesize and examine possible in vitro antioxidant effects of indole-based melatonin analogue compounds. As a part of our ongoing study nineteen indole hydrazide/hydrazone derivatives were synthesized, characterized and their in vitro antioxidant activity was investigated by [...] Read more.

The aim of this study was to synthesize and examine possible in vitro antioxidant effects of indole-based melatonin analogue compounds. As a part of our ongoing study nineteen indole hydrazide/hydrazone derivatives were synthesized, characterized and their in vitro antioxidant activity was investigated by three different assays: by evaluating their reducing effect against oxidation of a redox sensitive fluorescent probe, by examining their protective effect against H₂O₂-induced membrane lipid peroxidation and by determining their inhibitory effect on AAPH–induced hemolysis of human erythrocytes. The results indicated significant strong antioxidant activity for most of the compounds, when compared to melatonin. Full article

(This article belongs to the Special Issue Structure-Based Drug Design)

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14 pages, 2711 KiB

Open AccessReview

4D-QSAR: Perspectives in Drug Design

by Carolina H. Andrade, Kerly F. M. Pasqualoto, Elizabeth I. Ferreira and Anton J. Hopfinger

Molecules 2010, 15(5), 3281-3294; https://doi.org/10.3390/molecules15053281 - 4 May 2010

Cited by 110 | Viewed by 19385

Abstract

Drug design is a process driven by innovation and technological breakthroughs involving a combination of advanced experimental and computational methods. A broad variety of medicinal chemistry approaches can be used for the identification of hits, generation of leads, as well as to accelerate [...] Read more.

Drug design is a process driven by innovation and technological breakthroughs involving a combination of advanced experimental and computational methods. A broad variety of medicinal chemistry approaches can be used for the identification of hits, generation of leads, as well as to accelerate the optimization of leads into drug candidates. The quantitative structure–activity relationship (QSAR) formalisms are among the most important strategies that can be applied for the successful design new molecules. This review provides a comprehensive review on the evolution and current status of 4D-QSAR, highlighting present challenges and new opportunities in drug design. Full article

(This article belongs to the Special Issue Structure-Based Drug Design)

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