Open and reproducible research in materials science relies on the availability of data, code, and established metadata standards. Journal research data policies (RDPs) are a primary mechanism by which these community norms are enforced. We survey RDPs for 171 materials science journals spanning 17 publishers, using an expanded coding framework that captures both data-and-code sharing behavior as well as refereeing standards. We find clear signs of progress in comparison to earlier research on RDPs: nearly all journals provide an RDP, and most mention data availability statements. However, enforceable requirements remain uncommon, public deposition of underlying data is rarely mandatory, and FAIR publication is typically encouraged rather than required. Expectations for research software are substantially less developed than those for data, with limited attention to versioning and persistent identifiers, dependency disclosure, reproducible execution environments, or software quality practices. Aggregating the findings on policy features into an open research data score reveals pronounced heterogeneity across journals. Neither impact factor nor access model reliably predicts policy strength. Double-coding further shows that more complex policies and stricter policies can be more challenging to interpret consistently, and we highlight challenges in consistent RDP encoding across studies. Lastly, we conclude with recommended best practice directions for the future.

Developing small-molecule compounds as effective and safe pharmaceuticals relies on their ability to bind disease-associated proteins with high affinity and selectivity. However, achieving ultra-high affinity in the femtomolar range is a major challenge in medicinal chemistry due to the inherent constraints of protein-ligand interactions. Here, we introduce a novel class of di-meta-substituted fluorinated benzenesulfonamide compounds that achieve an extraordinary dissociation constant of 44 fM for carbonic anhydrase IX (CAIX). CAIX, a transmembrane enzyme implicated in hypoxic tumor progression through the increase of microenvironment acidity, represents a promising target for anticancer therapy. Inhibiting CAIX may help suppress tumor growth and improve cancer treatment outcomes. The newly developed compounds exhibit the highest affinity for CAIX reported to date and rank among the strongest known non-covalent small-molecule inhibitors.

X-ray crystallography rarely captures chemical bonding between atoms of a structure in question. Most of the time distance-based heuristics are applied to establish the pairs of bonded atoms. One class of such heuristics depends on a set of bonding radii that estimate the idealised size of each chemical element in a bond. This publication describes an unsupervised workflow for deriving a bonding radii set from crystal structure data in the Crystallography Open Database.

The development of selective drug candidate molecules for cancer-related carbonic anhydrase isozymes IX and XII is challenging due to high homology binding sites among 12 catalytically active isozymes. Starting from the trifluorinated benzenesulfonamide with cyclooctylamino substituent at the meta position, we designed and synthesized di-meta-substituted fluorinated benzenesulfonamides with up to 10-fold affinity improvement for CAIX, resulting in low picomolar binders. The resulting CAIX-targeting compounds showed up to 1000-fold selectivity over off-target CA isozymes. The crystal structures of CAIX and CAXII complexes with synthesized compounds revealed detailed insights into protein-ligand interactions and adopted complex conformation. The potential of compounds with reduced off-target effects as possible anticancer drugs is supported by this study.

Discovery of small-molecule drugs relies on their strong binding affinity compared to nontarget proteins, thus possessing selectivity. Minor chemical structure changes usually exhibit little change in the compound efficacy, with rare exceptions. We developed a series of nearly 50 ortho-substituted benzenesulfonamides and experimentally measured their interactions with the 12 catalytically active human carbonic anhydrase (CA) isozymes. Inhibitors were designed using seven different substituent groups, including 4-sulfanyl-substituted 3-sulfamoyl benzoates and benzamides, 4-sulfinyl-substituted 3-sulfamoyl benzoates and benzamides, 4-sulfonyl-substituted 3-sulfamoyl benzoates and benzamides, and 4-amino-substituted benzamides. The oxidation state of sulfur at the ortho position significantly influenced the compound's affinity for CAIX, a target for anticancer drugs, demonstrating affinities hundreds of thousands of times stronger than related compounds. Coupled with X-ray crystal structures and molecular docking, the relationship between structure and thermodynamics offers insights into how small changes in the structure lead to significant changes in affinity for drug design.

