N1-Alkyl pyrimidinediones as non-nucleoside inhibitors of HIV-1 reverse transcriptase

Mitchell, Michael; Son, Jae Cheol; Guo, Hongyan; Im, Yun-A; Cho, Eun Jung; Wang, Jianhong; Hayes, Jaclyn; Wang, Michael; Paul, Amber M.; Lansdon, E.B.; Chen, James M.; Graupe, Doris; Rhodes, Gerry; He, Gong-Xin; Geleziunas, Romas; Xu, Lianhong; Kim, Choung U.

doi:10.1016/j.bmcl.2010.01.085

Cited by 17 publications

(2 citation statements)

References 14 publications

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“…The application of HSA models to congeneric series is also more relevant to practical application in the context of lead optimization. Seven congeneric series with data on HSA binding affinity were available: aminoindans [55], diflunisal analogues [54], flavonoids [58], indole-3-acetic acid analogues [57], N1-alkyl pyrimidinediones [56], quinolones [59], and 2-(R)-phenylproionamides [54]. The results for the largest data set, indole-3-acetic acid analogues, are shown in Figure 7.…”

Section: Resultsmentioning

confidence: 99%

A Structure-Based Model for Predicting Serum Albumin Binding

2014

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One of the many factors involved in determining the distribution and metabolism of a compound is the strength of its binding to human serum albumin. While experimental and QSAR approaches for determining binding to albumin exist, various factors limit their ability to provide accurate binding affinity for novel compounds. Thus, to complement the existing tools, we have developed a structure-based model of serum albumin binding. Our approach for predicting binding incorporated the inherent flexibility and promiscuity known to exist for albumin. We found that a weighted combination of the predicted logP and docking score most accurately distinguished between binders and nonbinders. This model was successfully used to predict serum albumin binding in a large test set of therapeutics that had experimental binding data.

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Section: Resultsmentioning

confidence: 99%

A Structure-Based Model for Predicting Serum Albumin Binding

2014

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“…The less potent HEPT inhibitor, containing a small methyl group at the 5 position, is observed to bind the NNIBP and induce rotation of only Tyr188, while the more potent HEPT derivatives MKC-442 and TNK-651 contain larger isopropyl groups at the 5 position and induce conformational switching of both Tyr188 and Tyr181, resulting in an increase in favorable aromatic interactions and thus tighter binding. However, in their investigation of a closely related series of pyrimidinediones containing isopropyl groups at the 5 position, Mitchell et al observe that substitution of the smaller ethyl substituents at the 1 position induce rotation of only Tyr188 without a significant loss in inhibitor potency relative to the bulkier N 1 substituted inhibitors [32]. The comparative structural analysis of compounds 1 and 2 representative of the DATA class of NNRTIs presented here suggests the conformational switching of Tyr181 does not impact the binding affinity.…”

Section: Resultsmentioning

confidence: 99%

A mechanistic and structural investigation of modified derivatives of the diaryltriazine class of NNRTIs targeting HIV-1 reverse transcriptase

Mislak

Frey

Bollini

et al. 2014

Biochimica et Biophysica Acta (BBA) - General Subjects

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Background Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are vital in treating HIV-1 infection by inhibiting reverse transcriptase (RT). Drug toxicity and resistance drive the need for effective new inhibitors with improved physiochemical properties and potent antiviral activity. Computer-aided and structure-based drug design have guided the addition of solubilizing substituents to the diaryltriazine scaffold. These derivatives have markedly improved solubility and maintain low nanomolar antiviral activity against RT. The molecular and structural basis of inhibition for this series was determined to facilitate future inhibitor development with improved pharmacological profiles. Methods The molecular mechanism of inhibition was investigated using transient-state kinetic analysis. Crystal structures of RT in complex with each inhibitor were obtained to investigate the structural basis of inhibition. Results The diaryltriazine and its morpholine derivative have RT inhibition constants of 9±2 nM and 14±4 nM, respectively. They adopt differential binding modes within the non-nucleoside inhibitor binding pocket to distort the catalytic site geometry and primer grip regions. The novel morpholinopropoxy substituent extends into the RT/solvent interface of the NNIBP. Conclusions Kinetic and structural analyses show that these inhibitors behave as conventional NNRTIs and inhibit the polymerization step. This study confirms appending solubilizing substituents on the azine ring of diaryltriazine class of NNRTIs that extend into the RT/solvent interface effectively maintains low nanomolar potency and improves physiochemical properties. General Significance The modification of NNRTI scaffolds with solubilizing substituents, which extend into the RT/solvent interface, yields potent antivirals and is an effective strategy for developing novel inhibitors with improved pharmacological properties.

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Di-tert-butyl Chloromethyl Phosphate

Minozzi

Collins

2017

Encyclopedia of Reagents for Organic Synthesis

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N1-Alkyl pyrimidinediones as non-nucleoside inhibitors of HIV-1 reverse transcriptase

Cited by 17 publications

References 14 publications

A Structure-Based Model for Predicting Serum Albumin Binding

A Structure-Based Model for Predicting Serum Albumin Binding

A mechanistic and structural investigation of modified derivatives of the diaryltriazine class of NNRTIs targeting HIV-1 reverse transcriptase

Di-tert-butyl Chloromethyl Phosphate

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