A QSAR study investigating the effect of l-alanine ester variation on the anti-HIV activity of some phosphoramidate derivatives of d4T

Knaggs, Michael H.; McGuigan, Christopher; Harris, Stephanie J.; Heshmati, Parissa; Cahard, Dominique; Gilbert, Ian H.; Balzarini, Jan

doi:10.1016/s0960-894x(00)00397-8

Cited by 18 publications

(19 citation statements)

References 6 publications

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“…At the training stage, TRAIL excluded 11 compounds containing unique fragments (occurs only in one compound), thus reducing the three training sets to 66 compounds (Table 1). Three best fit models were selected: I(AB, , I(AB, [3][4], and I(AB, 2-4) coupled with fitting eq 1 for which R 2 ) 0.85-0.92, s ) 0.61-0.89, F ) 3-7, Q 2 ) 0.50-0.74, and FIT ) 0.1-0.2 ( Table 2). It should be noted that poor fitting results were obtained for compounds 31 and 44 (residuals are about 1.3-1.7).…”

Section: Structure-propertymentioning

confidence: 99%

Anti-HIV Activity of HEPT, TIBO, and Cyclic Urea Derivatives: Structure−Property Studies, Focused Combinatorial Library Generation, and Hits Selection Using Substructural Molecular Fragments Method

Solov'ev

Varnek

2003

J. Chem. Inf. Comput. Sci.

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Substructural molecular fragments (SMF) method [Solov'ev, V. P.; Varnek, A.; Wipff, G. J. Chem. Inf. Comput. Sci. 2000, 40, 847-858] was applied to assess anti-HIV activity for large data sets for three families of compounds: 1-[2-hydroxyethoxy)methyl]-6-(phenylthio)thymine (HEPT) derivatives, tetrahydroimidazobenzodiazepinone (TIBO) derivatives, and cyclic urea (CU) derivatives. The SMF method uses 49 types of topological descriptors (atom/bond sequences and "augmented atoms") which, being coupled with 3 linear and nonlinear fitting equations, allows the user to generate up to 147 structure-property models. For each family of compounds, the modeling was performed on several training sets followed by the validation calculations where three best fit models were applied. Calculated activities well reproduce available experimental data. On the basis of the "optimal" molecular fragments, the focused combinatorial library containing 252 virtual HEPT derivatives has been generated. Its filtering led to several hits potentially possessing anti-HIV activity.

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Section: Structure-propertymentioning

confidence: 99%

Anti-HIV Activity of HEPT, TIBO, and Cyclic Urea Derivatives: Structure−Property Studies, Focused Combinatorial Library Generation, and Hits Selection Using Substructural Molecular Fragments Method

Solov'ev

Varnek

2003

J. Chem. Inf. Comput. Sci.

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“…The TSAR methodology assumes that a suitable sampling of these structural descriptors provides all the information needed for understanding the biological properties. TSAR has been employed to investigate the effect of L-alanine ester variation on the anti-HIV activity and cytotoxicity of phosphoramidate derivatives [26]. Recently, Chang and coworkers [27] have applied TSAR to investigate the in-vitro neuroprotective activity of terpenoids on human neuroblastoma SH-SY5Y cell lines and found that neuroprotection was mainly governed by lipophilicity, shape index, and electrostatic property of the terpenoids studied.…”

Section: Introductionmentioning

confidence: 99%

QSAR Study on Dual 5‐HT_1Aand 5‐HT_1BAntagonists: An Insight into the Structural Requirement for Antidepressant Activity

Dessalew

2008

Archiv der Pharmazie

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The 5-HT autoreceptors have received considerable attention as potential targets for the development of antidepressants. With the purpose of designing new chemical entities with enhanced antagonist potencies against 5-HT1A and 5-HT1B, a QSAR study carried out on thienopyrimidinone derivatives as antagonists of serotonin autoreceptors is presented. The developed models were validated by standard QSAR parameters and through a detailed structural analysis on how the QSARs reproduce and explain the differences in the experimentally known activity data. The developed models showed a good correlative and predictive ability having a squared cross validated correlation co-efficients (r2 cv) of 0.780 for 5-HT1A and 0.638 5-HT1B antagonism. The squared conventional correlation co-efficients (r2) were found to be 0.824 for the 5-HT1A model and 0.745 for 5-HT1B antagonism. The study indicated that the 5-HT autoreceptor antagonistic activity exhibited by the series is largely explained by steric factors of substituents which underline the role of size and shape of thienopyrimidinones in making effective antagonist-autoreceptor interaction chemistry. A detailed comparative investigation was made between the two models and the insights gleaned from the study could be usefully employed to design dual antagonists with a much more enhanced potency and selectivity.

