Background. The human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is one of the most attractive targets in the design of new antivirals. It is a key enzyme for viral replication which has two associated catalytic functions: a DNA polymerase activity, that recognizes both RNA and DNA as template, and a ribonuclease H (RNase H) activity that selectively degrades the RNA of the hybrid RNA:DNA replicative intermediate. Recently, a few hydrazone derivatives has been reported to selectively inhibit the HIV-1 RNase H function. Methods. The highly optimized screening platform Rapid Overlay of Chemical Structures (ROCS) was used to perform in silico similarity screening. HIV-1 RT activities were measured in biochemical assays and HIV-1 replication was tested in cell culture assays. Results. We focused on the design of new scaffolds for the inhibition of the HIV-1 RT-associated RNase H function by performing a computer sided shape based similarity screening study whose driving force is the assumption that molecules with similar shape to known active ones should exhibit comparable biological properties. In particular, using the highly optimized screening platform ROCS for shape-based virtual screening of the large database obtained from the National Cancer Institute we have identified a set of molecules characterized by different scaffolds which have been tested on the HIV-1 RT functions. Compounds with different scaffolds have shown to inhibit one or both RT-associated activities. Conclusions. New scaffolds for the inhibition of the HIV-1 RT-associated RNase H function have been identified and will be further developed.
Shape based computer aided similarity screening: a valid tool in the discovery of new scaffolds for the inhibition of HIV-1 reverse transcriptase associated ribonuclease H function
DISTINTO, SIMONA;ESPOSITO, FRANCESCA;MACCIONI, ELIAS;Cardia M. C.;TRAMONTANO, ENZO
2010-01-01
Abstract
Background. The human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) is one of the most attractive targets in the design of new antivirals. It is a key enzyme for viral replication which has two associated catalytic functions: a DNA polymerase activity, that recognizes both RNA and DNA as template, and a ribonuclease H (RNase H) activity that selectively degrades the RNA of the hybrid RNA:DNA replicative intermediate. Recently, a few hydrazone derivatives has been reported to selectively inhibit the HIV-1 RNase H function. Methods. The highly optimized screening platform Rapid Overlay of Chemical Structures (ROCS) was used to perform in silico similarity screening. HIV-1 RT activities were measured in biochemical assays and HIV-1 replication was tested in cell culture assays. Results. We focused on the design of new scaffolds for the inhibition of the HIV-1 RT-associated RNase H function by performing a computer sided shape based similarity screening study whose driving force is the assumption that molecules with similar shape to known active ones should exhibit comparable biological properties. In particular, using the highly optimized screening platform ROCS for shape-based virtual screening of the large database obtained from the National Cancer Institute we have identified a set of molecules characterized by different scaffolds which have been tested on the HIV-1 RT functions. Compounds with different scaffolds have shown to inhibit one or both RT-associated activities. Conclusions. New scaffolds for the inhibition of the HIV-1 RT-associated RNase H function have been identified and will be further developed.
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