Glycine-induced formation and druggability score prediction of protein surface pockets

Abstract

Nowadays, it is well established that most of the human diseases which are not related to pathogen infections have their origin from DNA disorders. Thus, DNA mutations, waiting for the availability of CRISPR-like remedies, will propagate into proteomics, offering the possibility to select natural or synthetic molecules to fight against the effects of malfunctioning proteins. Drug discovery, indeed, is a flourishing field of biotechnological research to improve human health, even though the development of a new drug is increasingly more expensive in spite of the massive use of informatics in Medicinal Chemistry. CRISPR technology adds new alternatives to cure diseases by removing DNA defects responsible of genome-related pathologies. In principle, the same technology, however, could also be exploited to induce protein mutations whose effects are controlled by the presence of suitable ligands. In this paper, a new idea is proposed for the realization of mutated proteins, on the surface of which more spacious transient pockets are formed and, therefore, are more suitable for hosting drugs. In particular, new allosteric sites are obtained by replacing amino-acids with bulky side chains with glycine, Gly, the smallest natural amino-acid. We also present a machine learning approach to evaluate the druggability score of new (or enlarged) pockets. Preliminary experimental results are very promising, showing that 10% of the sites created by the Gly-pipe software are druggable.

Structural Bioinformatics Survey on Disease-inducing Missense Mutations

“…Moreover, arginine PMM tends not to stay in buried protein moieties or in protein-protein interfaces, whereas glycine PMMs exhibit the opposite trend. It is interesting to note that the latter glycyl mutations are well above the average more frequently found in protein-ligand interfaces, in agreement with the suggested role of this amino acid to stabilize concave moieties of the protein surface [30]. Prevalent localization of pathological glycine mutations indicates that its replacement with amino acids bearing larger side chains causes structural stress and, hence, functional changes in mutated proteins.…”

Characterization of amino acid residues of T-cell receptors interacting with HLA-A*02-restricted antigen peptides

“…This is confirmed by all available structural analysis protein-small molecule interfaces (25). The protein region partially exposed to the solvent lacks large side chains, which is conducive to close contact with small organic molecules, thereby changing or regulating the activity of the protein (26)(27)(28). Given this background, we herein searched the crystal structure of HLA-A*02 restricted antigen peptide-TCR complexes from PDB.…”

Some Mendelian Disorders could be fixed with a pill? A Structural Bioinformatic investigation

“…Then, we used Gly-pipe , a software that we have recently developed to check whether Gly mutations occurring close to the protein surface can cause changes in its shape [18]. This software compares native and Gly-mutated structures to find new pockets close to the mutation site.…”

“…To explore the structural consequences of Gly-mutations, we had to take into account only proteins having PDB reference files. Then, we could use Gly-pipe , a software pipeline for the prediction and identification of potentially druggable surface pockets induced by glycine substitutions [10]. We checked whether the sequence coordinate of Gly-mutation given by each ClinVar entry corresponded in the PDB file either to the wild-type amino acid or Gly.…”