Determining the viability of a new drug molecule is a time- and resource-intensive task that makes computer-aided assessments a vital approach to rapid drug discovery. Here we develop a machine learning algorithm, iMiner, that generates novel inhibitor molecules for target proteins by combining deep reinforcement learning with real-time 3D molecula...
We describe a structural and functional study of the G protein-coupled apelin receptor, which binds two endogenous peptide ligands, apelin and Elabela/Toddler (ELA), to regulate cardiovascular development and function. Characterisation of naturally occurring apelin receptor variants from the UK Genomics England 100,000 Genomes Project, and AlphaFol...
Breast cancer, the second most prevalent cancer among women worldwide, necessitates the exploration of novel therapeutic approaches. To target the four subgroups of breast cancer "hormone receptor-positive and HER2-negative, hormone receptor-positive and HER2-positive, hormone receptor-negative and HER2-positive, and hormone receptor-negative and H...
Biomolecular condensates are essential in various cellular processes, and their misregulation has been demonstrated to underlie disease. Small molecules that modulate condensate stability and material properties offer promising therapeutic approaches, but mechanistic insights into their interactions with condensates remain largely lacking. We emplo...
Angiotensin II (AngII) regulates cerebral circulation and binds with a similar affinity to AT1 and AT2 receptors. Biased AT1 agonists, such as TRV027, which are able to selectively activate β-arrestin while blocking the Gq pathway, appear promising as new therapeutics. New pharmacological tools are needed to further explore the impact of biased AT1...
Two sets of tripodal ligands resulting from the reaction of 2-hydroxy-3-methoxybenzaldehyde (o-vanillin) with 1,1,1-tris(aminomethyl)ethane, Me–C(CH2NH2)3, or with N,N′,N″-trimethylphosphorothioic trihydrazide, P(S)[NMe–NH2]3, yield heterotrinuclear 3dII–4fIII–3dII complexes in which the 3d ions (MnII, FeII, CoII, NiII, and ZnII) occupy the inner N...
CD45 is a cell surface phosphatase that shapes the T cell receptor signaling threshold but does not have a known ligand. A family of adenovirus proteins, including E3/49K, exploits CD45 to evade immunity by binding to the extracellular domain of CD45, resulting in the suppression of T cell signaling. We determined the cryo-EM structure of this comp...
Accurately describing protein-ligand binding and unbinding kinetics remains challenging. Computational calculations are difficult and costly, while experimental measurements often lack molecular detail and can be unobtainable. Here, we extend our multiscale milestoning method, Simulation-Enabled Estimation of Kinetics Rates (SEEKR), with metadynami...
The development of theranostic agents for radiopharmaceuticals based on therapeutic alpha emitters marks an important clinical need. We describe a strategy for the development of theranostic agents of this type via the functionalization of the ligand with the diagnostic radionuclide fluorine-18. An analogue of macropa, an 18-membered macrocyclic ch...
The μ-opioid receptor (μOR), a prototypical G protein-coupled receptor (GPCR), is the target of opioid analgesics such as morphine and fentanyl. Due to the severe side effects of current opioid drugs, there is considerable interest in developing novel modulators of μOR function. Most GPCR ligands today are small molecules, however biologics, includ...
