finDr: A web server for in silico D-peptide ligand identification

Synth Syst Biotechnol. 2021 Nov 23;6(4):402-413. doi: 10.1016/j.synbio.2021.11.004. eCollection 2021 Dec.


In the rapidly expanding field of peptide therapeutics, the short in vivo half-life of peptides represents a considerable limitation for drug action. D-peptides, consisting entirely of the dextrorotatory enantiomers of naturally occurring levorotatory amino acids (AAs), do not suffer from these shortcomings as they are intrinsically resistant to proteolytic degradation, resulting in a favourable pharmacokinetic profile. To experimentally identify D-peptide binders to interesting therapeutic targets, so-called mirror-image phage display is typically performed, whereby the target is synthesized in D-form and L-peptide binders are screened as in conventional phage display. This technique is extremely powerful, but it requires the synthesis of the target in D-form, which is challenging for large proteins. Here we present finDr, a novel web server for the computational identification and optimization of D-peptide ligands to any protein structure ( finDr performs molecular docking to virtually screen a library of helical 12-mer peptides extracted from the RCSB Protein Data Bank (PDB) for their ability to bind to the target. In a separate, heuristic approach to search the chemical space of 12-mer peptides, finDr executes a customizable evolutionary algorithm (EA) for the de novo identification or optimization of D-peptide ligands. As a proof of principle, we demonstrate the validity of our approach to predict optimal binders to the pharmacologically relevant target phenol soluble modulin alpha 3 (PSMα3), a toxin of methicillin-resistant Staphylococcus aureus (MRSA). We validate the predictions using in vitro binding assays, supporting the success of this approach. Compared to conventional methods, finDr provides a low cost and easy-to-use alternative for the identification of D-peptide ligands against protein targets of choice without size limitation. We believe finDr will facilitate D-peptide discovery with implications in biotechnology and biomedicine.

Keywords: D-AA, dextrorotatory amino acid; D-peptide; EA, evolutionary algorithm; Evolutionary algorithm; L-AA, levorotatory amino acid; MD, molecular dynamics; MIEA, mirror-image evolutionary algorithm; MIPD, mirror-image phage display; MIVS, mirror-image virtual screening; MRSA, methicillin-resistant Staphylococcus aureus; Mirror-image phage display; Molecular docking; NCL, native chemical ligation; PD-1, receptor programmed death 1; PPI, protein-protein interaction; PSMα3, phenol soluble modulin alpha 3; Peptide design; SPPS, solid phase peptide synthesis; Web server.