Three Dimensional Pharmacophore Modeling of Human CYP17 Inhibitors. Potential Agents for Prostate Cancer Therapy

Clement, Omoshile; Freeman, C. M.; Hartmann, Rolf W.; Handratta, Venkatesh; Vasaitis, Tadas S.; Brodie, Angela; Njar, Vincent C.O.

doi:10.1021/jm020576u

Cited by 77 publications

(40 citation statements)

References 23 publications

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“…This shows the potential of our pharmacophore model in identifying new and potent CYP17 inhibitors. Further refinement of the model is in progress with a view to identify and optimize new leads [44].…”

Section: Three Dimensional Pharmacophore Modeling Of Human Cyp17 Inhimentioning

confidence: 99%

QSAR and its Role in Target-Ligand Interaction

Singh¹,

Singh²

2013

TOBIOIJ

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Each molecule has its own specialty, structure and function and when these molecules are combined together they form a compound. Structure and function of a molecule are related to each other and QSARs (Quantitative StructureActivity relationships) are based on the criteria that the structure of a molecule must contain the features responsible for its physical, chemical, and biological properties, and on the ability to represent the chemical by one, or more, numerical descriptor(s). By QSAR models, the biological activity of a new or untested chemical can be inferred from the molecular structure of similar compounds whose activities have already been assessed. QSARs attempt to relate physical and chemical properties of molecules to their biological activities. For this there are so many descriptors (for example, molecular weight, number of rotatable bonds, Log P) and simple statistical methods such as Multiple Linear Regression (MLR) are used to predict a model. These models describe the activity of the data set and can predict activities for further sets of (untested) compounds. These types of descriptors are simple to calculate and allow for a relatively fast analysis. 3D-QSAR uses probe-based sampling within a molecular lattice to determine three-dimensional properties of molecules (particularly steric and electrostatic values) and can then correlate these 3D descriptors with biological activity. Physicochemical descriptors, include hydrophobicity, topology, electronic properties, and steric effects etc. These descriptors can be calculated empirically, statistically or through more recent computational methods. QSARs are currently being applied in many disciplines, with many pertaining to drug design and environmental risk assessment.

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Section: Three Dimensional Pharmacophore Modeling Of Human Cyp17 Inhimentioning

confidence: 99%

QSAR and its Role in Target-Ligand Interaction

Singh¹,

Singh²

2013

TOBIOIJ

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“…Абиратерон внедрён в клиническую практику в 2011 году в качестве препарата для лечения рака предстательной железы. Для стероидных ингибиторов CYP17A1 был разработан фармакофор [6], позволяющий предсказывать биологическую активность новых соединений. В 2012 году была определена пространственная структура комплексов CYP17A1 с абиратероном и галетероном [7].…”

Section: Introductionunclassified

Steroidal Inhibitors of CYP17A1 as a Template For Novel Anti-Cancer Agents Development

Latysheva

Misharin

2018

BMCRM

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This review deals with studies of researches of novel CYP17A1 steroidal inhibitors and relative compounds published over the last ten years. The review contains six chapters in which novel targets of well-known CYP17A1 inhibirors (abiraterone and galeterone), anti-cancer and anti-proliferative activities of them major metabolites and new synthetic analogs, and in addition another nitrogen-containing androstane and pregnane derivatives are considered. In the review 354 structures of novel steroid derivatives and them anti-cancer efficiency data are considered. Analysis of the literature data allows us to consider steroidal inhibitors of CYP17A1 as multi-target anti-cancer agents with high pharmacological potential.

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“…СYP17А1 катализирует 17a-гидроксилирование стероидного субстрата (прегненолона или прогестерона) и последующее образование андрогена (дегидроэпиандростерона или андростендиона) [2][3][4][5][6]. Mногие производные стероидов, модифицированные в кольце D азотсодержащими гетероциклами, являются эффективными и специфичными ингибиторами СYP17А1 [7][8][9][10][11][12][13], а андрост-5-ен-17-(3-пиридил)-3b-ол (препарат "абиратерон") рекомендован к широкому применению в качестве лекарства для лечения рака простаты.…”

Section: Introductionunclassified

“…Для стероидных ингибиторов CYP17А1 был предложен фармакофор [13,14], который включал следующие элементы: (i) наличие азотсодержащего заместителя при С17, в котором неподеленная электронная пара локализована на атоме азота; (ii) подходящая пространственная ориентация двух групп, способных к образованию водородной связи (3b-OH и атома азота в С17-заместителе), относительно стероидного ядра; (iii) отсутствие атома водорода при C-17; (iv) наличие гидрофобных заместителей с b-стороны стероидного фрагмента.…”

Section: Introductionunclassified

“…Ранее было показано, что 2'-{[(E)-3b-гидроксиандрост-5-ен-17-илиден]-метил}-4',5'-дигидро-1',3'-оксазол 1 связывается с рекомбинантным препаратом CYP17A1 и ингибирует каталитическую активность фермента подобно абиратерону [17]. В работе [18] [2][3][4][5][6][7][8][9][10][11][12][13].…”

Section: Introductionunclassified

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Interaction of novel oxazoline derivatives of 17(20)e-pregna-5,17(20)-diene with cytochrome P450 17A1

et al. 2016

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In order to find novel inhibitors of 17a-hydroxylase-17,20-lyase (cytochrome P450 17A1, CYP17A1), a key enzyme of biosynthesis of androgens, molecular docking of six new oxazoline-containing derivatives 17(20)E-pregna-5,17(20)-diene has been carried out to the active site of the crystal structure of CYP17A1 (pdb 3ruk). Results of this study indicate that: 1) complex formation of docked compounds with CYP17A1 causes their isomerization in energetically less favorable 17(20)Z-isomer; 2) the localization of the steroid moiety of all compounds in the active site is basically the same; 3) the structure of the oxazoline moiety significantly influences its position relative to heme as well as the energy of complex formation; 4) coordination of the nitrogen atom of the oxazoline moiety and the heme iron is only possible in the 17(20)Z-conformation with anti oriented double bonds 17(20), and C=N; 5) the presence of two substituents at C4' of the oxazoline moiety significantly impairs ligand binding; 6) oxazoline - and benzoxazole-containing derivatives 17(20)E-pregna-5,17(20)-diene can effectively inhibit the catalytic activity CYP17A1 and may be of interest as a basis for the development of new drugs for the treatment of androgen-dependent cancer.

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Three Dimensional Pharmacophore Modeling of Human CYP17 Inhibitors. Potential Agents for Prostate Cancer Therapy

Cited by 77 publications

References 23 publications

QSAR and its Role in Target-Ligand Interaction

QSAR and its Role in Target-Ligand Interaction

Steroidal Inhibitors of CYP17A1 as a Template For Novel Anti-Cancer Agents Development

Interaction of novel oxazoline derivatives of 17(20)e-pregna-5,17(20)-diene with cytochrome P450 17A1

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