Neeraj Mahindroo

Severe acute respiratory syndrome coronavirus (SARS-CoV) main protease (M(pro)), a protein required for the maturation of SARS-CoV, is vital for its life cycle, making it an attractive target for structure-based drug design of anti-SARS drugs. The structure-based virtual screening of a chemical database containing 58,855 compounds followed by the testing of potential compounds for SARS-CoV M(pro) inhibition leads to two hit compounds. The core structures of these two hits, defined by the docking study, are used for further analogue search. Twenty-one analogues derived from these two hits exhibited IC50 values below 50 microM, with the most potent one showing 0.3 microM. Furthermore, the complex structures of two potent inhibitors with SARS-CoV M(pro) were solved by X-ray crystallography. They bind to the protein in a distinct manner compared to all published SARS-CoV M(pro) complex structures. They inhibit SARS-CoV M(pro) activity via intensive H-bond network and hydrophobic interactions, without the formation of a covalent bond. Interestingly, the most potent inhibitor induces protein conformational changes, and the inhibition mechanisms, particularly the disruption of catalytic dyad (His41 and Cys145), are elaborated.

The design of novel anticancer agents based on the combretastatins, a group of antimitotic agents isolated from the bark of the South African willow tree Combretum caffrum Kuntz, is of considerable contemporary interest. Combretastatin A-4, the most active compound in the group, due to its unique dual features of antitubulin and antivascular properties, has drawn significant attention of medicinal chemists for the design of analogues as novel antitumor agents. To date, 252 references have been published since 1982 and 187 references have been published since 1998 related to combretastatins research. The 102 references related to chemistry efforts can be classified into three different categories including one-atom, two-atom, and three-atom bridgeheads as linker between two aryl rings of combretastatins. This review will particularly elucidate the rationale and strategic tactics towards the development of novel classes of antimitotic agents, based upon combretastatin A-4 as a promising lead.

ADVERTISEMENT RETURN TO ISSUEPerspectiveNEXTHedgehog-Gli Signaling Pathway Inhibitors as Anticancer AgentsNeeraj Mahindroo*, Chandanamali Punchihewa, and Naoaki FujiiView Author Information Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis 38105, Tennessee* To whom correspondence should be addressed. Phone: (+1) 901 595 5871. Fax: (+1) 901 595 5715. E-mail: [email protected]Cite this: J. Med. Chem. 2009, 52, 13, 3829–3845Publication Date (Web):March 23, 2009Publication History Received10 November 2008Published online23 March 2009Published inissue 9 July 2009https://pubs.acs.org/doi/10.1021/jm801420yhttps://doi.org/10.1021/jm801420yreview-articleACS PublicationsCopyright © 2009 American Chemical SocietyRequest reuse permissionsArticle Views5650Altmetric-Citations127LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InRedditEmail Other access optionsGet e-Alertsclose SUBJECTS:Cancer,Cell signaling,Cells,Genetics,Inhibitors Get e-Alerts

Solid cancers are one of the leading causes of cancer related deaths, characterized by rapid growth of tumour, and local and distant metastases. Current advances on multimodality care have substantially improved local control and metastasis-free survival of patients by resection of primary tumour. The major concern in disease prognosis is the timely detection of resectable or metastatic tumour, thus reinforcing the need for identification of biomarkers for premalignant lesions of solid cancer. This ultimately improves the outcome for the patients. Therefore, the purpose of this review is to update the recent advancements on prognostic and diagnostic biomarkers to enhance early detection of common solid cancers including, breast, lung, colorectal, prostate and stomach cancer. We also provide an insight into Food and Drug Administration (FDA)-approved solid cancers biomarkers; various conventional techniques used for detection of prognostic and diagnostic biomarkers and discuss approaches to turn challenges in this field into opportunities.

Peroxisome proliferator-activated receptor gamma (PPARgamma) is well-known as the receptor of thiazolidinedione antidiabetic drugs. In this paper, we present a successful example of employing structure-based virtual screening, a method that combines shape-based database search with a docking study and analogue search, to discover a novel family of PPARgamma agonists based upon pyrazol-5-ylbenzenesulfonamide. Two analogues in the family show high affinity for, and specificity to, PPARgamma and act as partial agonists. They also demonstrate glucose-lowering efficacy in vivo. A structural biology study reveals that they both adopt a distinct binding mode and have no H-bonding interactions with PPARgamma. The absence of H-bonding interaction with the protein provides an explanation why both function as partial agonists since most full agonists form conserved H-bonds with the activation function helix (AF-2 helix) which, in turn, enhances the recruitment of coactivators. Moreover, the structural biology and computer docking studies reveal the specificity of the compounds for PPARgamma could be due to the restricted access to the binding pocket of other PPAR subtypes, i.e., PPARalpha and PPARdelta, and steric hindrance upon the ligand binding.