SwePub - sökning: L773:2040 2503 OR L773:2040 25...

Numrering	Referens	Omslagsbild	Hitta
1.	Poongavanam, Vasanthanathan, et al. (författare) Structure-guided approach identifies a novel class of HIV-1 ribonuclease H inhibitors : binding mode insights through magnesium complexation and site-directed mutagenesis studies 2018 Ingår i: MedChemComm. - : ROYAL SOC CHEMISTRY. - 2040-2503 .- 2040-2511. ; 9:3, s. 562-575 Tidskriftsartikel (refereegranskat)abstract Persistent HIV infection requires lifelong treatment and among the 2.1 million new HIV infections that occur every year there is an increased rate of transmitted drug-resistant mutations. This fact requires a constant and timely effort in order to identify and develop new HIV inhibitors with innovative mechanisms. The HIV-1 reverse transcriptase (RT) associated ribonuclease H (RNase H) is the only viral encoded enzyme that still lacks an efficient inhibitor despite the fact that it is a well-validated target whose functional abrogation compromises viral infectivity. Identification of new drugs is a long and expensive process that can be speeded up by in silico methods. In the present study, a structure-guided screening is coupled with a similarity-based search on the Specs database to identify a new class of HIV-1 RNase H inhibitors. Out of the 45 compounds selected for experimental testing, 15 inhibited the RNase H function below 100 mu M with three hits exhibiting IC50 values < 10 mu M. The most active compound, AA, inhibits HIV-1 RNase H with an IC50 of 5.1 mu M and exhibits a Mg-independent mode of inhibition. Site-directed mutagenesis studies provide valuable insight into the binding mode of newly identified compounds; for instance, compound AA involves extensive interactions with a lipophilic pocket formed by Ala502, Lys503, and Trp (406, 426 and 535) and polar interactions with Arg557 and the highly conserved RNase H primer-grip residue Asn474. The structural insights obtained from this work provide the bases for further lead optimization.
2.	Riley, AM, et al. (författare) A synthetic diphosphoinositol phosphate analogue of inositol trisphosphate 2018 Ingår i: MedChemComm. - 2040-2503. ; 9:7, s. 1105-1113 Tidskriftsartikel (refereegranskat)

Poongavanam, Vasanthanathan, et al. (författare)
Structure-guided approach identifies a novel class of HIV-1 ribonuclease H inhibitors : binding mode insights through magnesium complexation and site-directed mutagenesis studies
2018
Ingår i: MedChemComm. - : ROYAL SOC CHEMISTRY. - 2040-2503 .- 2040-2511. ; 9:3, s. 562-575
Tidskriftsartikel (refereegranskat)abstract
- Persistent HIV infection requires lifelong treatment and among the 2.1 million new HIV infections that occur every year there is an increased rate of transmitted drug-resistant mutations. This fact requires a constant and timely effort in order to identify and develop new HIV inhibitors with innovative mechanisms. The HIV-1 reverse transcriptase (RT) associated ribonuclease H (RNase H) is the only viral encoded enzyme that still lacks an efficient inhibitor despite the fact that it is a well-validated target whose functional abrogation compromises viral infectivity. Identification of new drugs is a long and expensive process that can be speeded up by in silico methods. In the present study, a structure-guided screening is coupled with a similarity-based search on the Specs database to identify a new class of HIV-1 RNase H inhibitors. Out of the 45 compounds selected for experimental testing, 15 inhibited the RNase H function below 100 mu M with three hits exhibiting IC50 values < 10 mu M. The most active compound, AA, inhibits HIV-1 RNase H with an IC50 of 5.1 mu M and exhibits a Mg-independent mode of inhibition. Site-directed mutagenesis studies provide valuable insight into the binding mode of newly identified compounds; for instance, compound AA involves extensive interactions with a lipophilic pocket formed by Ala502, Lys503, and Trp (406, 426 and 535) and polar interactions with Arg557 and the highly conserved RNase H primer-grip residue Asn474. The structural insights obtained from this work provide the bases for further lead optimization.

Träfflista för sökning "L773:2040 2503 OR L773:2040 2511 srt2:(2018)"

Avgränsa träffmängd