Inspired by this blog post by the lovely Kate, I’ve been doing some BRICS decomposing of molecules myself. Like the structure-based goblin that I am, though, I’ve been applying it to 3D structures of molecules, rather than using the smiles approach she detailed. I thought it may be helpful to share the code snippets I’ve been using for this: unsurprisingly, it can also be done with RDKit!
I’ll use the same example as in the original blog post, propranolol.
Today’s blog post is about using PLIP to extract information about interactions between a protein and ligand in a bound complex, using data from PDBbind. The blog post will cover how to combine the protein pdb file and the ligand mol2 file into a pdb file, and how to use PLIP in a high-throughput manner with python.
In order for PLIP to consider the ligand as one molecule interacting with the protein, we need to modify the mol2 file of the ligand. The 8th column of the atom portion of a mol2 file (the portion starts with @<TRIPOS>ATOM) includes the ID of the ligand that the atom belongs to. Most often all the atoms have the same ligand ID, but for peptides for instance, the atoms have the ID of the residue they’re part of. The following code snippet will make the required changes:
ligand_file = 'data/5oxm/5oxm_ligand.mol2'
with open(ligand_file, 'r') as f:
ligand_lines = f.readlines()
mod = False
for i in range(len(ligand_lines)):
line = ligand_lines[i]
if line == '@<TRIPOS>BOND\n':
mod = False
if mod:
ligand_lines[i] = line[:59] + 'ISK ' + line[67:]
if line == '@<TRIPOS>ATOM\n':
mod = True
with open('data/5oxm/5oxm_ligand_mod.mol2', 'w') as g:
for j in ligand_lines:
g.write(j)
Deep learning (DL) methods in structural modelling are outcompeting force fields because they overcome the two main limitations to force fields methods – the prohibitively large search space for large systems and the limited accuracy of the description of the physics [4].
However, the two methods are also compatible. DL methods are helping to close the gap between the applications of force fields and ab initio methods [3]. The advantage of DL-based force fields is that the functional form does not have to be specified explicitly and much more accurate. Say goodbye to the 12-6 potential function.
In principle DL-based force fields can be applied anywhere where regular force fields have been applied, for example conformation generation [2]. The flip-side of DL-based methods commonly is poor generalization but it seems that force fields, when properly trained, generalize well. ANI trained on molecules with up to 8 heavy atoms is able to generalize to molecules with up to 54 atoms [1]. Excitingly for my research, ANI-2 [2] can replace UFF or MMFF as the energy minimization step for conformation generation in RDKit [5].
So let’s use Auto3D [2] to generated low energy conformations for the four molecules caffeine, Ibuprofen, an experimental hybrid peptide, and Imatinib:
CN1C=NC2=C1C(=O)N(C(=O)N2C)C CFF
CC(C)Cc1ccc(cc1)C(C)C(O)=O IBP
Cc1ccccc1CNC(=O)[C@@H]2C(SCN2C(=O)[C@H]([C@H](Cc3ccccc3)NC(=O)c4cccc(c4C)O)O)(C)C JE2
Cc1ccc(cc1Nc2nccc(n2)c3cccnc3)NC(=O)c4ccc(cc4)CN5CCN(CC5)C STI
Recently I’ve been thinking a lot about how to decompose a compound into smaller fragments specifically for a retrosynthetic purpose. My question is: given a compound, can I return building blocks that are likely to synthesize together to produce this compound simply by breaking likely bonds formed in a reaction? A method that is nearly 15 years old named, breaking of retrosynthetically interesting chemical substructures (BRICS), is one approach to do this. Here I’ll explore how BRICS can reflect synthetic accessibility.
When recently looking at some reaction data, I was confronted with the problem of atom-to-atom mapping (AAM) and what tools are available to tackle it. AAM refers to the process of mapping individual atoms in reactants to their corresponding atoms in the products, which is important for defining a reaction template and identifying which bonds are being formed and broken. This has many downstream uses for computational chemists, such as for reaction searching and forward and retrosynthesis planning1. The problem is that many reaction databases do not contain these mappings, and annotation by expert chemists is impractical for databases containing thousands (or more) data points.
Today’s post builds on my earlier blogpost on how to turn a SMILES string into an extended-connectivity fingerprint using RDKit and describes an interesting and easily implementable modification of the extended-connectivity fingerprint (ECFP) featurisation. This modification is based on representing the atoms in the input compound at a different (and potentially more useful) level of abstraction.
