Discovery of new cholesteryl ester transfer protein inhibitors via ligand-based pharmacophore modeling and QSAR analysis followed by synthetic exploration

Khalaf, Reema Abu; Sheikha, Ghassan Abu; Bustanji, Yasser; Taha, Mutasem O.

doi:10.1016/j.ejmech.2009.12.070

Cited by 56 publications

(73 citation statements)

References 53 publications

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“…The genus Leishmania is trypanosomatid protozoa and parasitic in nature which causes the disease known as leishmaniasis, which infects some 15 million people around the world in three clinical forms: cutaneous, mucocutaneous and visceral [23][24][25] . Current therapies for the disease are associated with a risk of high toxicity and development of drug resistant strains.…”

Section: Resultsmentioning

confidence: 99%

“…activities and properties of interest) of a series of molecules with their structural properties. It is a dynamic area that integrates new technologies at a staggering rate [25,26] . In the present study, we address the performance of a computer aided drug design protocol involving homology modeling of trypanothione reductase and structure based virtual screening as a tool for identifying novel classes of potent trypanothione reductase inhibitors.…”

Section: Resultsmentioning

confidence: 99%

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In Silico Analyses of Epicoccamides on Selected Leishmania Trypanothione Reductase Enzyme-based Target

Fatima¹,

Mumtaz²

2016

ijps

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Fatima, et al.: In silico analyses of epicoccamides on Leishmania trypanothione-reductase Leishmaniasis is a protozoal infection, which presents a broad spectrum drug resistance and causes diseases ranging from asymptomatic infections to significant mortality. The enzyme, trypanothione reductase from Leishmania infantumis is essential for the parasite survival. It is an attractive target to design new less toxic drugs against leishmaniasis as found absent in mammalian cells. The antileishmanial activity of epicoccamide derivatives was studied by in silico approaches. The crystallographic structure of trypanothione reductase was obtained from the protein data bank (ID: 2W0H) database. Binding mode of the epicoccamide inhibitors showed that they are stabilized in the active site of enzyme through hydrogen bond and hydrophobic interactions. These derivatives (A-D) showed significant binding affinities with trypanothione reductase with binding energies: -13.21, -13.44, -13.31, and -13.52 kcal/mol, respectively.The present study revealed new and effective antileishmanial compounds that can gain pharmaceutical importance.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

In Silico Analyses of Epicoccamides on Selected Leishmania Trypanothione Reductase Enzyme-based Target

Fatima¹,

Mumtaz²

2016

ijps

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“…15,[35][36][37][38] Thus, a classical QSAR analysis was employed to search for the best combination of orthogonal pharmacophores using a fit value and other structural descriptors (connectivity, topological, etc.) capable of explaining bioactivity variation across a collected list of the descriptors, allowing different pharmacophoric models competing within the 3D-QSAR framework.…”

Section: Resultsmentioning

confidence: 99%

Facile Synthesis and Quantitative Structure–Activity Relationship Study of Antitumor Active 2-(4-Oxo-thiazolidin-2-ylidene)-3-oxo-propionitriles

