Skip to main content
OSTI.GOVU.S. Department of Energy Office of Scientific and Technical Information
U.S. Department of Energy
Office of Scientific and Technical Information
 

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

Journal Article · · Biochemical Journal
DOI:https://doi.org/10.1042/bcj20200332· OSTI ID:1785206
 [1];  [2];  [3];  [3];  [4];  [3];  [4]
  1. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States); Univ. of Tennessee, Knoxville, TN (United States)
  2. Univ. of California, San Francisco, CA (United States)
  3. Vanderbilt Univ., Nashville, TN (United States)
  4. Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
+ Show Author Affiliations
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.
Research Organization:
Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
Sponsoring Organization:
USDOE
Grant/Contract Number:
AC05-00OR22725
OSTI ID:
1785206
Journal Information:
Biochemical Journal, Journal Name: Biochemical Journal Journal Issue: 19 Vol. 477; ISSN 0264-6021
Publisher:
Biochemical SocietyCopyright Statement
Country of Publication:
United States
Language:
English

References (56)

Clinical Presentation, Etiology, and Outcome of Infective Endocarditis in the 21st Century: The International Collaboration on Endocarditis–Prospective Cohort Study journal March 2009
The Amber biomolecular simulation programs journal January 2005
AutoDock4 and AutoDockTools4: Automated docking with selective receptor flexibility journal December 2009
AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading journal January 2009
VinaMPI: Facilitating multiple receptor high-throughput virtual docking on high-performance computers: Software News And Updates journal June 2013
Settle: An analytical version of the SHAKE and RATTLE algorithm for rigid water models journal October 1992
Nonlinear generalized Langevin equations journal November 1973
Clinical presentation of infective endocarditis caused by different groups of non-beta haemolytic streptococci journal November 2015
The Rule of Five for Non-Oral Routes of Drug Delivery: Ophthalmic, Inhalation and Transdermal journal October 2010
Anti-adhesion therapy of bacterial diseases: prospects and problems journal October 2003
Theoretical hydrogen bonding parameters for drug design journal June 2001
Ensemble-based docking: From hit discovery to metabolism and toxicity predictions journal October 2016
Discovery of a novel, CNS penetrant M4 PAM chemotype based on a 6-fluoro-4-(piperidin-1-yl)quinoline-3-carbonitrile core journal September 2017
Ensemble Docking in Drug Discovery journal May 2018
Molecular dynamics simulations of water and biomolecules with a Monte Carlo constant pressure algorithm journal January 2004
Lead- and drug-like compounds: the rule-of-five revolution journal December 2004
Management of serious meticillin-resistant Staphylococcus aureus infections: what are the limits? journal March 2011
Polypharmacology rescored: Protein–ligand interaction profiles for remote binding site similarity assessment journal November 2014
Structures of the Streptococcus sanguinis SrpA Binding Region with Human Sialoglycans Suggest Features of the Physiological Ligand journal October 2016
ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB journal July 2015
Fragment Hits: What do They Look Like and How do They Bind? journal February 2019
Discovery and Characterization of VU0529331, a Synthetic Small-Molecule Activator of Homomeric G Protein-Gated, Inwardly Rectifying, Potassium (GIRK) Channels journal August 2018
PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data journal June 2013
Role of the Key Mutation in the Selective Binding of Avian and Human Influenza Hemagglutinin to Sialosides Revealed by Quantum-Mechanical Calculations journal December 2010
Hydrogen-bonding parameter and its significance in quantitative structure-activity studies journal August 1977
Molecular Properties That Influence the Oral Bioavailability of Drug Candidates journal June 2002
