Structure based virtual screening identifies small molecule effectors for the sialoglycan binding protein Hsa

Agarwal, Rupesh; Bensing, Barbara; Mi, Dehui; Vinson, Paige; Baudry, Jerome Y.; Iverson, Tina; Smith, Jeremy C.

doi:10.1042/bcj20200332

Title: Structure based virtual screening identifies small molecule effectors for the sialoglycan binding protein Hsa

Journal Article · Mon Oct 05 00:00:00 EDT 2020 · Biochemical Journal

DOI:https://doi.org/10.1042/bcj20200332· OSTI ID:1785206

Agarwal, Rupesh ^[1]; Bensing, Barbara ^[2]; Mi, Dehui ^[3]; Vinson, Paige ^[3]; Baudry, Jerome Y. ^[4]; Iverson, Tina ^[3];

^[4]

Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Univ. of Tennessee, Knoxville, TN (United States)
Univ. of California, San Francisco, CA (United States)
Vanderbilt Univ., Nashville, TN (United States)
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

Infective endocarditis (IE) is a cardiovascular disease often caused by bacteria of the viridans group of streptococci, which includes Streptococcus gordonii and Streptococcus sanguinis. Previous research has found that serine-rich repeat (SRR) proteins on the S. gordonii bacterial surface play a critical role in pathogenesis by facilitating bacterial attachment to sialylated glycans displayed on human platelets. Despite their important role in disease progression, there are currently no anti-adhesive drugs available on the market. Here, we performed structure-based virtual screening using an ensemble docking approach followed by consensus scoring to identify novel small molecule effectors against the sialoglycan binding domain of the SRR adhesin protein Hsa from the S. gordonii strain DL1. The screening successfully predicted nine compounds which were able to displace the native ligand (sialyl-T antigen) in an in vitro assay and bind competitively to Hsa. Furthermore, hierarchical clustering based on the MACCS fingerprints showed that eight of these small molecules do not share a common scaffold with the native ligand. This study indicates that SRR family of adhesin proteins can be inhibited by diverse small molecules and thus prevent the interaction of the protein with the sialoglycans. This opens new avenues for discovering potential drugs against IE.

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Research Organization:: Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 1785206

Journal Information:: Biochemical Journal, Vol. 477, Issue 19; ISSN 0264-6021

Publisher:: Biochemical SocietyCopyright Statement

Country of Publication:: United States

Language:: English

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