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. 2018 Jul 31;3(7):7993-8002.
doi: 10.1021/acsomega.8b00659. Epub 2018 Jul 18.

SynPharm: A Guide to PHARMACOLOGY Database Tool for Designing Drug Control Into Engineered Proteins

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Free PMC article

SynPharm: A Guide to PHARMACOLOGY Database Tool for Designing Drug Control Into Engineered Proteins

Sam M Ireland et al. ACS Omega. .
Free PMC article

Abstract

A major challenge in synthetic biology, particularly for mammalian systems, is the inclusion of adequate external control for the synthetic system activities. Control at the transcriptional level can be achieved by adaptation of bacterial repressor-operator systems (e.g., TetR), but altering the activity of a protein by controlling transcription is indirect and for longer half-life mRNAs, decreasing activity this way can be inconveniently slow. Where possible, direct modulation of protein activity by soluble ligands has many advantages, including rapid action. Decades of drug discovery and pharmacological research have uncovered detailed information on the interactions between large numbers of small molecules and their primary protein targets (as well as off-target secondary interactions), many of which have been well studied in mammals, including humans. In principle, this accumulated knowledge would be a powerful resource for synthetic biology. Here, we present SynPharm, a tool that draws together information from the pharmacological database GtoPdb and the structural database, PDB, to help synthetic biologists identify ligand-binding domains of natural proteins. Consequently, as sequence cassettes, these may be suitable for building into engineered proteins to confer small-molecule modulation on them. The tool has ancillary utilities which include assessing contact changes among different ligands in the same protein, predicting possible effects of genetic variants on binding residues, and insights into ligand cross-reactivity among species.

Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Strategy used to produce a database of potentially useful interactions from known binding data.
Figure 2
Figure 2
SynPharm home page with summary statistics at http://synpharm.guidetopharmacology.org/.
Figure 3
Figure 3
Top section of the list served to a user entering the target sequence part of the database. http://synpharm.guidetopharmacology.org/sequences/.
Figure 4
Figure 4
Examples of the types of structural display found on the sequence details page for human β-secretase 1 in complex with the ligand AMG-8718 (sequence ID 84541). The top-left panel shows the three-dimensional structure interactive viewer where the binding segment is highlighted in purple, the rest of the target protein in green, and the ligand is shown in stick view. The top-right panel shows the residue distance matrix. The distance between any two residues in the target chain is denoted by color, green to red, and, on desktop screens, hovering over any pixel will provide an exact numerical distance in angstroms of the relevant residues. White portions denote residues missing from the PDB file of origin. The dotted line indicates the binding sequence. The central panel shows the binding portion of the sequence. The arrows allow the sequence sections to be extended outward beyond the first and last interaction residues (five are shown on each end in this case) The lower panel shows a zoomed-in section of the feature viewer. Binding residues are shown in context with secondary structure elements (α-helices and β-strands) and hydrophobicity over the peptide sequence.
Figure 5
Figure 5
Snapshot from the GtoPdb BACE1 target entry, with ligands ranked by affinity values. http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2330.
Figure 6
Figure 6
Differences in the contact residues extracted for the eight BACE1 ligands. The eight SynPharm sequences (in descending order) are 84891, 78993, 78985, 78477, 78900, 82636, 78987, and 84541. The latter (lowermost) is for AMG-8718 as shown in Figure 3. As for the SynPharm display, the uppercase letters indicate ligand contact residues.

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