Synthesis, Pharmacological, and Biological Evaluation of 2-FuroylBased MIF-1 Peptidomimetics and the Development of a GeneralPurpose Model for Allosteric Modulators (ALLOPTML)

This work describes the synthesis and pharmacological evaluation of 2-furoyl-based Melanostatin (MIF-1) peptidomimetics as dopamine D-2 modulating agents. Eight novel peptidomimetics were tested for their ability to enhance the maximal effect of tritiated N-propylapomorphine ([H-3]-NPA) at D2 receptors (D2R). In this series, 2-furoyl-L-leucylglycinamide (6a) produced a statistically significant increase in the maximal [3H]-NPA response at 10 pM (11 +/- 1%), comparable to the effect of MIF-1 (18 +/- 9%) at the same concentration. This result supports previous evidence that the replacement of proline residue by heteroaromatic scaffolds are tolerated at the allosteric binding site of MIF-1. Biological assays performed for peptidomimetic 6a using cortex neurons from 19-day-old Wistar-Kyoto rat embryos suggest that 6a displays no neurotoxicity up to 100 mu M. Overall, the pharmacological and toxicological profile and the structural simplicity of 6a makes this peptidomimetic a potential lead compound for further development and optimization, paving the way for the development of novel modulating agents of D2R suitable for the treatment of CNS-related diseases. Additionally, the pharmacological and biological data herein reported, along with >20 000 outcomes of preclinical assays, was used to seek a general model to predict the allosteric modulatory potential of molecular candidates for a myriad of target receptors, organisms, cell lines, and biological activity parameters based on perturbation theory (PT) ideas and machine learning (ML) techniques, abbreviated as ALLOPTML. By doing so, ALLOPTML shows high specificity Sp = 89.2/89.4%, sensitivity Sn = 71.3/72.2%, and accuracy Ac = 86.1%/86.4% in training/validation series, respectively. To the best of our knowledge, ALLOPTML is the first general-purpose chemoinformatic tool using a PTML-based model for the multioutput and multicondition prediction of allosteric compounds, which is expected to save both time and resources during the early drug discovery of allosteric modulators. [Graphics]

Automated summary

The synthesis and pharmacological evaluation of 2-furoyl-based Melanostatin (MIF-1) peptidomimetics as dopamine D-2 modulating agents were described in this work. Peptidomimetic 6a showed promising results without neurotoxicity at high concentrations, making it a potential lead compound for further development. Additionally, the ALLOPTML model, based on perturbation theory and machine learning, demonstrated high specificity, sensitivity, and accuracy in predicting the allosteric modulatory potential of molecular candidates.