CoMFA analysis of the interactions of antipicornavirus compounds in the binding pocket of human rhinovirus-14

Diana, Guy D.; Kowalczyk, Paul J.; Treasurywala, Adi M.; Oglesby, Richard C.; Pevear, Daniel C.; Dutko, Frank J.

doi:10.1021/jm00084a005

Cited by 32 publications

(18 citation statements)

References 1 publication

(2 reference statements)

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“…Although bulk is important, the nature of the binding pocket imposes limits on the amount of bulk and how it is oriented. Even though modelling showed that 10 could be accommodated within the binding pocket, it has been proposed that for Disoxaril and its analogues excessive bulk in the phenyl region of the inhibitor leads to decreased activity (Diana et al, 1992). Our modelling experiments indicated that the dibenzyl group is located in what would be the phenyl region of Disoxaril.…”

Section: Discussionmentioning

confidence: 73%

“…The steric factors discussed above could also apply in this case. In addition, it was reported that in some Disoxaril analogues the phenyl ring appeared to be in a stacking configuration with Tyr 12 8 and Tyr 1S2 of the capsid protein (Diana et al, 1992). Such pitype interactions may contribute to activity, and in the case of 18 such an interaction is obviously not possible.…”

Section: Discussionmentioning

confidence: 99%

“…Further modification resulted in the discovery of Disoxaril 2 which exhibited marked efficacy against a variety of picornaviruses both in vitro and in vivo (Diana et al, 1985b). Numerous analogues of Disoxaril have been prepared and detailed structure-activity relationships elucidated (Diana et al, 1987(Diana et al, , 1988(Diana et al, , 1990(Diana et al, , 1992(Diana et al, , 1993.…”

Section: Introductionmentioning

confidence: 99%

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Novel Azolylalkyloxy Compounds with Antipicornaviral Activity

Abel¹,

Cameron²,

Ha³

et al. 1995

Antivir Chem Chemother

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SummaryA novel series of azolylalkyloxy compounds was designed, synthesized and evaluated for antipicornaviral activity. Several of the compounds exhibited in vitro activity comparable to that of Disoxaril. An investigation of qualitative structure-activity relationships indicated that the optimal length of the alkyl chain is six or seven carbon atoms, with seven being marginally superior. The effect of different azole moieties on activity was relatively small, with 3-methylisoxazole and 4-methylthiazole being most effective. The nature of the oxy substituent was found to be extremely important for antipicornaviral activity. The 2-dibenzofuryl group proved to be the most effective oxy substituent for this class of compounds. Compounds 11 and 22, combining dibenzofuran with 3-methylisoxazole and 4-methylthiazole, respectively, were highly effective in vitro against a wide range of human rhinoviruses as well as several enteroviruses.

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Section: Discussionmentioning

confidence: 73%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Novel Azolylalkyloxy Compounds with Antipicornaviral Activity

Abel¹,

Cameron²,

Ha³

et al. 1995

Antivir Chem Chemother

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“…Interestingly, inhibitors behave differently in the binding process. Most prefer an orientation with the isoxazole at the so-called heel of the pocket, whereas other analogues choose the opposite direction [3,6,7]. Crystal structures of WIN compounds and several other co-crystallised inhibitors from the Brookhaven Protein Databank (PDB) [8] served as sources for pharmacophore model generation, docking processes, and virtual library design in this study.…”

Section: Introductionmentioning

confidence: 99%

DockingVersus Pharmacophore Model Generation: A Comparison of High-Throughput Virtual Screening Strategies for the Search of Human Rhinovirus Coat Protein Inhibitors

Steindl

Langer

2005

QSAR Comb. Sci.

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Inhibition of the human rhinovirus coat protein is an intensively studied approach towards finding a therapy for common cold. We present the results of a docking study using the tool LigandFit and a database of 1000 drug-like compounds seeded with known active HRV coat protein inhibitors. One scoring function performed especially well in ranking the active molecules at high positions. The conformations and positions from the docking process were found to be in good agreement with the X-ray data. Furthermore, highly selective pharmacophore hypotheses were generated in a structure-based approach. They include information on necessary chemical functions as well as on the required shape. When applied in 3D database screening, they selectively retrieved compounds with known antirhinoviral activity from large data sets. We compare these two virtual screening methods and summarise their benefits but also the observed disadvantages. Finally, a focussed virtual library for a special class of rhinovirus coat protein inhibitors was generated with our novel tool ilib diverse and screened with the pharmacophore models described.

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“…A number of applications of CoMFA in medicinal chemistry have been reported [18][19][20][21][22][23][24][25][26][27][28][29][30]. However, the methodology in its present state offers no explicit provision for management of different conformations of molecules with rotatable bonds [28].…”

Section: Introductionmentioning

confidence: 99%

QSAR of conformationally flexible molecules: Comparative Molecular Field Analysis of protein-tyrosine kinase inhibitors

Nicklaus¹,

Milne²,

Burke³

1992

J Computer-Aided Mol Des

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Comparative Molecular Field Analysis (CoMFA) has been applied to a study of quantitative structure-activity relationships (QSAR) of conformationally flexible molecules. The relationship between three-dimensional structure and activity of 20 styrene derivatives which inhibit protein-tyrosine kinase was determined. A technique was developed that allows accurate prediction of the inhibitory activity of these molecules and identification in each case of the active conformation. The problem of multiple energetically acceptable conformations was approached in an iterative procedure. Use was made of the varying degrees of symmetry among the molecules. First, CoMFA QSAR models were developed using only those compounds that possess a symmetrical substituent pattern on the phenyl ring. These CoMFA models were then used to select the active conformers of the less symmetrical compounds in the set. Allowing multiple conformers for each compound in the dataset yielded higher crossvalidated r2 values and better predictivity of the QSAR models. Different probe atoms (C+, O-, neutral C) were explored, the O- probe atom exhibiting the highest selectivity in the conformer selection process.

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CoMFA analysis of the interactions of antipicornavirus compounds in the binding pocket of human rhinovirus-14

Cited by 32 publications

References 1 publication

Novel Azolylalkyloxy Compounds with Antipicornaviral Activity

Novel Azolylalkyloxy Compounds with Antipicornaviral Activity

DockingVersus Pharmacophore Model Generation: A Comparison of High-Throughput Virtual Screening Strategies for the Search of Human Rhinovirus Coat Protein Inhibitors

QSAR of conformationally flexible molecules: Comparative Molecular Field Analysis of protein-tyrosine kinase inhibitors

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