We remember that each binary component of an ECFP indicates the presence or absence of a particular circular subgraph in the input compound. Circular subgraphs that are structurally isomorphic are further distinguished according to their inherited atom- and bond features, i.e. two structurally isomorphic circular subgraphs with distinct atom- or bond features correspond to different components of the ECFP. For chemical bonds, this distinction is made on the basis of simple bond types (single, double, triple, or aromatic). To distinguish atoms, standard ECFPs use seven features based on the Daylight atomic invariants [1]; but there is also another less commonly used and often overlooked version of the ECFP that uses pharmacophoric atom features instead [2]. Pharmacophoric atom features attempt to describe atomic properties that are critical for biological activity or binding to a target protein. These features try to capture the potential for important chemical interactions such as hydrogen bonding or ionic bonding. ECFPs that use pharmacophoric atom features instead of standard atom features are called functional-connectivity fingerprints (FCFPs). The exact sets of standard- vs. pharmacophoric atom features for ECFPs vs. FCFPs are listed in the table below.
In RDKit, ECFPs can be changed to FCFPs extremely easily by changing a single input argument. Below you can find a Python/RDKit implementation of a function that turns a SMILES string into an FCFP if use_features = True and into an ECFP if use_features = False.
# import packages
import numpy as np
from rdkit.Chem import AllChem
# define function that transforms a SMILES string into an FCFP if use_features = True and into an ECFP if use_features = False
def FCFP_from_smiles(smiles,
R = 2,
L = 2**10,
use_features = True,
use_chirality = False):
"""
Inputs:
- smiles ... SMILES string of input compound
- R ... maximum radius of circular substructures
- L ... fingerprint-length
- use_features ... if true then use pharmacophoric atom features, if false then use standard DAYLIGHT atom features
- use_chirality ... if true then append tetrahedral chirality flags to atom features
Outputs:
- np.array(feature_list) ... FCFP/ECFP with length L and maximum radius R
"""
molecule = AllChem.MolFromSmiles(smiles)
feature_list = AllChem.GetMorganFingerprintAsBitVect(molecule,
radius = R,
nBits = L,
useFeatures = use_features,
useChirality = use_chirality)
return np.array(feature_list)
The use of pharmacophoric atom features makes FCFPs more specific to molecular interactions that drive biological activity. In certain molecular machine-learning applications, replacing ECFPs with FCFPs can therefore lead to increased performance and decreased learning time, as important high-level atomic properties are presented to the learning algorithm from the start and do not need to be inferred statistically. However, the standard atom features used in ECFPs contain more detailed low-level information that could potentially still be relevant for the prediction task at hand and thus be utilised by the learning algorithm. It is often unclear from the outset whether FCFPs will provide a substantial advantage over ECFPs in a given application; however, given how easy it is to switch between the two, it is almost always worth trying out both options.
[1] Weininger, David, Arthur Weininger, and Joseph L. Weininger. “SMILES. 2. Algorithm for generation of unique SMILES notation.” Journal of Chemical Information and Computer Sciences 29.2 (1989): 97-101.
[2] Rogers, David, and Mathew Hahn. “Extended-connectivity fingerprints.” Journal of Chemical Information and Modeling 50.5 (2010): 742-754.
Now that machine learning has managed to get its proverbial fingers into just about every pie, people have started to worry about the generalisability of methods used. There are a few reasons for these concerns, but a prominent one is that the pressure and publication biases that have led to reproducibility issues in the past are also very present in ML-based science.
The Center for Statistics and Machine Learning at Princeton University hosted a workshop last July highlighting the scale of this problem. Alongside this, they released a running list of papers highlighting reproducibility issues in ML-based science. Included on this list are 20 papers highlighting errors from 17 distinct fields, collectively affecting a whopping 329 papers.
The Astex Diverse set [1] is a dataset containing the crystallized poses of 85 protein-ligand complexes. It was introduced in 2007 to address problems in previous datasets such as incorrect ligand representation.
Loading the 85 ligand files with today’s version of the cheminformatics toolkit RDKit [2] is, however, not as straightforward as you might expect.
ChatGPT remembers the previous discussion, admits its mistakes and can even ask for clarification on ambiguous questions. It is also trained to refuse answering questions it deems inappropriate or goes against OpenAI’s AI alignment policy.
