Accurate structure prediction of biomolecular interactions with AlphaFold 3.

The introduction of AlphaFold 2 has spurred a revolution in modelling the structure of proteins and their interactions, enabling a huge range of applications in protein modelling and design. Here we describe our AlphaFold 3 model with a substantially updated diffusion-based architecture that is capable of predicting the joint structure of complexes including proteins, nucleic acids, small molecules, ions and modified residues. The new AlphaFold model demonstrates substantially improved accuracy over many previous specialized tools: far greater accuracy for protein-ligand interactions compared with state-of-the-art docking tools, much higher accuracy for protein-nucleic acid interactions compared with nucleic-acid-specific predictors and substantially higher antibody-antigen prediction accuracy compared with AlphaFold-Multimer v.

Deorphaning a solute carrier 22 family member, SLC22A15, through functional genomic studies.

The human solute carrier 22A (SLC22A) family consists of 23 members, representing one of the largest families in the human SLC superfamily. Despite their pharmacological and physiological importance in the absorption and disposition of a range of solutes, eight SLC22A family members remain classified as orphans. In this study, we used a multifaceted approach to identify ligands of orphan SLC22A15.

Drug Metabolites Potently Inhibit Renal Organic Anion Transporters, OAT1 and OAT3.

Human OAT1 and OAT3 play major roles in renal drug elimination and drug-drug interactions. However, there is little information on the interactions of drug metabolites with transporters. The goal of this study was to characterize the interactions of drug metabolites with OAT1 and OAT3 and compare their potencies of inhibition with those of their corresponding parent drugs.

Discovery of Novel Inhibitors of a Critical Brain Enzyme Using a Homology Model and a Deep Convolutional Neural Network.

Rare neglected diseases may be neglected but are hardly rare, affecting hundreds of millions of people around the world. Here, we present a hit identification approach using AtomNet, the world's first deep convolutional neural network for structure-based drug discovery, to identify inhibitors targeting aspartate -acetyltransferase (ANAT), a promising target for the treatment of patients suffering from Canavan disease. Despite the lack of a protein structure or high sequence identity homologous templates, the approach successfully identified five low-micromolar inhibitors with drug-like properties.

Unraveling the functional role of the orphan solute carrier, SLC22A24 in the transport of steroid conjugates through metabolomic and genome-wide association studies.

Variation in steroid hormone levels has wide implications for health and disease. The genes encoding the proteins involved in steroid disposition represent key determinants of interindividual variation in steroid levels and ultimately, their effects. Beginning with metabolomic data from genome-wide association studies (GWAS), we observed that genetic variants in the orphan transporter, SLC22A24 were significantly associated with levels of androsterone glucuronide and etiocholanolone glucuronide (sentinel SNPs p-value <1x10-30).

Molecular Mechanisms for Species Differences in Organic Anion Transporter 1, OAT1: Implications for Renal Drug Toxicity.

Species differences in renal drug transporters continue to plague drug development with animal models failing to adequately predict renal drug toxicity. For example, adefovir, a renally excreted antiviral drug, failed clinical studies for human immunodeficiency virus due to pronounced nephrotoxicity in humans. In this study, we demonstrated that there are large species differences in the kinetics of interactions of a key class of antiviral drugs, acyclic nucleoside phosphonates (ANPs), with organic anion transporter 1 [(OAT1) SLC22A6] and identified a key amino acid residue responsible for these differences.

Human Concentrative Nucleoside Transporter 3 (hCNT3, SLC28A3) Forms a Cyclic Homotrimer.

Many anticancer and antiviral drugs are purine or pyrimidine analogues, which use membrane transporters to cross cellular membranes. Concentrative nucleoside transporters (CNTs) mediate the salvage of nucleosides and the transport of therapeutic nucleoside analogues across plasma membranes by coupling the transport of ligands to the sodium gradient. Of the three members of the human CNT family, CNT3 has the broadest selectivity and the widest expression profile.

Discovery of Competitive and Noncompetitive Ligands of the Organic Cation Transporter 1 (OCT1; SLC22A1).

Organic cation transporter 1 (OCT1) plays a critical role in the hepatocellular uptake of structurally diverse endogenous compounds and xenobiotics. Here we identified competitive and noncompetitive OCT1-interacting ligands in a library of 1780 prescription drugs by combining in silico and in vitro methods. Ligands were predicted by docking against a comparative model based on a eukaryotic homologue.

A phosphotyrosine switch regulates organic cation transporters.

Membrane transporters are key determinants of therapeutic outcomes. They regulate systemic and cellular drug levels influencing efficacy as well as toxicities. Here we report a unique phosphorylation-dependent interaction between drug transporters and tyrosine kinase inhibitors (TKIs), which has uncovered widespread phosphotyrosine-mediated regulation of drug transporters.

Quantitative correlation of the effect of process conditions on the capping tendencies of tablet formulations.

Capping is a mechanical defect in tablet formulation and manufacture. Understanding what influences tablet capping in terms of process variables and formulation properties and developing specialized techniques to correlate these variables with mechanical failures are practical interests of the pharmaceutical industry. Tablet compression emulator was used to rank order capping tendencies of a diverse sample set.

Impact of polymorphisms in drug pathway genes on disease-free survival in adults with acute myeloid leukemia.

Acute myeloid leukemia (AML) is a clinically heterogeneous disease, with a 5-year disease-free survival (DFS) ranging from under 10% to over 70% for distinct groups of patients. At our institution, cytarabine, etoposide and busulfan are used in first or second remission patients treated with a two-step approach to autologous stem cell transplantation (ASCT). In this study, we tested the hypothesis that polymorphisms in the pharmacokinetic and pharmacodynamic pathway genes of these drugs are associated with DFS in AML patients.