Common docking software, such as AutoDock Vina or AutoDock 4, require the ligand and receptor files to be converted into the PDBQT format. Once a correct pose has been identified, the pose will be produced also as a .pdbqt file.
Continue readingThis surprisingly simple question leads to a very interesting problem! If we take a benzene molecule, say, and rotate it 180 degrees, then we have the exact same molecule, but if we have a data structure in which our atoms are labelled, and we apply the same transformation to the atomic positions, the numbering does not reflect that symmetry. If we were then naively to calculate the RMSD it would be huge, despite the fact that the molecule is, chemically speaking, identical.
How can we make our RMSD calculations reflect these symmetries?
Continue readingIn this blogpost, I want to highlight the excellent work by Jahnke and collaborators. For the past 5 years, they have published an annual perspective covering fragment-to-lead success stories from the previous year. Very helpfully, their work includes a table detailing the hit fragment(s) and lead molecule, together with key experimental results and parameters.
Continue readingAfter the stunning announcement at CASP14 that DeepMind’s AlphaFold 2 had successfully predicted the structures of proteins from their sequence alone, it’s hard to believe we began this journey by representing molecules with punched cards…
Tales of carrying stacks of punched cards to the computer centre with a line drawn diagonally on the side of the stack, to help put them back in order should you trip and fall—seem like another universe—but this is what passed for the human-computer interface in much of the mid-20th century.
Continue readingFragment-based drug discovery (FBDD) is based on the idea that using small (< 300 Da), highly soluble compounds to screen against a target will give higher hit rates and sample chemical space more efficiently compared to screens using larger, drug-like compounds.
While entropy is a major driving force in many chemical changes and is a key component of the free energy of a molecule, it can be challenging to calculate with standard quantum thermochemical methods. With proper consideration in flexible molecules, we can break down the total entropy into different components, including vibrational, translational, rotational and conformational entropy. The calculation of conformational entropy is the most time-consuming as we have to sample all thermally-accessible conformers. Here, we attempt to understand the components that contribute to the conformational entropy of a molecule, and develop a physically-motivated statistical model to rapidly predict the conformational entropies of small molecules.
Continue readingIn drug discovery, compound promiscuity and selectivity refers to the ability of drug compounds to bind to several different- (promiscuous) or only one main target (selective). An important distinction here is that promiscuity is defined as specific interactions with multiple biological targets (polypharmacology) rather than a number of non-specific targets. At first glance, you might expect drugs to be designed to be as selective as possible, only hitting one biological target necessary to treat the disease and therefore reduce the chance of any side effects. This paradigm of single-target specificity has been challenged over the past two decades. Even between scientists in the drug discovery field, compound promiscuity is still a controversial topic. The field has increasingly paid attention to the topic of polypharmacology and studies have shown many pharmaceutically relevant compounds, including approved drugs to derive their biological activity from polypharmacology [1-3].
Continue readingICML is one of the largest machine learning conferences and, like many other conferences this year, is running virtually from 12th – 18th July.
The list of accepted papers can be found here, with 1,088 papers accepted out of 4,990 submissions (22% acceptance rate). Similar to my post on NeurIPS 2019 papers, I will highlight several of potential interest to the chem-/bio-informatics communities. As before, given the large number of papers, these were selected either by “accident” (i.e. I stumbled across them in one way or another) or through a basic search (e.g. Ctrl+f “molecule”).
Continue readingProCare [1] is a package developed at the University of Strasbourg which is able to align and score the similarity of protein cavities. The aim is to find ligand binding sites between different proteins that are similar enough to bind the same ligand. The method used in ProCare is designed to look particularly at fragment (~⅓ size of a druglike ligand) binding sites. The aim is to predict potential fragment hits by comparing the cavities of the targets.
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