HIV-1 integrase (IN) is an essential enzyme for viral replication and represents an intriguing target for the development of new drugs. Although a large number of compounds have been reported to inhibit IN in biochemical assays, no drug active against this enzyme has been approved by the FDA so far. In this study, we report, for the first time, the use of the electron-ion interaction potential (EIIP) technique in combination with molecular modeling approaches for the identification of new IN inhibitors. An innovative virtual screening approach, based on the determination of both short- and long-range interactions between interacting molecules, was employed with the aim of identifying molecules able to inhibit the binding of IN to viral DNA. Moreover, results from a database screening on the commercial Asinex Gold Collection led to the selection of several compounds. One of them showed a significant inhibitory potency toward IN in the overall integration assay. Biological investigations also showed, in agreement with modeling studies, that these compounds prevent recognition of DNA by IN in a fluorescence fluctuation assay, probably by interacting with the DNA binding domain of IN.

Tintori, C., Manetti, F., Veljkovic, N., Perovic, V., Vercammen, J., Hayes, S., et al. (2007). Novel virtual screening protocol based on the combined use of molecular modeling and electron-ion interaction potential techniques to design HIV-1 integrase inhibitors. JOURNAL OF CHEMICAL INFORMATION AND MODELING, 47(4), 1536-1544 [10.1021/ci700078n].

Novel virtual screening protocol based on the combined use of molecular modeling and electron-ion interaction potential techniques to design HIV-1 integrase inhibitors

Tintori, Cristina;Manetti, Fabrizio;Massa, Silvio;Botta, Maurizio
2007-01-01

Abstract

HIV-1 integrase (IN) is an essential enzyme for viral replication and represents an intriguing target for the development of new drugs. Although a large number of compounds have been reported to inhibit IN in biochemical assays, no drug active against this enzyme has been approved by the FDA so far. In this study, we report, for the first time, the use of the electron-ion interaction potential (EIIP) technique in combination with molecular modeling approaches for the identification of new IN inhibitors. An innovative virtual screening approach, based on the determination of both short- and long-range interactions between interacting molecules, was employed with the aim of identifying molecules able to inhibit the binding of IN to viral DNA. Moreover, results from a database screening on the commercial Asinex Gold Collection led to the selection of several compounds. One of them showed a significant inhibitory potency toward IN in the overall integration assay. Biological investigations also showed, in agreement with modeling studies, that these compounds prevent recognition of DNA by IN in a fluorescence fluctuation assay, probably by interacting with the DNA binding domain of IN.
2007
Tintori, C., Manetti, F., Veljkovic, N., Perovic, V., Vercammen, J., Hayes, S., et al. (2007). Novel virtual screening protocol based on the combined use of molecular modeling and electron-ion interaction potential techniques to design HIV-1 integrase inhibitors. JOURNAL OF CHEMICAL INFORMATION AND MODELING, 47(4), 1536-1544 [10.1021/ci700078n].
File in questo prodotto:
File Dimensione Formato  
2007JChemInfoModelIN.pdf

non disponibili

Tipologia: Post-print
Licenza: NON PUBBLICO - Accesso privato/ristretto
Dimensione 303.89 kB
Formato Adobe PDF
303.89 kB Adobe PDF   Visualizza/Apri   Richiedi una copia

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11365/20878
 Attenzione

Attenzione! I dati visualizzati non sono stati sottoposti a validazione da parte dell'ateneo