Consensus Scoring:  A Method for Obtaining Improved Hit Rates from Docking Databases of Three-Dimensional Structures into Proteins journal December 1999
The influence of drug-like concepts on decision-making in medicinal chemistry journal November 2007
Infective Endocarditis journal April 2013
Daptomycin versus Standard Therapy for Bacteremia and Endocarditis Caused by Staphylococcus aureus journal August 2006
A modified TIP3P water potential for simulation with Ewald summation journal November 2004
Molecular dynamics and protein function journal May 2005
Structural Basis for Sialoglycan Binding by the Streptococcus sanguinis SrpA Adhesin journal February 2016
Serious Infections Caused by Methicillin‐Resistant Staphylococcus aureus journal September 2010
ChemBioServer: a web-based pipeline for filtering, clustering and visualization of chemical compounds used in drug discovery journal September 2012
Bacteremia Due to Viridans Streptococci That Are Highly Resistant to Penicillin: Increase Among Neutropenic Patients with Cancer journal May 1995
Clinical Outcome and Long-Term Prognosis of Late Prosthetic Valve Endocarditis: A 20-Year Experience journal March 1997
Novel aspects of sialoglycan recognition by the Siglec-like domains of streptococcal SRR glycoproteins journal April 2016
Cl-π interactions in protein-ligand complexes journal July 2008
A serine-rich glycoprotein of Streptococcus sanguis mediates adhesion to platelets via GPIb journal April 2005
Binding of the Streptococcus gordonii surface glycoproteins GspB and Hsa to specific carbohydrate structures on platelet membrane glycoprotein Ibα: Specific GPIbα binding by BR of GspB and Hsa journal September 2005
Principles of early drug discovery: Principles of early drug discovery journal February 2011
A role for glycosylated serine-rich repeat proteins in Gram-positive bacterial pathogenesis: Role for SRRPs in Gram-positive pathogenesis journal June 2012
Discovery, Characterization, and Effects on Renal Fluid and Electrolyte Excretion of the Kir4.1 Potassium Channel Pore Blocker, VU0134992 journal June 2018
Regulation of protein-ligand binding affinity by hydrogen bond pairing journal March 2016
The Streptococcus gordonii Surface Proteins GspB and Hsa Mediate Binding to Sialylated Carbohydrate Epitopes on the Platelet Membrane Glycoprotein Ib  journal October 2004
Binding of the Streptococcal Surface Glycoproteins GspB and Hsa to Human Salivary Proteins journal March 2006
Impact of the NICE guideline recommending cessation of antibiotic prophylaxis for prevention of infective endocarditis: before and after study journal May 2011
Siglecs as Immune Cell Checkpoints in Disease journal April 2020
A Simple Statistical Parameter for Use in Evaluation and Validation of High Throughput Screening Assays journal April 1999
Physicochemical property space distribution among human metabolites, drugs and toxins journal December 2009
Spondylodiskitis and endocarditis due to Streptococcus gordonii journal October 2017
A Structural Model for Binding of the Serine-Rich Repeat Adhesin GspB to Host Carbohydrate Receptors journal July 2011
Oral Streptococci Utilize a Siglec-Like Domain of Serine-Rich Repeat Adhesins to Preferentially Target Platelet Sialoglycans in Human Blood journal December 2014
Anti-adhesion methods as novel therapeutics for bacterial infections journal December 2012
Effective anti-adhesives of uropathogenic Escherichia coli journal February 2018

Similar Records

Structures of the Streptococcus sanguinis SrpA Binding Region with Human Sialoglycans Suggest Features of the Physiological Ligand
Journal Article · Wed Sep 28 20:00:00 EDT 2016 · Biochemistry · OSTI ID:1331707
Tandem sialoglycan-binding modules in a Streptococcus sanguinis serine-rich repeat adhesin create target dependent avidity effects
Journal Article · Wed Aug 19 20:00:00 EDT 2020 · Journal of Biological Chemistry · OSTI ID:1712489
A Structural Model for Binding of the Serine-Rich Repeat Adhesin GspB to Host Carbohydrate Receptors
Journal Article · Thu Oct 02 00:00:00 EDT 2014 · PLoS Patho. · OSTI ID:1031944

Related Subjects

60 APPLIED LIFE SCIENCES