The Art and Science of Molecular Docking.

Molecular docking has become an essential part of a structural biologist's and medicinal chemist's toolkits. Given a chemical compound and the three-dimensional structure of a molecular target-for example, a protein-docking methods fit the compound into the target, predicting the compound's bound structure and binding energy. Docking can be used to discover novel ligands for a target by screening large virtual compound libraries. Docking can also provide a useful starting point for structure-based ligand optimization or for investigating a ligand's mechanism of action. Advances in computational methods, including both physics-based and machine learning approaches, as well as in complementary experimental techniques, are making docking an even more powerful tool. We review how docking works and how it can drive drug discovery and biological research. We also describe its current limitations and ongoing efforts to overcome them.

A synthetic agent ameliorates polycystic kidney disease by promoting apoptosis of cystic cells through increased oxidative stress.

Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of chronic kidney disease and the fourth leading cause of end-stage kidney disease, accounting for over 50% of prevalent cases requiring renal replacement therapy. There is a pressing need for improved therapy for ADPKD. Recent insights into the pathophysiology of ADPKD revealed that cyst cells undergo metabolic changes that up-regulate aerobic glycolysis in lieu of mitochondrial respiration for energy production, a process that ostensibly fuels their increased proliferation. The present work leverages this metabolic disruption as a way to selectively target cyst cells for apoptosis. This small-molecule therapeutic strategy utilizes 11beta-dichloro, a repurposed DNA-damaging anti-tumor agent that induces apoptosis by exacerbating mitochondrial oxidative stress. Here, we demonstrate that 11beta-dichloro is effective in delaying cyst growth and its associated inflammatory and fibrotic events, thus preserving kidney function in perinatal and adult mouse models of ADPKD. In both models, the cyst cells with homozygous inactivation of Pkd1 show enhanced oxidative stress following treatment with 11beta-dichloro and undergo apoptosis. Co-administration of the antioxidant vitamin E negated the therapeutic benefit of 11beta-dichloro in vivo, supporting the conclusion that oxidative stress is a key component of the mechanism of action. As a preclinical development primer, we also synthesized and tested an 11beta-dichloro derivative that cannot directly alkylate DNA, while retaining pro-oxidant features. This derivative nonetheless maintains excellent anti-cystic properties in vivo and emerges as the lead candidate for development.

Artificial Intelligence and Machine Learning for Lead-to-Candidate Decision-Making and Beyond.

The use of artificial intelligence (AI) and machine learning (ML) in pharmaceutical research and development has to date focused on research: target identification; docking-, fragment-, and motif-based generation of compound libraries; modeling of synthesis feasibility; rank-ordering likely hits according to structural and chemometric similarity to compounds having known activity and affinity to the target(s); optimizing a smaller library for synthesis and high-throughput screening; and combining evidence from screening to support hit-to-lead decisions. Applying AI/ML methods to lead optimization and lead-to-candidate (L2C) decision-making has shown slower progress, especially regarding predicting absorption, distribution, metabolism, excretion, and toxicology properties. The present review surveys reasons why this is so, reports progress that has occurred in recent years, and summarizes some of the issues that remain. Effective AI/ML tools to derisk L2C and later phases of development are important to accelerate the pharmaceutical development process, ameliorate escalating development costs, and achieve greater success rates.

ChemMORT: an automatic ADMET optimization platform using deep learning and multi-objective particle swarm optimization.

Drug discovery and development constitute a laborious and costly undertaking. The success of a drug hinges not only good efficacy but also acceptable absorption, distribution, metabolism, elimination, and toxicity (ADMET) properties. Overall, up to 50% of drug development failures have been contributed from undesirable ADMET profiles. As a multiple parameter objective, the optimization of the ADMET properties is extremely challenging owing to the vast chemical space and limited human expert knowledge. In this study, a freely available platform called Chemical Molecular Optimization, Representation and Translation (ChemMORT) is developed for the optimization of multiple ADMET endpoints without the loss of potency (https://cadd.nscc-tj.cn/deploy/chemmort/). ChemMORT contains three modules: Simplified Molecular Input Line Entry System (SMILES) Encoder, Descriptor Decoder and Molecular Optimizer. The SMILES Encoder can generate the molecular representation with a 512-dimensional vector, and the Descriptor Decoder is able to translate the above representation to the corresponding molecular structure with high accuracy. Based on reversible molecular representation and particle swarm optimization strategy, the Molecular Optimizer can be used to effectively optimize undesirable ADMET properties without the loss of bioactivity, which essentially accomplishes the design of inverse QSAR. The constrained multi-objective optimization of the poly (ADP-ribose) polymerase-1 inhibitor is provided as the case to explore the utility of ChemMORT.

