SwissADME: a free web tool to evaluate pharmacokinetics, drug-likeness and medicinal chemistry friendliness of small molecules

Abstract

To be effective as a drug, a potent molecule must reach its target in the body in sufficient concentration, and stay there in a bioactive form long enough for the expected biologic events to occur. Drug development involves assessment of absorption, distribution, metabolism and excretion (ADME) increasingly earlier in the discovery process, at a stage when considered compounds are numerous but access to the physical samples is limited. In that context, computer models constitute valid alternatives to experiments. Here, we present the new SwissADME web tool that gives free access to a pool of fast yet robust predictive models for physicochemical properties, pharmacokinetics, drug-likeness and medicinal chemistry friendliness, among which in-house proficient methods such as the BOILED-Egg, iLOGP and Bioavailability Radar. Easy efficient input and interpretation are ensured thanks to a user-friendly interface through the login-free website http://www.swissadme.ch. Specialists, but also nonexpert in cheminformatics or computational chemistry can predict rapidly key parameters for a collection of molecules to support their drug discovery endeavours.

Figure 1. SwissADME submission page.

The actual input is a list of SMILES, which contains one molecule per line with an optional name separated by a space. Molecules can be directly pasted or typed in SMILES format, or inserted through the molecular sketcher. The latter enables importing from databases, opening a local file or drawing a 2D chemical structure to be transferred to the list by clicking on the double-arrow button. When the list of molecules is ready to be submitted, the user can start the calculations by clicking on the “Run” button.

Figure 2. Computed parameter values are grouped in the different sections of the one-panel-par-molecule output (Physicochemical Properties, Lipophilicity, Pharmacokinetics, Drug-likeness and Medicinal Chemistry).

The panel is headed by the molecule name and an up-arrow button to scroll to the top of the page. The molecule is first described by its chemical structure and canonical SMILES together with the Bioavailability Radar (see Fig. 3). Contextual help can be displayed by leaving the mouse over the radar or different question mark icons next to some parameters.

Figure 3. The Bioavailability Radar enables a first glance at the drug-likeness of a molecule.

The pink area represents the optimal range for each properties (lipophilicity: XLOGP3 between −0.7 and +5.0, size: MW between 150 and 500 g/mol, polarity: TPSA between 20 and 130 Ų, solubility: log S not higher than 6, saturation: fraction of carbons in the sp hybridization not less than 0.25, and flexibility: no more than 9 rotatable bonds. In this example, the compound is predicted not orally bioavailable, because too flexible and too polar.

Figure 4. The BOILED-Egg

allows for intuitive evaluation of passive gastrointestinal absorption (HIA) and brain penetration (BBB) in function of the position of the molecules in the WLOGP-versus-TPSA referential. The white region is for high probability of passive absorption by the gastrointestinal tract, and the yellow region (yolk) is for high probability of brain penetration. Yolk and white areas are not mutually exclusive. In addition the points are coloured in blue if predicted as actively effluxed by P-gp (PGP+) and in red if predicted as non-substrate of P-gp (PGP−). For an interactive analysis, the user can leave the mouse over a dot to show the structure of the molecule and click on the dot to scroll to the corresponding output panel. In this example, Lapatinib is predicted as not absorbed and not brain penetrant (outside the Egg), Omeprazol is predicted well-absorbed but not accessing the brain (in the white) and PGP+ (blue dot), Sunitinib is predicted as passively crossing the BBB (in the yolk), but pumped-out from the brain (blue dot), and Palonosetron is predicted as brain-penetrant (in the yolk) and not subject to active efflux (red dot). One molecule is predicted not absorbed and not BBB permeant because outside of the range of the plot (streptomycin with a TPSA of 331.43 Å  and a WLOGP of −7.74).