Extensive Reliability Evaluation of Docking-Based Target-Fishing Strategies

Abstract

The development of target-fishing approaches, aimed at identifying the possible protein targets of a small molecule, represents a hot topic in medicinal chemistry. A successful target-fishing approach would allow for the elucidation of the mechanism of action of all therapeutically interesting compounds for which the actual target is still unknown. Moreover, target-fishing would be essential for preventing adverse effects of drug candidates, by predicting their potential off-targets, and it would speed up drug repurposing campaigns. However, due to the huge number of possible protein targets that a small-molecule might interact with, experimental target-fishing approaches are out of reach. In silico target-fishing represents a valuable alternative, and examples of receptor-based approaches, exploiting the large number of crystallographic protein structures determined to date, have been reported in the literature. To the best of our knowledge, no proper evaluation of such approaches is, however, reported yet. In the present work, we extensively assessed the reliability of docking-based target-fishing strategies. For this purpose, a set of X-ray structures belonging to different targets was selected, and a dataset of compounds, including 10 experimentally active ligands for each target, was created. A target-fishing benchmark database was then obtained, and used to assess the performance of 13 different docking procedures, in identifying the correct target of the dataset ligands. Moreover, a consensus docking-based target-fishing strategy was developed and evaluated. The analysis highlighted that specific features of the target proteins could affect the reliability of the protocol, which however, proved to represent a valuable tool in the proper applicability domain. Our study represents the first extensive performance assessment of docking-based target-fishing approaches, paving the way for the development of novel efficient receptor-based target fishing strategies.

Discovery of Novel µ-Opioid Receptor Inverse Agonist from a Combinatorial Library of Tetrapeptides through Structure-Based Virtual Screening

“…The 28,070 peptide ligands previously selected through the pharmacophore screening, were thus initially docked into MOR binding site, by using Glide SP and ranked according to the docking score associated to their predicted binding mode. Since in our previous studies Glide SP scoring function showed to be particularly reliable [43,44], and all peptides accurately docked by Glide SP in the reliability analysis showed docking scores lower than −8.0 kcal/mol, all screening compounds for which a docking score higher than –8.0 kcal/mol was obtained were discarded, while the remaining top-scored 913 peptides were subjected to a qualitative post-docking filter. Precisely, the selected compounds were superimposed with the receptor-based pharmacophore model and only those still matching the positively charged feature and at least two additional features of the model in their predicted binding mode were further considered.…”

Molecular Docking: Shifting Paradigms in Drug Discovery

“…Consensus approaches based on RD have also recently been reported for target fishing [143]. In particular, Lapillo and coworkers [143] performed an extensive benchmarking study on 13 different RD screening procedures to identify which method performed better in predicting targets for known ligands. Moreover, they also explored a docking-based consensus approach to improve RD target prediction performances [143].…”

“…In particular, Lapillo and coworkers [143] performed an extensive benchmarking study on 13 different RD screening procedures to identify which method performed better in predicting targets for known ligands. Moreover, they also explored a docking-based consensus approach to improve RD target prediction performances [143]. According to the results reported in this study, target-fishing performances of the different docking procedures ranged around 25% and 35% (in terms of true predictions) for single approaches, and 36% for the consensus.…”

“…According to the results reported in this study, target-fishing performances of the different docking procedures ranged around 25% and 35% (in terms of true predictions) for single approaches, and 36% for the consensus. However, this study also showed that the results of the applied RD approaches could be dependent on the features of the investigated proteins binding site [143].…”

Probabilistic divergence of a TBM methodology from the ideal protocol

“…Topological detail of a protein provides valuable resource for the routinely deployed life-science studies including the annotation of disulphide connectivity pattern [1,2], functional annotation [3–5], molecular docking and cross-talk based studies [6,7], enzyme design [8,9] and drug development [10]. For technical and resource limitations, the structure determination methodologies have failed to bridge the ever-increasing sequence-structure gap of the protein sequences [11], and have started deploying the predicted models for building more accurate solutions [12].…”