A series of novel derivatives of 3-amino-4-hydroxybenzenesulfonamide was synthesized. As the analyzed compounds possess a sulfonamide group, the affinity of these compounds for human carbonic anhydrases (CAs) was measured by fluorescent thermal shift assay, and compound selectivity for different isoenzymes was identified. The crystal structures of the complexes of compound 25 with CAI and CAII were determined. Additionally, the activity of compounds on the viability of three cancer cell lines—human glioblastoma U-87, triple-negative breast cancer MDA-MB-231, and prostate adenocarcinoma PPC-1—was established using the MTT assay and compared to CAIX-selective and non-selective comparative compounds U-104 and acetazolamide. The half-maximal concentration (EC50) was determined for the identified most active compounds, and their selectivity over fibroblasts was established. Compound 9 (inhibitor of multi-CAs) and compound 21 (not binding to CAs), considered the most promising candidates, were tested in cancer cell 3D cultures (cancer spheroids) by assessing their effect on spheroid growth and viability. Both compounds reduced the viability of spheroids from all cancer cell lines. U-87 and PPC-1 spheroids became looser in the presence of compound 9, while the growth of MDA-MB-231 spheroids was slower compared to the control. Compound 21 reduced the growth of U-87 and MDA-MB-231 3D cultures, with no significant effect on PPC-1 spheroids.

High affinity and selectivity for intended targets is an important goal of small molecule design in drug discovery, yet balancing molecular flexibility and rigidity remains a challenge. While flexible compounds can increase target affinity, they often result in non-specific interactions and reduced selectivity. In contrast, rigid compounds may recognize their target more precisely and have lower off-target effects. In this study, we incorporated a 1,1-dioxido-1,4-thiazine ring into fluorinated benzenesulfonamide derivatives with bulky meta-substituents to enhance selectivity for human carbonic anhydrase IX (CAIX), an important cancer-associated target. Due to the structural similarities of CAIX with other carbonic anhydrase isozymes, selective inhibition remains a significant challenge. A series of 3,4-substituted trifluorobenzenesulfonamides containing oxidized thiazine rings were synthesized using a novel synthetic pathway. Although the potency against CAIX was modestly reduced compared to more flexible analogs, selectivity increased significantly, with lead compounds 7 d and 7 e exhibiting over 1000-fold selectivity for CAIX over most other isozymes. X-ray crystallography revealed the structural basis for this selectivity, confirming the advantageous positioning of rigidified compounds within some CA isozyme active sites. These findings highlight the potential of molecular rigidity in the design of highly selective inhibitors for therapeutic applications.

We designed novel pre-drug compounds that transform into an active form that covalently modifies particular His residue in the active site, a difficult task to achieve, and applied to carbonic anhydrase (CAIX), a transmembrane protein, highly overexpressed in hypoxic solid tumors, important for cancer cell survival and proliferation because it acidifies tumor microenvironment helping invasion and metastases processes. The designed compounds have several functionalities: (1) primary sulfonamide group recognizing carbonic anhydrases (CA), (2) high-affinity moieties specifically recognizing CAIX among all CA isozymes, and (3) forming a covalent bond with the His64 residue. Such targeted covalent compounds possess both high initial affinity and selectivity for the disease target protein followed by complete irreversible inactivation of the protein via covalent modification. Our designed prodrug candidates bearing moderately active pre-vinylsulfone esters or weakly active carbamates optimized for mild covalent modification activity to avoid toxic non-specific modifications and selectively target CAIX. The lead inhibitors reached 2 pM affinity, the highest among known CAIX inhibitors. The strategy could be used for any disease drug target protein bearing a His residue in the vicinity of the active site.

The Open Databases Integration for Materials Design (OPTIMADE) application programming interface (API) empowers users with holistic access to a growing federation of databases, enhancing the accessibility and discoverability of materials and chemical data. Since the first release of the OPTIMADE specification (v1.0), the API has undergone significant development, leading to the upcoming v1.2 release, and has underpinned multiple scientific studies. In this work, we highlight the latest features of the API format, accompanying software tools, and provide an update on the implementation of OPTIMADE in contributing materials databases. We end by providing several use cases that demonstrate the utility of the OPTIMADE API in materials research that continue to drive its ongoing development.