Potassium jarosite seeding of soils decreases lead and arsenic bioaccessibility: A path toward concomitant remediation.

Soils are common sources of metal(loid) contaminant exposure globally. Lead (Pb) and arsenic (As) are of paramount concern due to detrimental neurological and carcinogenic health effects, respectively. Pb and/or As contaminated soils require remediation, typically leading to excavation, a costly and environmentally damaging practice of removing soil to a central location (e.g., hazardous landfill) that may not be a viable option in low-income countries. Chemical remediation techniques may allow for in situ conversion of soil contaminants to phases that are not easily mobilized upon ingestion; however, effective chemical remediation options are limited. Here, we have successfully tested a soil remediation technology using potted soils that relies on converting soil Pb and As into jarosite-group minerals, such as plumbojarosite (PLJ) and beudantite, possessing exceptionally low bioaccessibility [i.e., solubility at gastric pH conditions (pH 1.5 to 3)]. Across all experiments conducted, all new treatment methods successfully promoted PLJ and/or beudantite conversion, resulting in a proportional decrease in Pb and As bioaccessibility. Increasing temperature resulted in increased conversion to jarosite-group minerals, but addition of potassium (K) jarosite was most critical to Pb and As bioaccessibility decreases. Our methods of K-jarosite treatment yielded <10% Pb and As bioaccessibility compared to unamended soil values of approximately 70% and 60%, respectively. The proposed treatment is a rare dual remediation option that effectively treats soil Pb and As such that potential exposure is considerably reduced. Research presented here lays the foundation for ongoing field application.

Ultra-high-efficiency capture of lead ions over acetylenic bond-rich graphdiyne adsorbent in aqueous solution.

A satisfactory material with high adsorption capacity is urgently needed to solve the serious problem of environment and human health caused by lead pollution. Herein, hydrogen-substituted graphdiyne (HsGDY) was successfully fabricated and employed to remove lead ions from sewage and lead-containing blood. The as-prepared HsGDY exhibits the highest adsorption capacity of lead among the reported materials with a maximum adsorption capacity of 2,390 mg/g, i.e., ~five times larger than that of graphdiyne (GDY). The distinguished hexagonal hole and stack mode of HsGDY allows the adsorption of more lead via its inner side adsorption mode in one single unit space. In addition, the Pb 6s and H 1s hybridization promotes the strong bonding of lead atom adsorbed at the acetylenic bond of HsGDY, contributing to the high adsorption capacity. HsGDY can be easily regenerated by acid treatment and showed excellent regeneration ability and reliability after six adsorption-regeneration cycles. Langmuir isotherm model, pseudo second order, and density functional theory (DFT) demonstrated that the lead adsorption process in HsGDY is monolayer chemisorption. Furthermore, the HsGDY-based portable filter can handle 1,000 µg/L lead-containing aqueous solution up to 1,000 mL, which is nearly 6.67 times that of commercial activated carbon particles. And, the HsGDY shows good biocompatibility and excellent removal efficiency to 100 µg/L blood lead, which is 1.7 times higher than that of GDY. These findings suggest that HsGDY could be a promising adsorbent for practical lead and other heavy metal removal.

Half of US population exposed to adverse lead levels in early childhood.

SignificanceConsiderable effort is expended to protect today's children from lead exposure, but there is little evidence on the harms past lead exposures continue to hold for yesterday's children, who are victims of what we term legacy lead exposures. We estimate that over 170 million Americans alive today were exposed to high-lead levels in early childhood, several million of whom were exposed to five-plus times the current reference level. Our estimates allow future work to plan for the health needs of these Americans and to inform estimation of the true contributions of lead exposure to population health. We estimate population-level effects on IQ loss and find that lead is responsible for the loss of 824,097,690 IQ points as of 2015.

Early life lead exposure from private well water increases juvenile delinquency risk among US teens.

Early life exposure to environmental lead (Pb) has been linked to decreased IQ, behavior problems, lower lifetime earnings, and increased criminal activity. Beginning in the 1970s, limits on Pb in paint, gasoline, food cans, and regulated water utilities sharply curtailed US environmental Pb exposure. Nonetheless, hundreds of thousands of US children remain at risk. This study reports on how unregulated private well water is an underrecognized Pb exposure source that is associated with an increased risk of teenage juvenile delinquency. We build a longitudinal dataset linking blood Pb measurements for 13,580 children under age 6 to their drinking water source, individual- and neighborhood-level demographics, and reported juvenile delinquency records. We estimate how early life Pb exposure from private well water influences reported delinquency. On average, children in homes with unregulated private wells had 11% higher blood Pb than those with community water service. This higher blood Pb was significantly associated with reported delinquency. Compared to children with community water service, those relying on private wells had a 21% (95% CI: 5 to 40%) higher risk of being reported for any delinquency and a 38% (95% CI: 10 to 73%) increased risk of being reported for serious delinquency after age 14. These results suggest that there could be substantial but as-yet-unrecognized social benefits from intervention programs to prevent children's exposure to Pb from private wells, on which 13% of the US population relies.

