Abstract
Recent research shows that majority of the druggable human proteome is yet to be annotated and explored. Accurate identification of these unexplored druggable proteins would facilitate development, screening, repurposing, and repositioning of drugs, as well as prediction of new drug–protein interactions. We contrast the current drug targets against the datasets of non-druggable and possibly druggable proteins to formulate markers that could be used to identify druggable proteins. We focus on the markers that can be extracted from protein sequences or names/identifiers to ensure that they can be applied across the entire human proteome. These markers quantify key features covered in the past works (topological features of PPIs, cellular functions, and subcellular locations) and several novel factors (intrinsic disorder, residue-level conservation, alternative splicing isoforms, domains, and sequence-derived solvent accessibility). We find that the possibly druggable proteins have significantly higher abundance of alternative splicing isoforms, relatively large number of domains, higher degree of centrality in the protein-protein interaction networks, and lower numbers of conserved and surface residues, when compared with the non-druggable proteins. We show that the current drug targets and possibly druggable proteins share involvement in the catalytic and signaling functions. However, unlike the drug targets, the possibly druggable proteins participate in the metabolic and biosynthesis processes, are enriched in the intrinsic disorder, interact with proteins and nucleic acids, and are localized across the cell. To sum up, we formulate several markers that can help with finding novel druggable human proteins and provide interesting insights into the cellular functions and subcellular locations of the current drug targets and potentially druggable proteins.
Highlights
Recent research approximates that the druggable human proteome has
1,750 drug targets if we include proteins that share high sequence similarity to drug targets that were annotated in other organisms
This is in contrast to the prior studies that compare drug targets
Summary
Knowledge of the drug-target interactions is essential for numerous applications including screening of drug candidates (Schneider, 2010; Núñez et al, 2012; Dalkas et al, 2013; Tseng and Tuszynski, 2015), drug repositioning and repurposing (Chong and Sullivan, 2007; Haupt and Schroeder, 2011; Oprea and Mestres, 2012; Hu and Bajorath, 2013; Li et al, 2016), characterization and mitigation of side-effects of drugs (Lounkine et al, 2012; Wang et al, 2012b; Kuhn et al, 2013; Tarcsay and Keserű, 2013; Hu et al, 2014), and prediction of novel protein-drug interactions (Wang et al, 2016a; LotfiMarkers of Druggable Human ProteinsShahreza et al, 2017; Ezzat et al, 2018; Hao et al, 2019; Wang and Kurgan, 2019; Wang and Kurgan, 2018; Wang et al, 2019). While the historically typical drug targets include G-protein coupled receptors, nuclear receptors, ion channels, and some of the enzymes (Overington et al, 2006; Imming et al, 2007), recent works suggest that many of the nonenzymes (e.g., scaffolding, regulatory, and structural proteins) and proteins involved in specific protein-protein interactions (PPIs) should be targeted by drugs (Makley and Gestwicki, 2013; Ozdemir et al, 2019), effectively expanding the list of potential drug targets These observations point to the fact that many of the drug targets remain to be discovered and characterized. We focus on the former definition where both the interactions and the therapeutic effects are considered
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