Exploration of Pan-ABC Transporter Modulators through Cutting-edge In Silico and In Vitro Methodologies to Generate Potential Targets, Diagnostics, and Therapeutics (PANABC)
Funding organisations: DFG (Germany)
Sven Marcel Stefan, University Medical Center Schleswig-Holstein (UKSH), LIED, Pahnke Lab, Lübeck, Germany & University of Oslo (UiO), Norway
Vigneshwaran Namasivayam, University Medical Center Schleswig-Holstein (UKSH), LIED, Pahnke Lab, Lübeck, Germany
Several major human diseases are associated with ABC transporter dysfunction, such as Alzheimer’s disease, atherosclerosis, or cancer. In addition, many orphan diseases are connected to ABC transporter defects, as for example, adrenoleukodystrophy, Stargardt’s disease, or Tangier disease. In the very most cases, no therapeutic options are available. The fundamental reason is that the vast majority of ABC transporters can be considered as ‘under-studied’ – and cannot be addressed by small-molecule modulators.
The PANABC project was founded in 2018 with the long-term prospect to provide selective agents to pharmacology and medicine which target all under-studied ABC transporters. The proposed project serves this objective by generating, discovering, developing, and exploring small-molecules to address less- and under-studied ABC transporters through a multitarget approach. Pan-ABC transporter modulators have received increased interest over the last years, and major advances have been made by high-throughput screening and/or synthesis approaches. Very recently, a computational approach was reported (‘C@PA’ – computer-aided pattern analysis) that allowed for the prediction of multitarget ABC transporter inhibitors. This model in its adapted forms has reached a biological hit rate of impressive 40%. However, these prediction rates account only for the well-studied ABC transporters ABCB1, ABCC1, and ABCG2, and their true multitarget characteristic still needs to be validated. Nevertheless, several drugs already demonstrated a truly multitarget nature, such as cyclosporine A, glibenclamide, or verapamil, indicating the existence of either similar or mutually overlapping binding sites amongst the ABC transporter superfamily. This ultimately gives the unique chance to explore less- and under-studied ABC transporters.
The subsequent improvement of C@PA with ABC transporter subfamily-specific datasets generated through extensive literature search and curation as well as processing of qualified data for the prediction of novel multitarget agents is the main goal of the proposed study. Hit molecules will eventually be validated in vitro covering various ABC transporters. In addition, molecular dynamic simulations and blind docking experiments in combination with mutagenesis studies will decipher the proposed common binding site of pan-ABC transporter modulators. Through cutting-edge computational chemistry and state-of-the-art cell-biology, this project will not only provide new potential drug targets, but also novel diagnostics and innovative therapeutics to approach common and rare human diseases.
Keywords: ABC transporters; multitargeting; polypharmacology; pattern analysis; bioactivity landscape; computational chemistry
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