Abstract:The ability of small molecules to interact with multiple proteins is referred to as polypharmacology. This property is often linked to the therapeutic action of drugs but it is known also to be responsible for many of their side effects. Because of its importance, the development of computational methods that can predict drug polypharmacology has become an important line of research that led recently to the identification of many novel targets for known drugs. Nowadays, the majority of these methods are based … Show more
“…The similarities of other promiscuous ligands in Additional file 1: Table S2 also seem to be mainly hydrophobic and this is consistent with previous observations that promiscuity correlates with hydrophobicity [7, 45]. This correlation between promiscuity and hydrophobicity seems to hold for targets as well.…”
Section: Resultssupporting
confidence: 89%
“…The ability of a ligand to bind multiple targets likely depends on ligand-based and target-based properties, as both are inter-dependent. Ligand hydrophobicity is generally correlated with promiscuity [7]. Haupt et al also found a correlation between binding promiscuity and ligand flexibility [8].…”
BackgroundPromiscuity in molecular interactions between small-molecules, including drugs, and proteins is widespread. Such unintended interactions can be exploited to suggest drug repurposing possibilities as well as to identify potential molecular mechanisms responsible for observed side-effects.MethodsWe perform a large-scale analysis to detect binding-site molecular interaction field similarities between the binding-sites of the primary target of 400 drugs against a dataset of 14082 cavities within 7895 different proteins representing a non-redundant dataset of all proteins with known structure. Statistically-significant cases with high levels of similarities represent potential cases where the drugs that bind the original target may in principle bind the suggested off-target. Such cases are further analysed with docking simulations to verify if indeed the drug could, in principle, bind the off-target. Diverse sources of data are integrated to associated potential cross-reactivity targets with side-effects.ResultsWe observe that promiscuous binding-sites tend to display higher levels of hydrophobic and aromatic similarities. Focusing on the most statistically significant similarities (Z-score ≥ 3.0) and corroborating docking results (RMSD < 2.0 Å), we find 2923 cases involving 140 unique drugs and 1216 unique potential cross-reactivity protein targets. We highlight a few cases with a potential for drug repurposing (acetazolamide as a chorismate pyruvate lyase inhibitor, raloxifene as a bacterial quorum sensing inhibitor) as well as to explain the side-effects of zanamivir and captopril. A web-interface permits to explore the detected similarities for each of the 400 binding-sites of the primary drug targets and visualise them for the most statistically significant cases.ConclusionsThe detection of molecular interaction field similarities provide the opportunity to suggest drug repurposing opportunities as well as to identify potential molecular mechanisms responsible for side-effects. All methods utilized are freely available and can be readily applied to new query binding-sites. All data is freely available and represents an invaluable source to identify further candidates for repurposing and suggest potential mechanisms responsible for side-effects.Electronic supplementary materialThe online version of this article (doi:10.1186/s40360-017-0128-7) contains supplementary material, which is available to authorized users.
