As a cheminformatician in a drug discovery campaign or an algorithm developer making the perfect Figure 1, when one generates a list of compounds for a given target there is a deep desire that the compounds are well received by the reviewer, be it a med chemist on the team or a peer reviewer. This ..read more

aka when to use a CutomBuildCommand or a CustomInstallCommand when building python packages with setup.py Bioinformatics software is complicated, and often a little bit messy. Recently I found myself wading through a python package building quagmire and thought I could share something I learnt about when to use a custom build command and when to ..read more

Background¶ Sort and Slice (SNS) was developed by a former OPIGlet, Markus, as a method for improving Extended Connectivity Fingerprints (ECFPs) by overcoming bit collisions. ECFPs are a form of topological fingerprint which denote the absence and presence of circular substructures in a molecule. The steps for deriving an ECFP from a molecule are as ..read more

The spatial or 3D structure of a molecule is particularly relevant to modeling its activity in QSAR. The 3D structural information affects molecular properties and chemical reactivities and thus it is important to incorporate them in deep learning models built for molecules. A key aspect of the spatial structure of molecules is the flexible distribution ..read more

In any task in the realm of virtual screening, there need to be many filters applied to a dataset of ligands to downselect the ‘best’ ones on a number of parameters to produce a manageable size. One popular filter is if a compound has a physical pose and good affinity as predicted by tools such as docking or energy minimisation. In my pipeline for downselecting elaborations of compounds proposed as fragment follow-ups, I calculate the pose and ΔΔG by energy minimizing the ligand with atom restraints to matching atoms in the fragment inspiration. I either use RDKit using its MMFF94 forcefield o ..read more

Some molecular pose generation methods benefit from an energy relaxation post-processing step. Example of a small molecule pose before and after energy minimization. The pose before minimization is shown in white, the optimized prediction is shown in pink, and a crystal pose is shown as reference in light blue. Note how the aromatic rings are flattened and the leftmost bond is shortened by the optimization. Here is a quick way to do this using OpenMM via a short script I prepared: 1. Get script git clone https://github.com/maabuu/posebusters_em.git cd posebusters_em 2. Setup environment con ..read more

Whereas it is easy to say in a paper “Given the HT-Sequential-ITC results, 42 led to 113, a substituted decahydro-2,6-methanocyclopropa[f]indene”, it is frequently rather trickier algorithmically figure out which atoms map to which. In Fragmenstein, for the placement route, for example, a lot goes on behind the scenes, yet for some cases human provided mapping may be required. Here I discuss how to get the mapping from Fragmenstein and what goes on behind the scenes. Here be dragons! (Not of any kind, but kaijū of the terrible sequel variety) When there is a single parent hit and it is a sing ..read more

I attended RSC Fragments 2024 (Hinxton, 4–5 March 2024), a conference dedicated to fragment-based drug discovery. The various talks were really good, because they gave overviews of projects involving teams across long stretches of time. As a result there were no slides discussing wet lab protocol optimisations and not a single Western blot was seen. The focus was primarily either illustrating a discovery platform or recounting a declassified campaign. The latter were interesting, although I’d admit I wish there had been more talk of organic chemistry —there was not a single moan/gloat about a ..read more

Have you ever needed to find a reaction SMARTS pattern for a certain reaction but don’t have it already written out? Do you have a reaction SMARTS pattern but need to test it on a set of reactants and products to make sure it transforms them correctly and doesn’t allow for odd reactants to work? I recently did and I spent some time developing functions that can: Generate a reaction SMARTS for a reaction given two reactants, a product, and a reaction name. Check the reaction SMARTS on a list of reactants and products that have the same reaction name. What is SMARTS? SMARTS stands for SMiles A ..read more

Fragmenstein is a Python module that combine hits or position a derivative following given templates by being very strict in obeying them. This is done by creating a “monster”, a compound that has the atomic positions of the templates, which then reanimated by very strict energy minimisation. This is done in two steps, first in RDKit with an extracted frozen neighbourhood and then in PyRosetta within a flexible protein. The mapping for both combinations and placements are complicated, but I will focus here on a particular step the minimisation, primarily in answer to an enquiry, namely how doe ..read more