Carbonic anhydrase (CA) was among the first proteins whose X-ray crystal structure was solved to atomic resolution. CA proteins have essentially the same fold and similar active centers that differ in only several amino acids. Primary sulfonamides are well defined, strong and specific binders of CA. However, minor variations in chemical structure can significantly alter their binding properties. Over 1000 sulfonamides have been designed, synthesized and evaluated to understand the correlations between the structure and thermodynamics of their binding to the human CA isozyme family. Compound binding was determined by several binding assays: fluorescence-based thermal shift assay, stopped-flow enzyme activity inhibition assay, isothermal titration calorimetry and competition assay for enzyme expressed on cancer cell surfaces. All assays have advantages and limitations but are necessary for deeper characterization of these protein-ligand interactions. Here, the concept and importance of intrinsic binding thermodynamics is emphasized and the role of structure-thermodynamics correlations for the novel inhibitors of CA IX is discussed - an isozyme that is overexpressed in solid hypoxic tumors, and thus these inhibitors may serve as anticancer drugs. The abundant structural and thermodynamic data are assembled into the Protein-Ligand Binding Database to understand general protein-ligand recognition principles that could be used in drug discovery.

Argonaute (Ago) proteins are found in all three domains of life. The best-characterized group is eukaryotic Argonautes (eAgos). Being the structural core of RNA interference machinery, they use guide RNA molecules for RNA targeting. Prokaryotic Argonautes (pAgos) are more diverse, both in terms of structure (there are eAgo-like ‘long’ and truncated ‘short’ pAgos) and mechanism, as many pAgos are specific for DNA, not RNA guide and/or target strands. Some long pAgos act as antiviral defence systems. Their defensive role was recently demonstrated for short pAgo-encoding systems SPARTA and GsSir2/Ago, but the function and action mechanisms of all other short pAgos remain unknown. In this work, we focus on the guide and target strand preferences of AfAgo, a truncated long-B Argonaute protein encoded by an archaeon Archaeoglobus fulgidus . We demonstrate that AfAgo associates with small RNA molecules carrying 5′-terminal AUU nucleotides in vivo, and characterize its affinity to various RNA and DNA guide/target strands in vitro. We also present X-ray structures of AfAgo bound to oligoduplex DNAs that provide atomic details for base-specific AfAgo interactions with both guide and target strands. Our findings broaden the range of currently known Argonaute-nucleic acid recognition mechanisms.

MOTIVATION:Identifying the probable positions of the protein side-chains is one of the protein modelling steps that can improve the prediction of protein-ligand and protein-protein interactions. Most of the strategies predicting the side-chain conformations use predetermined dihedral angle lists, also called rotamer libraries, that are usually generated from a subset of high-quality protein structures. Although these methods are fast to apply, they tend to average out geometries instead of taking into account the surrounding atoms and molecules and ignore structures not included in the selected subset. Such simplifications can result in inaccuracies when predicting possible side-chain atom positions. RESULTS:We propose an approach that takes into account both of these circumstances by scanning through sterically accessible side-chain conformations and generating dihedral angle libraries specific to the target proteins. The method avoids the drawbacks of lacking conformations due to unusual or rare protein structures and successfully suggests potential rotamers with average RMSD closer to the experimentally determined side-chain atom positions than other widely used rotamer libraries. AVAILABILITY AND IMPLEMENTATION:The technique is implemented in open-source software package rotag and available at GitHub: https://www.github.com/agrybauskas/rotag, under GNU Lesser General Public License.

Knowledge about the 3-dimensional structure, orientation and interaction of chemical compounds is important in many areas of science and technology. X-ray crystallography is one of the experimental techniques capable of providing a large amount of structural information for a given compound, and it is widely used for characterisation of organic and metal-organic molecules. The method provides precise 3D coordinates of atoms inside crystals, however, it does not directly deliver information about certain chemical characteristics such as bond orders, delocalization, charges, lone electron pairs or lone electrons. These aspects of a molecular model have to be derived from crystallographic data using refined information about interatomic distances and atom types as well as employing general chemical knowledge. This publication describes a curated automatic pipeline for the derivation of chemical attributes of molecules from crystallographic models. The method is applied to build a catalogue of chemical entities in an open-access crystallographic database, the Crystallography Open Database (COD). The catalogue of such chemical entities is provided openly as a derived database. The content of this catalogue and the problems arising in the fully automated pipeline are discussed, along with the possibilities to introduce manual data curation into the process.