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“…The TSAR methodology assumes that a suitable sampling of these structural descriptors provides all the information needed for understanding their biological properties. TSAR has been employed to investigate the effect of l-alanine ester variation on the anti-HIV activity and cytotoxicity of phosphoramidate derivatives [29]. Recently, researchers have applied the methodology to study the neuroprotective activity of terpenoids and found that the neuroprotection was mainly governed by lipophilicity, shape index, and electrostatic property of the terpenoids studied [30].…”

Section: Introductionmentioning

confidence: 99%

QSAR Study on Piperidinecarboxamides as Antiretroviral Agents: An Insight Into the Structural Basis for HIV Coreceptor Antagonist Activity

Dessalew

2008

QSAR Comb. Sci.

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Chemokines receptors have emerged as important drug targets for the development of agents against the Human Immunodeficiency Virus (HIV)/AIDS pandemic. With the purpose of designing new chemical entities with enhanced antiretroviral potencies, the Quantitative Structure -Activity Relationships (QSAR) study carried out on 122 novel piperidin-4-carboxamide derivatives as antagonists of HIV Chemokine Receptor 5 (CCR5) coreceptor binding is presented. The developed model was validated by standard QSAR parameters and through a detailed structural investigation on how it explains and reproduces the quantitative differences observed in the experimentally known activity data. The model showed a good correlative and predictive ability having a cross-validated correlation coefficient (r 2 cv ) of 0.794 and the conventional correlation coefficient (r 2 ) was found to be 0.830. The study revealed that the CCR5 antagonistic activity exhibited by the series is largely explained by lipophilicity and steric bulkiness of substituents and that substituents with higher lipophilicity and steric superiority are required to make favorable antagonist -CCR5 interaction chemistry. A detailed investigation was made on the structural basis for the antiretroviral activity and the insights gleaned from the study could be usefully employed to design antagonists with a much more enhanced potency and selectivity.

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A QSAR study investigating the effect of l-alanine ester variation on the anti-HIV activity of some phosphoramidate derivatives of d4T

Cited by 18 publications

References 6 publications

Anti-HIV Activity of HEPT, TIBO, and Cyclic Urea Derivatives: Structure−Property Studies, Focused Combinatorial Library Generation, and Hits Selection Using Substructural Molecular Fragments Method

Anti-HIV Activity of HEPT, TIBO, and Cyclic Urea Derivatives: Structure−Property Studies, Focused Combinatorial Library Generation, and Hits Selection Using Substructural Molecular Fragments Method

QSAR Study on Dual 5‐HT_1Aand 5‐HT_1BAntagonists: An Insight into the Structural Requirement for Antidepressant Activity

QSAR Study on Piperidinecarboxamides as Antiretroviral Agents: An Insight Into the Structural Basis for HIV Coreceptor Antagonist Activity

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A QSAR study investigating the effect of l-alanine ester variation on the anti-HIV activity of some phosphoramidate derivatives of d4T

Cited by 18 publications

References 6 publications

Anti-HIV Activity of HEPT, TIBO, and Cyclic Urea Derivatives: Structure−Property Studies, Focused Combinatorial Library Generation, and Hits Selection Using Substructural Molecular Fragments Method

Anti-HIV Activity of HEPT, TIBO, and Cyclic Urea Derivatives: Structure−Property Studies, Focused Combinatorial Library Generation, and Hits Selection Using Substructural Molecular Fragments Method

QSAR Study on Dual 5‐HT1A and 5‐HT1B Antagonists: An Insight into the Structural Requirement for Antidepressant Activity

QSAR Study on Piperidinecarboxamides as Antiretroviral Agents: An Insight Into the Structural Basis for HIV Coreceptor Antagonist Activity

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QSAR Study on Dual 5‐HT_1Aand 5‐HT_1BAntagonists: An Insight into the Structural Requirement for Antidepressant Activity