Motivation Root mean square deviation (RMSD) is one of the most useful and straightforward features for structural comparison between different conformations of the same molecule. Commonly, protein-ligand docking programs have included some utilities that allow the calculation of this value; however, they only work efficiently when exists a complete atom label equivalence between the evaluated conformations. Results We present LigRMSD, a free web-server for the automatic matching and RMSD calculations among identical or similar chemical compounds. This server allows the user to submit only a pair of identical or similar molecules or dataset of similar compounds to compare their three-dimensional conformations. Availability and implementation LigRMSD can be freely accessed at https://ligrmsd.appsbio.utalca.cl. Supplementary information Supplementary data are available at Bioinformatics online.

Evidence from systems biology indicates that promiscuous drugs, i.e. those that act simultaneously at various protein targets, are clinically better in terms of efficacy, than those that act in a more selective fashion. This has generated a new trend in drug development called polypharmacology. However, the rational design of promiscuous compounds is a difficult task, particularly when the drugs are aimed to act at receptors with diverse structure, function and endogenous ligand. In the present work, using docking and molecular dynamics methodologies, we established the most probable binding sites of SB-206553, a drug originally described as a competitive antagonist of serotonin type 2B/2C metabotropic receptors (5-HT2B/2CRs) and more recently as a positive allosteric modulator of the ionotropic α7 nicotinic acetylcholine receptor (nAChR). To this end, we employed the crystal structures of the 5-HT2BR and acetylcholine binding protein as templates to build homology models of the 5-HT2CR and α7 nAChR, respectively. Then, using a statistical algorithm, the similarity between these binding sites was determined. Our analysis showed that the most plausible binding sites for SB-206553 at 5-HT2Rs and α7 nAChR are remarkably similar, both in size and chemical nature of the amino acid residues lining these pockets, thus providing a rationale to explain its affinity towards both receptor types. Finally, using a computational tool for multiple binding site alignment, we determined a consensus binding site, which should be useful for the rational design of novel compounds acting simultaneously at these two types of highly different protein targets.

BackgroundSince the structure of proteins is more conserved than the sequence, the identification of conserved three-dimensional (3D) patterns among a set of proteins, can be important for protein function prediction, protein clustering, drug discovery and the establishment of evolutionary relationships. Thus, several computational applications to identify, describe and compare 3D patterns (or motifs) have been developed. Often, these tools consider a 3D pattern as that described by the residues surrounding co-crystallized/docked ligands available from X-ray crystal structures or homology models. Nevertheless, many of the protein structures stored in public databases do not provide information about the location and characteristics of ligand binding sites and/or other important 3D patterns such as allosteric sites, enzyme-cofactor interaction motifs, etc. This makes necessary the development of new ligand-independent methods to search and compare 3D patterns in all available protein structures.ResultsHere we introduce Geomfinder, an intuitive, flexible, alignment-free and ligand-independent web server for detailed estimation of similarities between all pairs of 3D patterns detected in any two given protein structures. We used around 1100 protein structures to form pairs of proteins which were assessed with Geomfinder. In these analyses each protein was considered in only one pair (e.g. in a subset of 100 different proteins, 50 pairs of proteins can be defined). Thus: (a) Geomfinder detected identical pairs of 3D patterns in a series of monoamine oxidase-B structures, which corresponded to the effectively similar ligand binding sites at these proteins; (b) we identified structural similarities among pairs of protein structures which are targets of compounds such as acarbose, benzamidine, adenosine triphosphate and pyridoxal phosphate; these similar 3D patterns are not detected using sequence-based methods; (c) the detailed evaluation of three specific cases showed the versatility of Geomfinder, which was able to discriminate between similar and different 3D patterns related to binding sites of common substrates in a range of diverse proteins.ConclusionsGeomfinder allows detecting similar 3D patterns between any two pair of protein structures, regardless of the divergency among their amino acids sequences. Although the software is not intended for simultaneous multiple comparisons in a large number of proteins, it can be particularly useful in cases such as the structure-based design of multitarget drugs, where a detailed analysis of 3D patterns similarities between a few selected protein targets is essential.Electronic supplementary materialThe online version of this article (doi:10.1186/s13321-016-0131-9) contains supplementary material, which is available to authorized users.

The dopamine transporter (DAT) plays a crucial role in the regulation of brain dopamine (DA) homeostasis through the re-uptake of DA back into the presynaptic terminal. In addition to re-uptake, DAT is also able to release DA through a process referred to as DAT-mediated DA efflux. This is the mechanism by which potent and highly addictive psychostimulants, such as amphetamine (AMPH) and its analogues, increase extracellular DA levels in motivational and reward areas of the brain. Recently, we discovered that G protein βγ subunits (Gβγ) binds to the DAT, and that activation of Gβγ results in DAT-mediated efflux - a similar mechanism as AMPH. Previously, we have shown that Gβγ binds directly to a stretch of 15 residues within the intracellular carboxy terminus of DAT (residues 582–596). Additionally, a TAT peptide containing residues 582 to 596 of DAT was able to block the Gβγ-induced DA efflux through DAT. Here, we use a combination of computational biology, mutagenesis, biochemical, and functional assays to identify the amino acid residues within the 582–596 sequence of the DAT carboxy terminus involved in the DAT-Gβγ interaction and Gβγ-induced DA efflux. Our in-silico protein-protein docking analysis predicted the importance of F587 and R588 residues in a network of interactions with residues in Gβγ. In addition, we observed that mutating R588 to alanine residue resulted in a mutant DAT which exhibited attenuated DA efflux induced by Gβγ activation. We demonstrate that R588, and to a lesser extent F5837, located within the carboxy terminus of DAT play a critical role in the DAT-Gβγ physical interaction and promotion of DA efflux. These results identify a potential new pharmacological target for the treatment of neuropsychiatric conditions in which DAT functionality is implicated including ADHD and substance use disorder.

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.