Skip to main content

Molecular databases and molecule complexity - part 2

Let have some examples - benzene (chembl277500) is unambiguous, it has no possibility of forming any tautomers, it cannot become protonated or lose a proton (i.e. act as a base or acid) under anything approaching physical conditions, it has no stereocenters, and furthermore has no internal degrees of freedom (it it conformationally rigid). So there is no ambiguity over calculated properties such as logP, molecular weight, etc, and you could take the structure directly from a database and do things like docking with it.

Next is pyridine (chembl266158), this has two biological forms, it is still rigid, and has no stereocenters or tautomeric forms, however, it can act as a base, and so can exist in a protonated form. These two forms have different molecular weights, overall charge and many other differences (for example, it's molecular dipole).

In particular, the binding to a receptor will be very different for these two forms, pyridine can act as a hydrogen bond acceptor, while the protonated for can't, but can act as a hydrogen bond donor - in one important factor the two forms of pyridine are opposite. The fraction of the two forms in biological systems will depend on the pH of the biological or experimental system, and also the pKa of pyridine (around 5.2 for the pKa of the conjugate acid). Typically, chemical databases will calculate and display properties for the neutral form of pyridine. Users, performing tasks such as docking, will probably need to consider both forms and dock two molecules not one.

A slightly more complicated case is 2-hydroxypyridine (chembl662), which is a classic case of tautomerism. The structure can be drawn with alternate bonding, but the two forms can rapidly interconvert. The is a small free energy difference between these two forms. The other tautomer (and the form found in solid samples of 2-hydroxypyridine) has the trivial name 2-pyridone. In solution, both forms are found, with the fractions found of each form depending on the solvent polarity.

These forms have the same molecular mass, have no stereochemical centers, but will have different calculated properties - the clogP will be different for the two forms. It is important to remember though that due to the fact they are rapidly interconvertable, they will appear to have a single logP experimentally. Again, due to the differences in hydrogen bonding potential, two forms need to be considered for a tasks like docking. What chemical databases do with cases like this varies, but typically a single tautomeric form will be used to calculate properties such as logP. What tautomer is used will depend on the particular software used.

Finally, another simple system, this time showing ambiguity over charge - 3-hydroxypyridine (chembl237847). This molecule exists in solution as an equilibrium of two physical forms, a neutral form, and a zwitterion. Calculated properties of these two forms for things like clogP will be different, the molecular weight will be the same, but again, for docking explicit consideration of the two distinct forms is required.

So hopefully, some simple examples showing that a single 2D structure of a molecule in a database can have multiple physically differing forms that can affect the calculation of properties and also have large impact on their use in modelling. Hopefully, I've also highlighted that this complexity is usually poorly handled in chemical databases (not least the current version of ChEMBL).

In the next part, we'll talk about just how complex this ambiguity is, the astronomical number of distinct structural forms possible for some molecules, and also address stereochemistry and conformational flexibility. 


Nice post!

Benzene is unambiguous, because of symmetry only. However, it's delocalization feature does pose problems for databases. Take 1,2-dimethylbenzene, which breaks the symmetry, and you run into the problem that the ring bond between the two methyls can be single or double, or, and that is what many databases do, aromatic.

I am still puzzled why the cheminformatics field did not choose for 'delocalized' instead; aromaticity is just a crappy concept.

Popular posts from this blog

A python client for accessing ChEMBL web services

Motivation The CheMBL Web Services provide simple reliable programmatic access to the data stored in ChEMBL database. RESTful API approaches are quite easy to master in most languages but still require writing a few lines of code. Additionally, it can be a challenging task to write a nontrivial application using REST without any examples. These factors were the motivation for us to write a small client library for accessing web services from Python. Why Python? We choose this language because Python has become extremely popular (and still growing in use) in scientific applications; there are several Open Source chemical toolkits available in this language, and so the wealth of ChEMBL resources and functionality of those toolkits can be easily combined. Moreover, Python is a very web-friendly language and we wanted to show how easy complex resource acquisition can be expressed in Python. Reinventing the wheel? There are already some libraries providing access to ChEMBL d

ChEMBL 29 Released

  We are pleased to announce the release of ChEMBL 29. This version of the database, prepared on 01/07/2021 contains: 2,703,543 compound records 2,105,464 compounds (of which 2,084,724 have mol files) 18,635,916 activities 1,383,553 assays 14,554 targets 81,544 documents Data can be downloaded from the ChEMBL FTP site: .  Please see ChEMBL_29 release notes for full details of all changes in this release: New Deposited Datasets EUbOPEN Chemogenomic Library (src_id = 55, ChEMBL Document IDs CHEMBL4649982-CHEMBL4649998): The EUbOPEN consortium is an Innovative Medicines Initiative (IMI) funded project to enable and unlock biology in the open. The aims of the project are to assemble an open access chemogenomic library comprising about 5,000 well annotated compounds covering roughly 1,000 different proteins, to synthesiz

Julia meets RDKit

Julia is a young programming language that is getting some traction in the scientific community. It is a dynamically typed, memory safe and high performance JIT compiled language that was designed to replace languages such as Matlab, R and Python. We've been keeping an an eye on it for a while but we were missing something... yes, RDKit! Fortunately, Greg very recently added the MinimalLib CFFI interface to the RDKit repertoire. This is nothing else than a C API that makes it very easy to call RDKit from almost any programming language. More information about the MinimalLib is available directly from the source . The existence of this MinimalLib CFFI interface meant that we no longer had an excuse to not give it a go! First, we added a BinaryBuilder recipe for building RDKit's MinimalLib into Julia's Yggdrasil repository (thanks Mosè for reviewing!). The recipe builds and automatically uploads the library to Julia's general package registry. The build currently targe

Identifying relevant compounds in patents

  As you may know, patents can be inherently noisy documents which can make it challenging to extract drug discovery information from them, such as the key targets or compounds being claimed. There are many reasons for this, ranging from deliberate obfuscation through to the long and detailed nature of the documents. For example, a typical small molecule patent may contain extensive background information relating to the target biology and disease area, chemical synthesis information, biological assay protocols and pharmacological measurements (which may refer to endogenous substances, existing therapies, reaction intermediates, reagents and reference compounds), in addition to description of the claimed compounds themselves.  The SureChEMBL system extracts this chemical information from patent documents through recognition of chemical names, conversion of images and extraction of attached files, and allows patents to be searched for chemical structures of interest. However, the curren

New Drug Warnings Browser

As mentioned in the announcement post of  ChEMBL 29 , a new Drug Warnings Browser has been created. This is an updated version of the entity browsers in ChEMBL ( Compounds , Targets , Activities , etc). It contains new features that will be tried out with the Drug Warnings and will be applied to the other entities gradually. The new features of the Drug Warnings Browser are described below. More visible buttons to link to other entities This functionality is already available in the old entity browsers, but the button to use it is not easily recognised. In the new version, the buttons are more visible. By using those buttons, users can see the related activities, compounds, drugs, mechanisms of action and drug indications to the drug warnings selected. The page will take users to the corresponding entity browser with the items related to the ones selected, or to all the items in the dataset if the user didn’t select any. Additionally, the process of creating the join query is no