A New Strategy for Multitarget Drug Discovery/Repositioning Through the Identification of Similar 3D Amino Acid Patterns Among Proteins Structures: The Case of Tafluprost and its Effects on Cardiac Ion Channels

Abstract

The identification of similar three-dimensional (3D) amino acid patterns among different proteins might be helpful to explain the polypharmacological profile of many currently used drugs. Also, it would be a reasonable first step for the design of novel multitarget compounds. Most of the current computational tools employed for this aim are limited to the comparisons among known binding sites, and do not consider several additional important 3D patterns such as allosteric sites or other conserved motifs. In the present work, we introduce Geomfinder2.0, which is a new and improved version of our previously described algorithm for the deep exploration and discovery of similar and druggable 3D patterns. As compared with the original version, substantial improvements that have been incorporated to our software allow: (i) to compare quaternary structures, (ii) to deal with a list of pairs of structures, (iii) to know how druggable is the zone where similar 3D patterns are detected and (iv) to significantly reduce the execution time. Thus, the new algorithm achieves up to 353x speedup as compared to the previous sequential version, allowing the exploration of a significant number of quaternary structures in a reasonable time. In order to illustrate the potential of the updated Geomfinder version, we show a case of use in which similar 3D patterns were detected in the cardiac ions channels NaV1.5 and TASK-1. These channels are quite different in terms of structure, sequence and function and both have been regarded as important targets for drugs aimed at treating atrial fibrillation. Finally, we describe the in vitro effects of tafluprost (a drug currently used to treat glaucoma, which was identified as a novel putative ligand of NaV1.5 and TASK-1) upon both ion channels’ activity and discuss its possible repositioning as a novel antiarrhythmic drug.

CaviDB: a database of cavities and their features in the structural and conformational space of proteins

“…Promiscuous proteins are a breaking point in the “structure–function” paradigm and the concept of biological specificity ( 38 , 39 ). Promiscuous protein behavior presents both challenges and opportunities for drug discovery programs and has been explored as a strategy for drug repurposing ( 40–42 ).…”

CaviDB: a database of cavities and their features in the structural and conformational space of proteins

“…Promiscuous proteins are a breaking point in the ‘structure–function’ paradigm and the biological specificity concept [2,26]. The promiscuous behavior of proteins offers both challenges and opportunities to drug discovery programs and has been explored as a strategy for drug repurposing [10,16,57].…”

Common Structural Pattern for Flecainide Binding in Atrial-Selective Kv1.5 and Nav1.5 Channels: A Computational Approach

“…Similarly, four domains are also present in K v 1.5, but they are divided in four identical chains or subunits. To our knowledge, the comparison of the drug BS in ion channels is still limited; the first evidence of a common structural pattern in the Na v 1.5 and TASK-1 drug BS was recently reported [ 18 ]. The comparison of the BS contributes to an understanding of the promiscuity nature of a ligand, the discovery of new MTDLs, drug repurposing and analysis of side effects [ 19 ].…”