Hanna

George

2012

CHEMICAL & PHARMACEUTICAL BULLETIN

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2-(5-Arylidene-4-oxo-3-phenyl-thiazolidin-2-ylidene)-3-oxo-propionitriles 4a-j were prepared via condensation of aromatic aldehydes with 4-thiazolidinones 3a, b. The latter was obtained via electrophilic attack of phenylisothiocyanate on 3-oxo-propionitriles 1a, b followed by reaction with chloroacetyl chloride under basic condition. Additionally, 2-(5-heteroalicyclic methylene) analogues 5a-h were prepared via Mannich reaction of the appropriate secondary amines and formaldehyde with 4-thiazolidinones 3a, b. Many of the synthesized compounds exhibited promising antitumor properties against colon HCT116 and breast T47D cell lines. 3D-Pharmacophore modeling and quantitative structure-activity relationship (QSAR) analysis were combined to explain the observed antitumor properties.Key words thiazolidinone; quantitative structure-activity relationship; antitumor activity; 3-oxo-propionitrile; HCT116; T47D Cancer ranks second in diseases leading to mortality, following only cardiovascular diseases. One-quarter of all deaths in the United States are caused by cancer.1) Out of the many cancer diseases, breast cancer is the most prevalent cancer in women and represents the second highest leading cause of cancer death in this population after lung cancer.2) Colorectal cancer is the third most common cancer in both men and women, 91% of cases are diagnosed in individuals 50 years of age and older. 1) Chemotherapy is widely used to treat and control cell growth and limit the spread of cancer cells to other sites. Although, there is a success with certain forms of cancer, drug therapy has only limited impact against the three major killers: carcinoma of lung, breast and colorectal system. Therefore, there is a need to develop novel antitumor agents to treat and combat this disease.Several promising antitumor agents containing thiazolidine and thiazolidinone scaffolds have been identified to have a broad range of anticancer activities.3-14) Previously, we reported promising antitumor properties of a variety of 5-arylidene thiazolidinone derivatives Ia-c (Fig. 1) exhibiting considerable cytotoxic activity against colon HCT116 cancer cell lines compared with Doxorubicin (reference standard, IC 50 =0.00686 mM).15) In continuation of these previous findings and in order to optimize novel antitumor active agents possessing the same thiazolidinone core, it is intended in the present work to perform some modifications in the adopted structures via inserting heteroalicyclic amines (morpholinyl or piperidinyl functions, 4a-j) instead of the aromatic amines Ia-c due to their hydrophilic properties. Moreover, a series of heteroalicyclic methylene containing compounds 5a-h will be also prepared replacing the arylidene moiety of Ia-c (Fig. 1). Additionally, many morpholine and piperidine containing compounds were known as anticancer active agents that exerted their actions via inhibition of different targets such as phosphatidylinositol 3-kinases (PI3Ks) and histone deacetylase (HDAC). [16][17][18][19][20] Moreover, the piperidine deriva...

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“…CATALYST pharmacophores have been used as 3D queries for database searching and in 3D-QSAR studies. [54][55][56][57][58][59][60][61][62][63][64][65][66] Although pharmacophore modeling employing HYPOGEN has been heavily reviewed in the literature, [68][69][70][71][72][73][74][75][76] a brief discussion of this algorithm is provided herein to allow better readability of the chapter.…”

Section: The Algorithmmentioning

confidence: 99%

“…We previously reported the successful use of this combination to probe the induced fit flexibilities of activated factor X 53 and towards the discovery of new inhibitory leads against glycogen synthase kinase-3β, 54 bacterial MurF, 55 protein tyrosine phosphatase, 56 DPP IV, 57 hormone sensitive lipase, 58 β-secretase, 59 influenza neuraminidase, 60 cholesteryl ester transfer protein, 61 cycline dependent kinase, 62 Heat shock protein, 63 estrogen receptor β, 64 β-D-Glucosidase, 65 and β-D-Galactosidase. 66 The author intends in this chapter to discuss the basic theoretical principles of this successful ligand-based approach and to provide interested audiences with experimental details related to this approach.…”

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confidence: 99%

Mixing Pharmacophore Modeling and Classical QSAR Analysis as Powerful Tool for Lead Discovery

Taha¹

2012

Virtual Screening

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Discovery of new cholesteryl ester transfer protein inhibitors via ligand-based pharmacophore modeling and QSAR analysis followed by synthetic exploration

Cited by 56 publications

References 53 publications

In Silico Analyses of Epicoccamides on Selected Leishmania Trypanothione Reductase Enzyme-based Target

In Silico Analyses of Epicoccamides on Selected Leishmania Trypanothione Reductase Enzyme-based Target

Facile Synthesis and Quantitative Structure–Activity Relationship Study of Antitumor Active 2-(4-Oxo-thiazolidin-2-ylidene)-3-oxo-propionitriles

Mixing Pharmacophore Modeling and Classical QSAR Analysis as Powerful Tool for Lead Discovery

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