Current Computer-Aided Drug Design

ISSN: 1573-4099

Current Computer-Aided Drug Design
Volume 3, Number 3, September 2007

Contents

Anti-Viral Agents and Emerging Diseases: Part - II
Guest Editor: Supa Hannongbua


Computational Studies of HIV-1 Integrase and its Inhibitors Pp. 160-190
Nadtanet Nunthaboot, Somsak Pianwanit, Vudhichai Parasuk, Sirirat Kokpol and James M. Briggs
[Abstract]


Discovery of Potent Anti-SARS-CoV M^Pro Inhibitors Pp. 191-200
Suzanne Sirois, Rui Zhang, Weina Gao, Hui Gao, Yun Li, Huiqin Zheng and Dong-Qing Wei
[Abstract]


Current Development on HIV-1 Protease Inhibitors Pp. 201-213
Ornjira Aruksakunwong, Siriporn Promsri, Kitiyaporn Wittayanarakul, Piyarat Nimmanpipug, Vannajan S. Lee, Atchara Wijitkosoom, Pornthep Sompornpisut and Supot Hannongbua
[Abstract]


General Article


Molecular Modelling and QSAR in the Discovery of HIV-1 Integrase Inhibitors Pp. 214-233
Anna M. Almerico, Marco Tutone, Mario Ippolito and Antonino Lauria
[Abstract]




Abstracts


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Computational Studies of HIV-1 Integrase and its Inhibitors
Nadtanet Nunthaboot, Somsak Pianwanit, Vudhichai Parasuk, Sirirat Kokpol and James M. Briggs

Integration of the genome of the human immunodeficiency virus (HIV) into that of the host genome is catalyzed by HIV integrase (IN) and is an essential step in HIV-1 life cycle. Therefore, drug discovery efforts have been undertaken to identify selective IN inhibitors with the goal of improving the outcome of AIDS therapy using Highly Active Anti Retroviral Therapy (HAART). As computational technology has grown rapidly and is increasingly being used worldwide to accelerate the drug discovery processes, the aim of this review is to summarize the applications of the computer-aided drug design (CADD) techniques to HIV-1 IN and its inhibitors. The following applications are emphasized, including two- and three-dimensional quantitative structure activity relationships (2D/3D-QSAR), pharmacophore modeling, database searching, molecular docking, molecular dynamics simulations, and de novo methodologies.


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Discovery of Potent Anti-SARS-CoV M^Pro Inhibitors
Suzanne Sirois, Rui Zhang, Weina Gao, Hui Gao, Yun Li, Huiqin Zheng and Dong-Qing Wei

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 M^Pro, 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 M^Pro. 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 M^Pro.


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Current Development on HIV-1 Protease Inhibitors
Ornjira Aruksakunwong, Siriporn Promsri, Kitiyaporn Wittayanarakul, Piyarat Nimmanpipug, Vannajan S. Lee, Atchara Wijitkosoom, Pornthep Sompornpisut and Supot Hannongbua

Although a number of potent and selective inhibitors have been developed and approved as drugs for the treatment of HIV infection, efforts still needed in order to develop new inhibitors that are more potent, have unique resistance patterns, and minimal side effects. This review focuses to the HIV-1 protease (HIV-1 PR), the enzyme belongs to the family of aspartic acid based on the identification of the Asp-Thr-Gly catalytic triad. In the first part, general features of the HIV-1 PR as well as its structure and functions were given. Afterwards, the review was targeted to discovery, characteristic, activity and emergence of drug resistant of the nine FDA (Food and Drug Administration) approval inhibitors, indinavir, saquinavir, nelfinavir, ritonavir, lopinavir, amprenavir, tipranavir, atazanavir and fosamprenavir. In addition, the two promising inhibitors (brecanavir, darunavir), which are currently under development, as well as a competitive non-peptide based inhibitors (water soluble C60 derivatives) were also introduced.


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Molecular Modelling and QSAR in the Discovery of HIV-1 Integrase Inhibitors
Anna M. Almerico, Marco Tutone, Mario Ippolito and Antonino Lauria

The treatment regimens for the HIV-1 have mainly included reverse transcriptase or protease inhibitors but their long-term clinical utility is limited by severe side effects and viral drug resistance. A new attractive target for chemotherapeutic intervention can be the Integrase enzyme, that mediates the integration of HIV-1 DNA into a host chromosome, for which there is no known counterparts in the host cell. A number of derivatives have been found to inhibit IN in in vitro assays, but no successful drug based on them has emerged so far, although many compounds have been proposed. Moreover most of the inhibitors do not belong to a very precise structural class: this fact makes these compounds a suitable target to be approached by all QSAR methods (classical and 3D) which therefore have been used to study the IN inhibitors. This review focuses on the molecular basis and rationale for developing integrase inhibitors and assesses the literature results of the chemometric study on classes of these inhibitors. Rational drug design by mean of the pharmacophore approach, rigid and flexible docking methods, and de novo design contributed to the identification of the most promising class of inhibitors, the DKAs. Moreover molecular dynamics studies were included since they can contribute to give further insight into the inhibitors binding modes already explored by means of the docking simulations.