De Novo help page

Overview

This feature aims to generate 100 drug-like derivatives from a specified starting molecule. The results are returned in SMILES and as a html page with 2D representations.

Usage

Draw in the molecule or cut and paste a SMILES string into the panel displayed with the Open tool.
Enter your email address. If you enter the wrong address you won't get any results!
Check that your happy with the molecule option filters
Increase the Atom Insertion Curb if you desire bigger changes to the molecule.
In most circumstances, do not increase in the maximum number of hits.
Click the Submit button.

Potential Problems

If the starting molecule is not drug-like (ie fails the THINK standard drug-like criteria) then generating derivatives is challenging as they have to be big enough to create a drug-like molecules.

When drawing a 6,5 fused aromatic system, such as indole, it is best to drop the cyclopentadiene ring first and fuse benzene to it. Following the reverse steps results in strange bond orders which would need to be corrected prior to submitting the request.

2D Search

Overview

A 2D substructure search is performed on a collection of approximately 300,000 drug-like molecules which were used in the Find-a-Drug project and at that time they were commercially available from at least one supplier. The results are returned in SMILES and as a html page with 2D representations.

Usage

Draw in the molecule or cut and paste a SMILES string into the panel displayed with the Open tool.
Enter your email address. If you enter the wrong address you won't get any results!
Check that your happy with the molecule option filters
In most circumstances, do not increase in the maximum number of hits.
Click the Submit button.

Potential Problems

The number of molecules found can vary greatly with simplistic substructures returning vast numbers of hits whilst unusual queries may return very few or no hits. The number of hits is limited to 1000.

When drawing a 6,5 fused aromatic system, such as indole, it is best to drop the cyclopentadiene ring first and fuse benzene to it. Following the reverse steps results in strange bond orders which would need to be corrected prior to submitting the request.

RGroup Search

Overview

A 2D substructure search is performed on a collection of approximately 12,700 R-groups which were used in the Find-a-Drug project and at that time they were commercially available from at least one supplier. The results are returned in SMILES and as a html page with 2D representations.

Usage

Draw in the molecule or cut and paste a SMILES string into the panel displayed with the Open tool. This should include * for the attachment position.
Enter your email address. If you enter the wrong address you won't get any results!
Check that your happy with the molecule option filters
In most circumstances, do not increase in the maximum number of hits.
Click the Submit button.

Potential Problems

The number of molecules found can vary greatly with simplistic substructures returning vast numbers of hits whilst unusual queries may return very few or no hits. The number of hits is limited to 1000.

When drawing a 6,5 fused aromatic system, such as indole, it is best to drop the cyclopentadiene ring first and fuse benzene to it. Following the reverse steps results in strange bond orders which would need to be corrected prior to submitting the request.

Similarity Search

Overview

This search aims to retrieve similar molecules to the query based on a Tanimoto similarity index calculated on the functional group keys from a collection of approximately 300,000 drug-like molecules which were used in the Find-a-Drug project and at that time they were commercially available from at least one supplier. The results are returned in SMILES and as a html page with 2D representations.

Usage

Draw in the molecule or cut and paste a SMILES string into the panel displayed with the Open tool.
Enter your email address. If you enter the wrong address you won't get any results!
Check that your happy with the molecule option filters
In most circumstances, do not increase in the maximum number of hits.
Click the Submit button.

Potential Problems

The number of molecules found is difficult to predict and can change with relatively small changes to the molecule. The number of hits is limited to 1000.

When drawing a 6,5 fused aromatic system, such as indole, it is best to drop the cyclopentadiene ring first and fuse benzene to it. Following the reverse steps results in strange bond orders which would need to be corrected prior to submitting the request.

Docking

Overview

A collection of approximately 300,000 drug-like molecules is searched for candidates which dock into the specified binding site using a pharmacophore docking algorithm. The site is identified using either the PDB SITE record or a previously docked ligand. The later approach allows preferred interactions to be more readily duplicated. Both approaches invite users to specify residues with which interactions are required. The results are returned in MACCS SD file and as a html page with 2D representations. In general, it is best to try the default number of pharmacophores and warp speed before decreasing the number of centres and decreasing the warp speed - both of which will increase the number of hits and the time taken for the searches.

Usage

Upload the protein PDB file.
Enter your email address. If you enter the wrong address you won't get any results!
Check that your happy with the molecule option filters.
Click on one or more residues with which interactions are required.
Either select the target SITE or the ligand (HET group) which is bound in the desired site.
Reduce the number of pharmacophore centres or the warp speed if a previous search has return few or no hits.
In most circumstances, do not increase in the maximum number of hits.
Click the Submit button.

Potential Problems

If the required residues are not in the specified binding site then they are ignored!

The advanced scoring functions used by THINK mean that you do not need to be concerned about hydrogen addition or tautomerism.

