Abstract
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.
Highlights
Promiscuity in molecular interactions between small-molecules, including drugs, and proteins is widespread
Molecular promiscuity can be described as the situation in which small molecules and proteins participate in molecular interactions beyond those naturally selected or, in the case of drugs, designed
Redundant drugs include acetazolamide (14 entries), tretinoin (7 entries) as well as zanamivir, progesterone, sirolimus, liothyronine, vorinostat, estradiol and tetrahydrobiopterine represented in 6 entries each (Additional file 1: Table S1)
Summary
Promiscuity in molecular interactions between small-molecules, including drugs, and proteins is widespread. Experimental assays of 72 inhibitors with 442 kinases showed that 64% of the compounds bind 20% of kinases with an affinity threshold of 3 μM [1]. Among these 72 inhibitors, 11 are FDA-approved drugs. Another inter-family large-scale study with data for 238 655 compounds and 2876 targets, showed that promiscuity is often within the same protein family, and among members of different protein families [2]. Promiscuity can play a role in the appearance of sideeffects, but could be leveraged in polypharmacological strategies or repurposing
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