Racial residential segregation shapes the relationship between early childhood lead exposure and fourth-grade standardized test scores.

Racial/ethnic disparities in academic performance may result from a confluence of adverse exposures that arise from structural racism and accrue to specific subpopulations. This study investigates childhood lead exposure, racial residential segregation, and early educational outcomes. Geocoded North Carolina birth data is linked to blood lead surveillance data and fourth-grade standardized test scores (n = 25,699). We constructed a census tract-level measure of racial isolation (RI) of the non-Hispanic Black (NHB) population. We fit generalized additive models of reading and mathematics test scores regressed on individual-level blood lead level (BLL) and neighborhood RI of NHB (RINHB). Models included an interaction term between BLL and RINHB. BLL and RINHB were associated with lower reading scores; among NHB children, an interaction was observed between BLL and RINHB. Reading scores for NHB children with BLLs of 1 to 3 µg/dL were similar across the range of RINHB values. For NHB children with BLLs of 4 µg/dL, reading scores were similar to those of NHB children with BLLs of 1 to 3 µg/dL at lower RINHB values (less racial isolation/segregation). At higher RINHB levels (greater racial isolation/segregation), children with BLLs of 4 µg/dL had lower reading scores than children with BLLs of 1 to 3 µg/dL. This pattern becomes more marked at higher BLLs. Higher BLL was associated with lower mathematics test scores among NHB and non-Hispanic White (NHW) children, but there was no evidence of an interaction. In conclusion, NHB children with high BLLs residing in high RINHB neighborhoods had worse reading scores.

Tricuspid valve disease and cardiac implantable electronic devices.

The role of cardiac implantable electronic device (CIED)-related tricuspid regurgitation (TR) is increasingly recognized as an independent clinical entity. Hence, interventional TR treatment options continuously evolve, surgical risk assessment and peri-operative care improve the management of CIED-related TR, and the role of lead extraction is of high interest. Furthermore, novel surgical and interventional tricuspid valve treatment options are increasingly applied to patients suffering from TR associated with or related to CIEDs. This multidisciplinary review article developed with electrophysiologists, interventional cardiologists, imaging specialists, and cardiac surgeons aims to give an overview of the mechanisms of disease, diagnostics, and proposes treatment algorithms of patients suffering from TR associated with CIED lead(s) or leadless pacemakers.

A Roadmap for Ferroelectric-Antiferroelectric Phase Transition.

Antiferroelectric materials have shown great potential in electronic devices benefiting from the reversible phase transition between ferroelectric and antiferroelectric phases. Understanding the dipole arrangements and clear phase transition pathways is crucial for design of antiferroelectric materials-based energy storage and conversion devices. However, the specific phase transition details remain largely unclear and even controversial to date. Here, we have grown a series of PbZrO3 on SrTiO3 substrates and elucidated the fine atom structures and phase transition pathways using atomic-resolution transmission electron microscopy. Specifically, a roadmap for ferroelectric to antiferroelectric phase transitions, here with increasing film thickness, is determined as ferroelectric rhombohedral (R3c)-ferroelectric monoclinic (Pc)-ferrielectric orthorhombic (Ima2)-antiferroelectric orthorhombic (Pbam), where Pc and Ima2 phases act as structural bridges. Moreover, the phase transition pathway is strongly related to the synergistic effect of oxygen octahedral tilting and cation displacement. These findings provide an insightful understanding for the theories and related properties of antiferroelectrics.

Oriented Assembly of Lead Halide Perovskite Nanocrystals.

Cesium lead halide nanostructures have highly tunable optical and optoelectronic properties. Establishing precise control in forming perovskite single-crystal nanostructures is key to unlocking the full potential of these materials. However, studying the growth kinetics of colloidal cesium lead halides is challenging due to their sensitivity to light, electron beam, and environmental factors like humidity. In this study, in situ observations of CsPbBr3-particle dynamics were made possible through extremely low dose liquid cell transmission electron microscopy, showing that oriented attachment is the dominant pathway for the growth of single-crystal CsPbBr3 architectures from primary nanocubes. In addition, oriented assembly and fusion of ligand-stabilized cubic CsPbBr3 nanocrystals are promoted by electron beam irradiation or introduction of polar additives that both induce partial desorption of the original ligands and polarize the nanocube surfaces. These findings advance our understanding of cesium lead halide growth mechanisms, aiding the controlled synthesis of other perovskite nanostructures.