The time taken and number of hits can vary greatly depending on the number of pharmacophore centres and warp speed specified.

Unlike the native and KNIME interfaces to THINK, there is no access to the functionality to locate binding sites. This means that a PDB SITE record or bound ligand is required.

Covid-19 Protease Inhibitor Search

Overview

This search uses a query based on SARS-CoV-2 mainprotease (pdb code 5RF7) with pharmacophores selected based on the series of fragment crystal structures discussed at PostEra. In practice, this means that molecules are docked to interact with at least 3 key residues with which ligand binding has been observed experimentally (in crystal structures). A docking score is also returned.

Usage

Draw in the molecule or cut and paste a SMILES string into the panel displayed with the Open tool.
Enter your email address. If you enter the wrong address you won't get any results!
Check that your happy with the molecule option filters
Click the Submit button.

Potential Problems

If the starting molecule is not drug-like (ie fails the THINK standard drug-like criteria) then it will be rejected (and reported as such).

When drawing a 6,5 fused aromatic system, such as indole, it is best to drop the cyclopentadiene ring first and fuse benzene to it. Following the reverse steps results in strange bond orders which would need to be corrected prior to submitting the request.

Many molecules which are predicted to bind are not confirmed as inhibitors experimentally. There can be many reasons for this not least that the calculations ignore energy changes associated with solvation and desolvation.

Fragment Based Drug Design

Overview

A small previous docked fragment bound within a site is grown into a larger drug-like molecule using THINK's De Novo capabilities, improving the binding potential. Specifying target residues allows the growth to be directed.

Usage

Upload the protein PDB file.
Enter your email address. If you enter the wrong address you won't get any results!
Check that your happy with the molecule option filters.
Click on one or more residues with which interactions are desired.
Select the bound fragment (HET group) to be grown.
There is not normally any reason to reduce the size of curb on non-H atoms added.
In most circumstances, do not increase in the maximum number of hits.
Click the Submit button.

Potential Problems

If the required residues are not in the specified binding site then they are ignored!

The advanced scoring functions used by THINK mean that you do not need to be concerned about hydrogen addition or tautomerism. However, the geometry of the ligand needs to be adequate to deduce bond orders. If this is not the case then the fragment should be omitted from the PDB file and the option to use an SD file should be used for the ligand coordinates and bond orders. (Without bond orders the numbers of hydrogens and the chemistry cannot be deduced).

If the starting fragment is not drug-like this can be problematic especially if it contains some functional group which is rejected because of toxicity or metabolic exclusions. Any R-group addition cannot remove such forbidden functional groups and the scope for De Novo generation is greatly restricted.

P450 Profile help page

Overview

Inhibition of one or more of the P450 family of enzymes is widely recognised as causing drug-drug interactions and in some circumstances toxicity. Clinical trials include experimental measurements of P450 inhibition. However, it can be argued that it would be better to have eliminated such series of molecules in early research and ideally not have made these molecules in the first instance.

Usage

Draw in the molecule or cut and paste a SMILES string into the panel displayed with the Open tool.
Enter your email address. If you enter the wrong address you won't get any results!
Click the Submit button.

Potential Problems

If the molecule does not pass the THINK drug-like criteria the job will fail and your account will be credited for the cost of this profile.

There are large number of marketed drugs which exhibit P450 inhibition and drug-drug interactions. Consequently it is expected that a high proportion of molecules will be predicted to exhibit some P450 inhibition.

Terms and Conditions of use

By using this website you agree to these terms and conditions of use.

You understand that this website is hosted on a public webserver which may inprinciple be hacked. A third party might possibly access chemical structures and the results of calculations.

You may use the results of calculations in whatever way or ways you consider appropriate but you may not publish or sell such results without permission.

The molecules are processed in the order in which they are submitted and the results sent by email. The time taken for the calculations is considerable and at times of peak demand it may take more than 24 hours.

Treweren Consultants (TC) reserves the right to reschedule, delay or cancel jobs and refund any payment.

Any payment you make is for services rendered and not for protection of confidential and/or proprietary information.

TC warrants that it has taken reasonable care writing the software but accepts no liability for errors, limitations, inaccuracies of the calculations.

TC shall not knowingly publish or utilise your confidential or proprietary information such as chemical structures without your prior written consent but does not warrant that such information will be kept confidential.

You are encouraged to purchase the THINK software and run it on your own secure servers if you wish to protect your chemical structures, calculation results etc as you might protect your confidential and proprietary information.

Ketcher (the 2D sketch program) is available on a GNU Affero General Public License and this modified version can be downloaded from here.

Covid-19

E-mail

Property Filters
Molecule mass min		max
Interaction centres min		max
N+O surface area min		max
Rotatable bonds min		max

Smiles

Note

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