Flexible docking of pyridinone derivatives into the non-nucleoside inhibitor binding site of HIV-1 reverse transcriptase

Medina‐Franco, José L.; Rodrı́guez-Morales, Sergio; Juarez‐Gordiano, Cecilia; Hernández‐Campos, Alicia; Jiménez‐Barbero, Jesús; Castillo, Rafael

doi:10.1016/j.bmc.2004.09.008

Cited by 12 publications

(16 citation statements)

References 45 publications

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“…[32] Docking results showed a good agreement with previous 2D-QSAR studies. According to the binding model, pyridinone analogues adopt a butterfly-like conformation in the binding pocket, a common feature of several NNRTIs, [6] and have a similar binding mode to other NNRTIs such as nevirapine (Figure 3).…”

Section: Discovery and Developmentsupporting

confidence: 84%

“…[32] Noteworthy, the binding model for 8 was proposed before the crystal structures of HIV-1 RT in complex with other pyridinone-HEPT hybrids were published (vide infra). Docking results showed that both hybrids adopt a butterflylike conformation into the binding pocket.…”

Section: Pyridinone-efavirenz and -Hept Hybrids: Modelling Studies Anmentioning

confidence: 99%

“…According to the binding model, pyridinone analogues adopt a butterfly-like conformation in the binding pocket, a common feature of several NNRTIs, [6] and have a similar binding mode to other NNRTIs such as nevirapine (Figure 3). [32] The docking model suggested a key interaction that helps the stabilization of the pyridin-2(1H)-one ring into the NNRTI pocket, namely hydrogen bonding of the nitrogen at the pyridinone ring with the main chain oxygen of K101. From the binding model it was also concluded that hydrophobic contacts between the aromatic ring of Y181 and the benzoxazole ring of the potent Merck pyridinones may stabilize the complex and also be responsible for the decrease in activity upon mutation of this residue.…”

Section: Discovery and Developmentmentioning

confidence: 99%

“…It was also predicted that the N-dimethyl substituent of 8 occupys the same binding pocket as the linker of Merck pyridinones. [32] In a recent work, compounds 8 and R157208 (10) were manually docked into the NNRTIs binding pocket and the derived models were geometrically optimized. [24] Results suggested that both molecules bind in the same general orientation as that previously calculated for 8.…”

Section: Pyridinone-efavirenz and -Hept Hybrids: Modelling Studies Anmentioning

confidence: 99%

“…From the binding model it was also concluded that hydrophobic contacts between the aromatic ring of Y181 and the benzoxazole ring of the potent Merck pyridinones may stabilize the complex and also be responsible for the decrease in activity upon mutation of this residue. [32] Automated docking studies were extended to a series of 40 Merck pyridinones. Docked conformations were the starting point of three-dimensional quantitative structure-activity relationship analyses (3D-QSAR).…”

Section: Discovery and Developmentmentioning

confidence: 99%

See 4 more Smart Citations

Pyridin‐2(1H)‐ones: A Promising Class of HIV‐1 Non‐nucleoside Reverse Transcriptase Inhibitors

Medina‐Franco¹,

Martínez‐Mayorga²,

Juarez‐Gordiano³

et al. 2007

ChemMedChem

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Section: Discovery and Developmentsupporting

confidence: 84%

Section: Pyridinone-efavirenz and -Hept Hybrids: Modelling Studies Anmentioning

confidence: 99%

Section: Discovery and Developmentmentioning

confidence: 99%

Section: Pyridinone-efavirenz and -Hept Hybrids: Modelling Studies Anmentioning

confidence: 99%

Section: Discovery and Developmentmentioning

confidence: 99%

See 3 more Smart Citations

Pyridin‐2(1H)‐ones: A Promising Class of HIV‐1 Non‐nucleoside Reverse Transcriptase Inhibitors

Medina‐Franco¹,

Martínez‐Mayorga²,

Juarez‐Gordiano³

et al. 2007

ChemMedChem

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Quantitative Structure–activity Relationship Analysis of Pyridinone HIV-1 Reverse Transcriptase Inhibitors using the k Nearest Neighbor Method and QSAR-based Database Mining

Medina‐Franco

Gelbukh

Oloff

et al. 2005

J Comput Aided Mol Des

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We have developed quantitative structure-activity relationship (QSAR) models for 44 non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs) of the pyridinone derivative type. The k nearest neighbor (kNN) variable selection approach was used. This method utilizes multiple descriptors such as molecular connectivity indices, which are derived from two-dimensional molecular topology. The modeling process entailed extensive validation including the randomization of the target property (Y-randomization) test and the division of the dataset into multiple training and test sets to establish the external predictive power of the training set models. QSAR models with high internal and external accuracy were generated, with leave-one-out cross-validated R2 (q2) values ranging between 0.5 and 0.8 for the training sets and R2 values exceeding 0.6 for the test sets. The best models with the highest internal and external predictive power were used to search the National Cancer Institute database. Derivatives of the pyrazolo[3,4-d]pyrimidine and phenothiazine type were identified as promising novel NNRTIs leads. Several candidates were docked into the binding pocket of nevirapine with the AutoDock (version 3.0) software. Docking results suggested that these types of compounds could be binding in the NNRTI binding site in a similar mode to a known non-nucleoside inhibitor nevirapine.

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Design and synthesis of novel 5,6-disubstituted pyridine-2,3-dione-3-thiosemicarbazone derivatives as potential anticancer agents

Xie

Zhou

et al. 2014

European Journal of Medicinal Chemistry

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Flexible docking of pyridinone derivatives into the non-nucleoside inhibitor binding site of HIV-1 reverse transcriptase

Cited by 12 publications

References 45 publications

Pyridin‐2(1H)‐ones: A Promising Class of HIV‐1 Non‐nucleoside Reverse Transcriptase Inhibitors

Pyridin‐2(1H)‐ones: A Promising Class of HIV‐1 Non‐nucleoside Reverse Transcriptase Inhibitors

Quantitative Structure–activity Relationship Analysis of Pyridinone HIV-1 Reverse Transcriptase Inhibitors using the k Nearest Neighbor Method and QSAR-based Database Mining

Design and synthesis of novel 5,6-disubstituted pyridine-2,3-dione-3-thiosemicarbazone derivatives as potential anticancer agents

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