Superior Phonon-Limited Exciton Mobility in Lead-Free Two-Dimensional Perovskites.

Tin-based two-dimensional (2D) perovskites are emerging as lead-free alternatives in halide perovskite materials, yet their exciton dynamics and transport remain less understood due to defect scattering. Addressing this, we employed temperature-dependent transient photoluminescence (PL) microscopy to investigate intrinsic exciton transport in three structurally analogous Sn- and Pb-based 2D perovskites. Employing conjugated ligands, we synthesized high-quality crystals with enhanced phase stability at various temperatures. Our results revealed phonon-limited exciton transport in Sn perovskites, with diffusion constants increasing from 0.2 cm2 s-1 at room temperature to 0.6 cm2 s-1 at 40 K, and a narrowing PL line width. Notably, Sn-based perovskites exhibited greater exciton mobility than their Pb-based equivalents, which is attributed to lighter effective masses. Thermally activated optical phonon scattering was observed in Sn-based compounds but was absent in Pb-based materials. These findings, supported by molecular dynamics simulations, demonstrate that the phonon scattering mechanism in Sn-based halide perovskites can be distinct from their Pb counterparts.

Spatially Resolved Anion Diffusion and Tunable Waveguides in Bismuth Halide Perovskites.

Bismuth halide perovskites are widely regarded as nontoxic alternatives to lead halide perovskites for optoelectronics and solar energy harvesting applications. With a tailorable composition and intriguing optical properties, bismuth halide perovskites are also promising candidates for tunable photonic devices. However, robust control of the anion composition in bismuth halide perovskites remains elusive. Here, we established chemical vapor deposition and anion exchange protocols to synthesize bismuth halide perovskite nanoflakes with controlled dimensions and variable compositions. In particular, we demonstrated the gradient bromide distribution by controlling the anion exchange and diffusion processes, which is spatially resolved by time-of-flight secondary ion mass spectrometry. Moreover, the optical waveguiding properties of bismuth halide perovskites can be modulated by flake thicknesses and anion compositions. With a unique gradient anion distribution and controllable optical properties, bismuth halide perovskites provide new possibilities for applications in optoelectronic devices and integrated photonics.

Inhibiting the Appearance of Green Emission in Mixed Lead Halide Perovskite Nanocrystals for Pure Red Emission.

Mixed halide perovskites exhibit promising optoelectronic properties for next-generation light-emitting diodes due to their tunable emission wavelength that covers the entire visible light spectrum. However, these materials suffer from severe phase segregation under continuous illumination, making long-term stability for pure red emission a significant challenge. In this study, we present a comprehensive analysis of the role of halide oxidation in unbalanced ion migration (I/Br) within CsPbI2Br nanocrystals and thin films. We also introduce a new approach using cyclic olefin copolymer (COC) to encapsulate CsPbI2Br perovskite nanocrystals (PNCs), effectively suppressing ion migration by increasing the corresponding activation energy. Compared with that of unencapsulated samples, we observe a substantial reduction in phase separation under intense illumination in PNCs with a COC coating. Our findings show that COC enhances phase stability by passivating uncoordinated surface defects (Pb2+ and I-), increasing the formation energy of halide vacancies, improving the charge carrier lifetime, and reducing the nonradiative recombination density.

AFM-IR of Electrohydrodynamically Printed PbS Quantum Dots: Quantifying Ligand Exchange at the Nanoscale.

Colloidal quantum dots (cQDs), semiconductor materials with widely tunable properties, can be printed in submicrometer patterns through electrohydrodynamic printing, avoiding aggressive photolithography steps. Postprinting ligand exchange determines the final optoelectronic properties of the cQD structures. However, achieving a complete bulk exchange is challenging, and the conventional vibrational analysis lacks the required spatial resolution. Infrared nanospectroscopy enables quantitative analysis of vibrational signals and structural topography on the nanometer scale upon ligand substitution on lead sulfide cQDs. A solution of ethanedithiol led to rapid (∼60 s) exchange of ≤90% of the ligands, in structures up to ∼750 nm thick. Prolonged exposures (>1 h) caused the degradation of the microstructures, with a systematic removal of cQDs regulated by surface:bulk ratios and solvent interactions. This study establishes a method for the development of devices through a combination of tunable photoactive materials, additive manufacturing of microstructures, and their quantitative nanometer-scale analysis.

