2019
DOI: 10.1021/acs.jcim.8b00892
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How to Computationally Stack the Deck for Hit-to-Lead Generation: In Silico Molecular Interaction Energy Profiling for de Novo siRNA Guide Strand Surrogate Selection

Abstract: The Argonaute-2 protein is part of the RNA-induced silencing complex (RISC) and anchors the guide strand of the small interfering RNA (siRNA). The 3′-end of the RNA contains two unpaired nucleotides (3′-overhang) that interact with the PAZ (PIWI/Argonaute/Zwille) domain of the protein. Theoretical and experimental evidence points toward a direct connection between the PAZ/3′-overhang binding affinity and siRNA’s potency and specificity. Among the challenges to overcome when deploying siRNA molecules as therape… Show more

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Cited by 6 publications
(5 citation statements)
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“…No binding is observed within a physiologically relevant range hence the two do not interact directly. ( f ) Expanded ribbon model of molecular docking of GRB2 (green; PDB: 1GRI 77 ) to AGO2 PAZ domain (cyan; red and blue indicate positive and negative charges respectively; PDB: 6RA4 78 ). The 323 PHLP 326 sequence is shown (yellow).…”
Section: Resultsmentioning
confidence: 99%
See 1 more Smart Citation
“…No binding is observed within a physiologically relevant range hence the two do not interact directly. ( f ) Expanded ribbon model of molecular docking of GRB2 (green; PDB: 1GRI 77 ) to AGO2 PAZ domain (cyan; red and blue indicate positive and negative charges respectively; PDB: 6RA4 78 ). The 323 PHLP 326 sequence is shown (yellow).…”
Section: Resultsmentioning
confidence: 99%
“…Prior to docking, structures of GRB2 (PDB: 1GRI 77 ) and AGO2 PAZ domain (PDB: 6RA4 78 ) were prepared and energy minimised using MDWeb 79 . Molecular docking was performed using HADDOCK2.2 40 .…”
Section: Methodsmentioning
confidence: 99%
“…The middle (MID) domain interacts with the 5 end of small RNA, and the PAZ domain interacts with the 2 nt 3 overhang of small RNA in a conserved pocket. Furthermore, the PIWI domain cleaves the mRNA (Greenidge et al, 2019).…”
Section: Involvement Of Dicer In Sirna Loading Onto Riscmentioning
confidence: 99%
“…These dinucleotide siRNA guide strand surrogates represent potential new siRNA-based therapeutics (when attached to siRNA to form bioconjugates) featuring improved efficacy, specificity, stability, and cellular uptake. This project yielded a portfolio of seven patent applications, two of which have been granted to date …”
mentioning
confidence: 99%
“…This project yielded a portfolio of seven patent applications, two of which have been granted to date. 28 The development of fast and accurate approaches to the socalled inverse molecular docking problem is important. Many applications can be facilitated, such as the repurposing of existing drugs; the discovery of hidden risks and potential side effects of current drugs; the design of future lead candidates by minimizing cross-effects; and the acceleration of the discovery of new natural products, which are frequently discovered during the early stages of drug development using cell-based assays with poor molecular specificity.…”
mentioning
confidence: 99%