Structure-Activity Relationships and Rational Design Strategies for Radical- Scavenging Antioxidants

Author(s):

Hong-Yu ZhangPages 257-273 (17)

Abstract:

In the past two decades, there has been growing interest in finding novel and non-toxic antioxidants to meet the requirements in chemical, food and pharmaceutical industries. To accelerate the antioxidant discovery process, various theoretical methods have been employed to investigate the structure-activity relationships of antioxidants. Accordingly, some rational-design strategies for antioxidants have been proposed and applied in practice. This review summarizes the current knowledge on this topic, which will be helpful to direct the practice in related fields.

Keywords:

antioxidant, radical, structure-activity relationship, rational design

Affiliation:

Shandong Provincial Research Center for Bioinformatic Engineering and Technique, Center forAdvanced Study, Shandong University of Technology, Zibo 255049, P. R. China.

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Discovery of Potent Anti-SARS-CoV MPro Inhibitors

Author(s):

Suzanne Sirois, Rui Zhang, Weina Gao, Hui Gao, Yun Li, Huiqin Zheng and Dong-Qing WeiPages 191-200 (10)

Abstract:

SARS is a viral respiratory illness caused by a previously unrecognized coronavirus, called SARS-associated coronavirus (SARS-CoV). Because of the potential for a rapid spread of the disease, it is vitally important to identify drugs that effectively inhibit a known target of the SARS coronavirus. Because of its essential role in proteolytic processing, the main protease MPro, a cysteine protease, is considered an attractive target for antiviral drugs against SARS and other coronavirus infections. In this review, we will present both peptidic and non-peptidic inhibitors that have been designed against SARS MPro. The most challenging requirement in designing cysteine inhibitors is to obtain a selective non-covalent electrophilic isostere that can react with the catalytic nucleophile. Emphasis will be put on our recent results, both experimental and theoretical, in the search for potent wide-spectrum inhibitors. The antiviral activity of the octopeptide AVLQSGFR against SARS-associated coronavirus will be presented as well as the recent hits obtained from virtual high throughput screening (vHTS) based on the identification of six hydrogen bond pharmacophore points from KZ7088 docked into the active site of SARS MPro.

Keywords:

SARS, severe acute respiratory syndrome, coronavirus main proteinase, KZ7088, pharmacophore search, binding pocket, computer-assisted drug design, docking, virtual screening

Affiliation:

College of Life Science and Technology, Shanghai Jiaotong University, 800 Dongchuan Road,Minhang District, Shanghai, 200240, China.

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Structure-Guided Design of Antibodies

Author(s):

Justin A. Caravella, Deping Wang, Scott M. Glaser and Alexey LugovskoyPages 128-138 (11)

Abstract:

Monoclonal antibodies capable of recognizing antigens with high affinity and specificity represent a wellestablished class of biological agents. Since the development of hybridoma technology in 1975, advances in recombinant DNA technologies and computational and biophysical methods have allowed us to develop a better understanding of the relationships between antibody sequence, structure, and function. These advances enable us to manipulate antibody sequences with the goal of improving upon, or creating new biological or biophysical properties. In this review we will focus on recent successes in using structure-guided computational methods to design antibodies and antibody-like molecules with optimized affinity and specificity to antigen and for enhancing protein stability.

Keywords:

Antibody engineering, structure-based design, affinity maturation, effector function, protein stability

Affiliation:

Physical Biochemistry, Drug Discovery, Biogen Idec Inc., 14 Cambridge Center, Cambridge, MA 02142, USA.

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Antiprotozoal Nitazoxanide Derivatives: Synthesis, Bioassays and QSAR Study Combined with Docking for Mechanistic Insight

Author(s):

Thomas Scior, Jorge Lozano-Aponte, Subhash Ajmani, Eduardo Hernández-Montero, Fabiola Chávez-Silva, Emanuel Hernández-Núñez, Rosa Moo-Puc, Andres Fraguela-Collar and Gabriel Navarrete-VázquezPages 21-31 (11)

Abstract:

In view of the serious health problems concerning infectious diseases in heavily populated areas, we followed the strategy of lead compound diversification to evaluate the near-by chemical space for new organic compounds. To this end, twenty derivatives of nitazoxanide (NTZ) were synthesized and tested for activity against Entamoeba histolytica parasites. To ensure drug-likeliness and activity relatedness of the new compounds, the synthetic work was assisted by a quantitative structure-activity relationships study (QSAR). Many of the inherent downsides – well-known to QSAR practitioners – we circumvented thanks to workarounds which we proposed in prior QSAR publication. To gain further mechanistic insight on a molecular level, ligand-enzyme docking simulations were carried out since NTZ is known to inhibit the protozoal pyruvate ferredoxin oxidoreductase (PFOR) enzyme as its biomolecular target.

Keywords:

3D-QSAR, 4D-QSAR, 5D-QSAR, mathematical regularization, nitrothiazole, PFOR, QSAR pitfalls, tizoxanide.

Affiliation:

Department of Pharmacy, Facultad de Ciencias Químicas, Benemérita Universidad Autónoma de Puebla, Ciudad Universitaria, Edificio 105 C/106, C.P. 72570 Puebla, PUE., Mexico

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Current Status of Computer-Aided Drug Design for Type 2 Diabetes

Author(s):

Shabana Bibi and Katsumi SakataPages 167-177 (11)

Abstract:

Background: Diabetes is a metabolic disorder that requires multiple therapeutic approaches. The pancreas loses its functionality to properly produce the insulin hormone in patients with diabetes mellitus. In 2012, more than one million people worldwide died as a result of diabetes, which was the eighth leading cause of death.

Objective: Most drugs currently available and approved by the U.S. Food and Drug Administration cannot reach an adequate level of glycemic control in diabetic patients, and have many side effects; thus, new classes of compounds are required. Efforts based on computer-aided drug design (CADD) can mine a large number of databases to produce new and potent hits and minimize the requirement of time and dollars for new discoveries.

Methods: Pharmaceutical sciences have made progress with advances in drug design concepts. Virtual screening of large databases is most compatible with different computational methods such as molecular docking, pharmacophore, quantitative structure-activity relationship, and molecular dynamic simulation. Contribution of these methods in selection of antidiabetic compounds has been discussed.

Results: The Computer-Aided Drug Design (CADD) approach has contributed to successful discovery of novel antidiabetic agents. This mini-review focuses on CADD approach on currently approved drugs and new therapeutic agents-indevelopment that may achieve suitable glucose levels and decrease the risk of hypoglycemia, which is a major obstacle to glucose control and a special concern for therapies that increase insulin levels.

Conclusion: Drug design and development for type 2 diabetes have been actively studied. However, a large number of antidiabetic drugs are still in early stages of development. The conventional target- and structure-based approaches can be regarded as part of the efforts toward therapeutic mechanism-based drug design for treatment of type 2 diabetes. It is expected that further improvement in CADD approach will enhance the new discoveries.

Keywords:

Computer-aided drug design, diabetes mellitus, FDA-approved therapeutic options, glucose level, hypoglycemia, therapeutic mechanism-based drug design.

Affiliation:

Department of Environment and Life Engineering, Graduate School of Engineering, Maebashi Institute of Technology, Maebashi, Gunma 371-0816, Japan.

Graphical Abstract:

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