Ultrafast Dynamics of Self-Trapped Excitons in Cs2AgInCl6:Al3+ Double Perovskite Nanocrystals.

It is a huge challenge to increase the photoluminescence (PL) of lead-free halide perovskites, and understanding the mechanism behind exciton dynamics can provide a valuable solution. Herein, we achieved enhanced broad-band emission at ambient conditions in Cs2AgInCl6 by tuning self-trapped excitons (STEs) through Al3+ doping. Cryogenic measurements showed an inhomogeneous nature of STE emission due to the presence of defect states and is subject to thermal quenching. An increased Huang-Rhys factor (S-factor) resulted in better electron-phonon coupling and high-density STE states post Al3+ doping. Femtosecond transient absorption (fs-TA) results provided insights into the distribution dynamics of excitons, which occurs through gradient energy levels from free excitons (FE) to STEs, where each STE state potentially possesses higher quantized energy states. Overall, this study aims to comprehend the origins of self-trapping and decay of STEs in Cs2AgInCl6:Al3+ and emphasizes the potential of compositional engineering to mitigate self-trapping in this material.

Enhancing the Thermoelectric and Mechanical Properties of p-Type PbS through Band Convergence and Microstructure Regulation.

While lead sulfide shows notable thermoelectric properties, its production costs remain high, and its mechanical hardness is low, which constrains its commercial viability. Herein, we demonstrate a straightforward and cost-effective method to produce PbS nanocrystals at ambient temperature. By introducing controlled amounts of silver, we achieve p-type conductivity and fine-tune the energy band structure and lattice configuration. Computational results show that silver shifts the Fermi level into the valence band, facilitating band convergence and thereby enhancing the power factor. Besides, excess silver is present as silver sulfide, which effectively diminishes the interface barrier and enhances the Seebeck coefficient. Defects caused by doping, along with dislocations and interfaces, reduce thermal conductivity to 0.49 W m-1 K-1 at 690 K. Moreover, the alterations in crystal structure and chemical composition enhance the PbS mechanical properties. Overall, optimized materials show thermoelectric figures of merit approximately 10-fold higher than that of pristine PbS, alongside an average hardness of 1.08 GPa.

Scintillation Properties of CsPbBr3 Nanocrystals Prepared by Ligand-Assisted Reprecipitation and Dual Effect of Polyacrylate Encapsulation toward Scalable Ultrafast Radiation Detectors.

Lead halide perovskite nanocrystals (LHP-NCs) embedded in polymeric hosts are gaining attention as scalable and low-cost scintillation detectors for technologically relevant applications. Despite rapid progress, little is currently known about the scintillation properties and stability of LHP-NCs prepared by the ligand assisted reprecipitation (LARP) method, which allows mass scalability at room temperature unmatched by any other type of nanostructure, and the implications of incorporating LHP-NCs into polyacrylate hosts are still largely debated. Here, we show that LARP-synthesized CsPbBr3 NCs are comparable to particles from hot-injection routes and unravel the dual effect of polyacrylate incorporation, where the partial degradation of LHP-NCs luminescence is counterbalanced by the passivation of electron-poor defects by the host acrylic groups. Experiments on NCs with tailored surface defects show that the balance between such antithetical effects of polymer embedding is determined by the surface defect density of the NCs and provide guidelines for further material optimization.

Lead-Free Chiral Perovskite for High Degree of Circularly Polarized Light Emission and Spin Injection.

We report a zero-dimensional (0D) lead-free chiral perovskite (S-/R-MBA)4Bi2I10 with a high degree of circularly polarized light (CPL) emission. Our 0D lead-free chiral perovskite exhibits an average degree of circular polarization (DOCP) of 19.8% at 78 K under linearly polarized laser excitation, and the maximum DOCP can reach 25.8%, which is 40 times higher than the highest DOCP of 0.5% in all reported lead-free chiral perovskites to the best of our knowledge. The high DOCP of (S-/R-MBA)4Bi2I10 is attributed to the free exciton emission with a Huang-Rhys factor of 2.8. In contrast, all the lead-free chiral perovskites in prior reports are dominant by self-trapped exciton in which the spin relaxation reduces DOCP dramatically. Moreover, we realize the manipulation of the valley degree of freedom of monolayer WSe2 by using the spin injection of the 0D chiral lead-free perovskites. Our results provide a new perspective to develop lead-free chiral perovskite devices for CPL light source, spintronics, and valleytronics.