“…The similarities of other promiscuous ligands in Additional file 1: Table S2 also seem to be mainly hydrophobic and this is consistent with previous observations that promiscuity correlates with hydrophobicity [7, 45]. This correlation between promiscuity and hydrophobicity seems to hold for targets as well.…”
Section: Resultssupporting
confidence: 89%
“…The ability of a ligand to bind multiple targets likely depends on ligand-based and target-based properties, as both are inter-dependent. Ligand hydrophobicity is generally correlated with promiscuity [7]. Haupt et al also found a correlation between binding promiscuity and ligand flexibility [8].…”
BackgroundPromiscuity in molecular interactions between small-molecules, including drugs, and proteins is widespread. Such unintended interactions can be exploited to suggest drug repurposing possibilities as well as to identify potential molecular mechanisms responsible for observed side-effects.MethodsWe perform a large-scale analysis to detect binding-site molecular interaction field similarities between the binding-sites of the primary target of 400 drugs against a dataset of 14082 cavities within 7895 different proteins representing a non-redundant dataset of all proteins with known structure. Statistically-significant cases with high levels of similarities represent potential cases where the drugs that bind the original target may in principle bind the suggested off-target. Such cases are further analysed with docking simulations to verify if indeed the drug could, in principle, bind the off-target. Diverse sources of data are integrated to associated potential cross-reactivity targets with side-effects.ResultsWe observe that promiscuous binding-sites tend to display higher levels of hydrophobic and aromatic similarities. Focusing on the most statistically significant similarities (Z-score ≥ 3.0) and corroborating docking results (RMSD < 2.0 Å), we find 2923 cases involving 140 unique drugs and 1216 unique potential cross-reactivity protein targets. We highlight a few cases with a potential for drug repurposing (acetazolamide as a chorismate pyruvate lyase inhibitor, raloxifene as a bacterial quorum sensing inhibitor) as well as to explain the side-effects of zanamivir and captopril. A web-interface permits to explore the detected similarities for each of the 400 binding-sites of the primary drug targets and visualise them for the most statistically significant cases.ConclusionsThe detection of molecular interaction field similarities provide the opportunity to suggest drug repurposing opportunities as well as to identify potential molecular mechanisms responsible for side-effects. All methods utilized are freely available and can be readily applied to new query binding-sites. All data is freely available and represents an invaluable source to identify further candidates for repurposing and suggest potential mechanisms responsible for side-effects.Electronic supplementary materialThe online version of this article (doi:10.1186/s40360-017-0128-7) contains supplementary material, which is available to authorized users.
“…Moreover, a study based on the similarity ensemble approach showed that similar ligands were able to bind proteins with distantly related sequences (Keiser et al, 2007). Overall, local binding site similarities can be more important than global similarities to determine polypharmacology and drug repurposing (Jalencas and Mestres, 2013b; Anighoro et al, 2015). …”
Section: Structure-based Approaches In Drug Repurposingmentioning
confidence: 99%
“…Chemoisosterism can be defined as the property of two protein environments to bind the same molecular fragment, and can shed light into the inherent cross-pharmacology between protein targets. The degree of chemoisosterism was found to be related to the polypharmacology of chemical fragments (Jalencas and Mestres, 2013b). This approach allows the creation of interaction networks connecting chemical fragments to chemoisosteric protein environments.…”
Section: Structure-based Approaches In Drug Repurposingmentioning
Drug repurposing has become an important branch of drug discovery. Several computational approaches that help to uncover new repurposing opportunities and aid the discovery process have been put forward, or adapted from previous applications. A number of successful examples are now available. Overall, future developments will greatly benefit from integration of different methods, approaches and disciplines. Steps forward in this direction are expected to help to clarify, and therefore to rationally predict, new drug–target, target–disease, and ultimately drug–disease associations.
“…In the light of systems biology, it seems reasonable to first select a combination of receptors that will modify the biological network as desired, and then design a ligand that it is able to simultaneously bind them [3]. Unfortunately, in practice, most target combinations that are identified in the network analysis step will not show cross-pharmacology, since the discovery of intended promiscuous drugs is still restricted to members of the same protein family [4]. Besides few remarkable exceptions [5–9], the rational molecular design of ligands that intentionally bind several unrelated proteins is far too complicated, yielding ambivalent, non-drug like molecules.…”
In the era of systems biology, multi-target pharmacological strategies hold promise for tackling disease-related networks. In this regard, drug promiscuity may be leveraged to interfere with multiple receptors: the so-called polypharmacology of drugs can be anticipated by analyzing the similarity of binding sites across the proteome. Here, we perform a pairwise comparison of 90,000 putative binding pockets detected in 3,700 proteins, and find that 23,000 pairs of proteins have at least one similar cavity that could, in principle, accommodate similar ligands. By inspecting these pairs, we demonstrate how the detection of similar binding sites expands the space of opportunities for the rational design of drug polypharmacology. Finally, we illustrate how to leverage these opportunities in protein-protein interaction networks related to several therapeutic classes and tumor types, and in a genome-scale metabolic model of leukemia.
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