Gallery of SPROUT output screen images

A 24 bit TrueColor TIFF high resolution version of each image is provided by clicking on the small inline images. The size of the large resolution images vary from 0.1MB to 3MB.

APPA (cylinder bonds, carbon atoms are gold) in the binding site of Trypsin (stick & ball representation, carbon atoms are green). The accessible surface of the receptor is coloured according to the desired ligand interaction: hydrogen bond acceptor ligand atoms are expected at red, donors at blue patches. Yellow clouds represent hydrophobic pockets. Some hydrogen bonding regions that are not satisfied by the ligand are indicated by solid objects: the red is a place for H-bond acceptor atom, the light blue (with white core) is for H-bond donor, the dark blue is for double donor and the magenta is for dual group.

Guanine diphosphate (GDP: cylinder bonds, carbon atoms are gold) in the binding site of P21 (stick & ball representation, carbon atoms are green). The accessible surface of the receptor is rendered translucent indicating the distance from the ligand atoms, i.e. close van der Waals contacts are opaque and the translucency increases by the square of distance between the van der Waals spheres until it becomes completely transparent at 2.5A. Surface colouring and the solid objects have the same meaning as on the previous image.

A different view of the GDP - P21 interaction site. In this image the complete transparency is reached at 1.8A. A different set of H-bonding sites is shown. The yellow patches of the surface indicate a combination of hydrophobic and hydrogen bond acceptor activity requirement (red plus green gives yellow).

PPACK (cylinder bonds, carbon atoms are gold) in the active site of Thrombin (stick & ball representation, carbon atoms are green). Accessible surface and hydrogen bonding site representation as on the previous images.

The active site of the protein P21. Some potential interaction sites are shown including the metal ion interaction which is indicated by a grey region near the magenta magnesium ion. The hydrogen bonding regions are shown with the same colour coding as on the previous images. The hydrophobic regions are indicated by small yellow crosses.

A complete inventory of the interactions between GDP and P21. All the interaction sites are shown that are satisfied by the ligand. Solid regions represent interactions that are satisfied with geometric parameters within the default tolerances of SPROUT. Other interactions (rendered by grid wire) occur with parameters that require adjustment to the default tolerances, i.e. these are weaker than average interactions. A key hydrophobic region is rendered by translucent yellow surface allowing to see the guanine aromatic system inside the hydrophobic pocket.

The accessible surface of the active site of P21 is shown in grid wire representation with the bound ligand, GDP inside.

Small functional groups are docked by SPROUT to some of the key interaction sites of P21 as a first step of generating novel potential ligands.

P21-GDP binding. The solvent accessible surface coloured by interaction type (red acceptor, blue - donor, green - hydrophobic) is shown first without the bound ligand in the upper half and then for the complex including the ligand. The solvation effects of the ligand binding can be observed by comparing the two pictures. The above one has a deep hydrophobic pocket (green on the right side) which is filled by the ligand and the complex shows mainly hydrophilic surface except for the sides of the pocket. Perhaps a larger hydrophobic ligand could do a better job?

Interaction possibilities of P21 that are missed by GDP. This figure highlights the missing interactions by clipping out the parts of the surface where GDP can satisfy the needs of the protein. Another small hydrophobic pocket (behind but too far from the sugar ring) emerges from this view suggesting possible targets for a blocking drug.

Thermolysin complexed with a small inhibitor. The accessible surface is coloured by the usual way (red acceptor, blue - donor, green - hydrophobic) and Zinc binding site is shown in grey grid-wire. The hydrophobic sidechain, the amide and the nitrogen of the phosphonamide have perfect interactions but one of the oxygens of the phosphonamide seems to reside in a place where hydrogen bond donor would be expected. The source of the surface color is a glutamate residue which is assumed to be deprotonated, hence electronegative. Is it possible that there is a protonated carboxylic acid next to a Zn2+ ion ?

Two views (180 degree rotation about the vertical axes) of a larger inhibitor complexed with thermolysin. More hydrophobic moieties, all of them placed perfectly nearby hydrophobic (green) surface patches. It looks like a better fit, indeed the biological activity of this ligand is higher by two order of magnitudes than the previous.

Yet another thermolysin inhibitor in two views. The phenyl ring on the left is a bit too far, it would be better above the hydrophobic area instead of the oxygen atoms.

This color coded interaction surface offers an insight into the inhibition of thrombin by TAPAP. The two views differ by a 90 degree rotation about the vertical axes. The left view shows the hydrophobic fits at the open part of the binding pocket and some hydrogen bonding from the sulfunamide and the carbonyl behind. The right view shows the interaction of the benzamidine with the deep pocket. The empty tunnel from this pocket with the hydrophobic end offers an interesting opportunity to improve binding.

Two other thrombin inhibitor are compared by a paralell (compatible orientation) view: argatroban (left) and NAPAP (right). It is appearent that both the hydrophobic and the hydrogen bonding interactions are satisfied better by NAPAP and the difference in biological activities supports this prediction.

Finally, the strongest thrombin inhibitor, PPACK is shown in two different views. In fact, PPACK forms an irreversible covalent interaction with thrombin. The covalent interaction possibility is predicted by SPROUT: there is a small green region in the upper right corner of the right image. The oxygen of the carbonyl group is involved in hydrogen bonding making the attached carbon open for a nucleophilic attack by the oxygen of the serine residue. The hydroxyl group is activated by deprotonation from the aspartate histidine catalytic hydrogen bonding pattern (visible in front of the ligand in stick and ball representation).

Growing a novel partial structure (cyan colour) from the phosphate binding pocket of P21. The structure is anchored by the metal ion and complex hydrogen bonding interaction sites. The growth is aimed towards the green sphere representing a hydrophobic region.

The counterpart of the previous structure grown from the hydrogen bonding group on the right towards the phosphate pocket on the left through the hydrophobic region (satisfied by the phenyl ring).

The final solution set is clustered according to 2D similarity for the sake of easier visual inspection. This picture shows 9 cluster centroids and part of the dendogram representing the result of the hierarchical clustering.

The generated structures are sorted according to different complexity measures (e.g. number of fusions, spiro joins, gauche interactions...). The picture shows the 3 simpliest (top row) and the 3 most complicated structure out of the 80 total generated by a half an hour run.