TY - JOUR
T1 - SPIDR: Small-Molecule Peptide-Influenced Drug Repurposing
T2 - Small-molecule peptide-influenced drug repurposing
AU - King, Matthew D.
AU - Long, Thomas
AU - Pfalmer, Daniel L.
AU - Andersen, Timothy L.
AU - McDougal, Owen M.
N1 - King, Matthew D.; Long, Thomas; Pfalmer, Daniel L.; Andersen, Timothy L.; and McDougal, Owen M. (2018). "SPIDR: Small-Molecule Peptide-Influenced Drug Repurposing". BMC Bioinformatics, 19, 138-1 - 138-11. http://dx.doi.org/10.1186/s12859-018-2153-y
PY - 2018/4/16
Y1 - 2018/4/16
N2 - Background: Conventional de novo drug design is costly and time consuming, making it accessible to only the best resourced research organizations. An emergent approach to new drug development is drug repurposing, in which compounds that have already gone through some level of clinical testing are examined for efficacy against diseases divergent than their original application. Repurposing of existing drugs circumvents the time and considerable cost of early stages of drug development, and can be accelerated by using software to screen existing chemical databases to identify suitable drug candidates. Results: Small-molecule Peptide-Influenced Drug Repurposing (SPIDR) was developed to identify small molecule drugs that target a specific receptor by exploring the conformational binding space of peptide ligands. SPIDR was tested using the potent and selective 16-amino acid peptide α -conotoxin MII ligand and the α 3 β 2 -nicotinic acetylcholine receptor (nAChR) isoform. SPIDR incorporates a genetic algorithm-based, heuristic search procedure, which was used to explore the ligand binding domain of the α 3 β 2 -nAChR isoform using a library consisting of 640,000 α -conotoxin MII peptide analogs. The peptides that exhibited the highest affinity for α 3 β 2 -nAChR were used as models for a small-molecule structure similarity search of the PubChem Compound database. SPIDR incorporates the SimSearcher utility, which generates shape distribution signatures of molecules and employs multi-level K-means clustering to insure fast database queries. SPIDR identified non-peptide drugs with estimated binding affinities nearly double that of the native α -conotoxin MII peptide. Conclusions: SPIDR has been generalized and integrated into DockoMatic v 2.1. This software contains an intuitive graphical interface for peptide mutant screening workflow and facilitates mapping, clustering, and searching of local molecular databases, making DockoMatic a valuable tool for researchers in drug design and repurposing.
AB - Background: Conventional de novo drug design is costly and time consuming, making it accessible to only the best resourced research organizations. An emergent approach to new drug development is drug repurposing, in which compounds that have already gone through some level of clinical testing are examined for efficacy against diseases divergent than their original application. Repurposing of existing drugs circumvents the time and considerable cost of early stages of drug development, and can be accelerated by using software to screen existing chemical databases to identify suitable drug candidates. Results: Small-molecule Peptide-Influenced Drug Repurposing (SPIDR) was developed to identify small molecule drugs that target a specific receptor by exploring the conformational binding space of peptide ligands. SPIDR was tested using the potent and selective 16-amino acid peptide α -conotoxin MII ligand and the α 3 β 2 -nicotinic acetylcholine receptor (nAChR) isoform. SPIDR incorporates a genetic algorithm-based, heuristic search procedure, which was used to explore the ligand binding domain of the α 3 β 2 -nAChR isoform using a library consisting of 640,000 α -conotoxin MII peptide analogs. The peptides that exhibited the highest affinity for α 3 β 2 -nAChR were used as models for a small-molecule structure similarity search of the PubChem Compound database. SPIDR incorporates the SimSearcher utility, which generates shape distribution signatures of molecules and employs multi-level K-means clustering to insure fast database queries. SPIDR identified non-peptide drugs with estimated binding affinities nearly double that of the native α -conotoxin MII peptide. Conclusions: SPIDR has been generalized and integrated into DockoMatic v 2.1. This software contains an intuitive graphical interface for peptide mutant screening workflow and facilitates mapping, clustering, and searching of local molecular databases, making DockoMatic a valuable tool for researchers in drug design and repurposing.
KW - DockoMatic
KW - GAMPMS
KW - SimSearcher
KW - drug repurposing
KW - repositioning
UR - https://scholarworks.boisestate.edu/chem_facpubs/117
UR - http://www.scopus.com/inward/record.url?scp=85045432981&partnerID=8YFLogxK
U2 - 10.1186/s12859-018-2153-y
DO - 10.1186/s12859-018-2153-y
M3 - Article
C2 - 29661129
VL - 19
JO - Chemistry and Biochemistry Faculty Publications and Presentations
JF - Chemistry and Biochemistry Faculty Publications and Presentations
IS - 1
M1 - 138
ER -