Structure-activity Relationship Research Articles

Fluorinated Coumarin Derivatives as Selective PET Tracer for MAO-B Imaging.

Monoamine oxidase-B (MAO-B), predominantly exists on the outer mitochondrial membrane of astrocytes, serves as a crucial biomarker for reactive astrocytes during neuroinflammatory responses and various neurodegenerative diseases. In this study, we synthesized a series of fluorinated coumarin derivatives and evaluated their structure-activity relationship and subtype selectivity for MAO-B. Following this, the preclinical bioevaluation containing in vivo positron emission tomography (PET) imaging and ex vivo autoradiography studies led to the identification of the novel PET tracer, [18F]8, which demonstrated high affinity for MAO-B (IC50 = 0.59 nM) and appreciable brain pharmacokinetics (SUVmax = 2.15 at 2 min, brain2min/60min = 7.67) in rats. Furthermore, the radioactivates from [18F]8 in regions of MAO-B expression could be effectively inhibited by Selegiline. All these positive findings supported that [18F]8 is a promising candidate for MAO-B PET imaging, which merits further evaluation.

A comprehensive dataset on cytotoxicity of ionic liquids

Ionic liquids (ILs) are structurally tunable salts with applications ranging from chemical synthesis to batteries, novel materials and medicine. Despite their potential, the toxicity of ILs poses significant environmental and biological challenges. This study introduces a comprehensive dataset of cytotoxicity of 1227 ILs, compiled from 151 research papers and encompassing 3837 data entries. For each entry, the following information is provided: substance name, empirical formula, CAS, SMILES, molecular weight, cytotoxicity value, details on the experimental setup (incubation time, cell line, assay used, etc.), and reference to the original publication. This dataset can be used for deriving structure‒activity relationships and establishing the major structural elements that govern the cytotoxic effects of ILs on eukaryotic cells. The dataset is available freely to all researchers.

Eradication of Therapy-Resistant Cancer Stem Cells by Novel Telmisartan Derivatives.

The present structure-activity relationship study investigates the development of novel chemosensitizers targeting therapy-resistant cancer stem cells (CSCs). We used 4'-((2-propyl-1H-benzo[d]imidazole-1-yl)methyl)-[1,1'-biphenyl]-2-carboxylic acid, derived from the angiotensin II type 1 receptor blocker telmisartan, as a lead structure, demonstrating that the biphenyl moiety is essential for chemosensitizing activity. Introducing a methyl carboxylate or carboxamide instead of the COOH-group significantly enhanced this effect, leading to the development of highly potent compounds. These novel, noncytotoxic chemosensitizers effectively target CSCs and overcome drug resistance by interfering with CSC persistence mechanisms─hyperactivated STAT5 signaling and increased drug transporter activity─with demonstrated efficacy in leukemia, ovarian, and prostate cancers. The carboxamide of telmisartan (telmi-amide, 7c) significantly reduced tumor growth in an imatinib-resistant leukemia xenograft model, both as monotherapy and combined with imatinib, showing promising oral bioavailability and tolerability. In summary, telmisartan derivatives act as effective chemosensitizers and offer an innovative strategy for targeting CSCs in various malignant diseases.

Thermal degradation of tertiary amine for CO2 capture: Structure–activity relationships and density functional theory calculations

AbstractAqueous amine solution is a promising absorbent for CO2 capture, yet irreversible reaction, that is, degradation can happen for amine and leads to performance decrease and many operating difficulties. Despite numerous research on reaction between amine and CO2 for absorption, the reaction of amine degradation is not fully understood, especially for tertiary amine which is a vital component in constructing high‐performance CO2 absorbent. Considering the variety of tertiary amines, this article studied the thermal stability of five tertiary amine solutions at different temperatures to mimic the regeneration condition. The density functional theory (DFT) calculation was applied to reveal the degradation mechanism. The alkylation reaction that triggered the degradation of tertiary amine was deemed as the limiting step. Then the molecular simulation method was extended to 12 tertiary amines, aiming to further illustrate the influence of molecular structure on the alkylation reaction. These results provide basic data and theoretical guidance for developing the anti‐degradation CO2 absorbent.

Late-Stage Tailoring Steps in the Biosynthesis of β-Rubromycin Involve Successive Terminal Oxidations, a Selective Hydroxyl Reduction, and Distinctive O-Methylations.

β-Rubromycin (1) has a unique O-methylated naphthoquinone moiety and is an efficient inhibitor of human telomerase. Through in vivo and in vitro investigations, we elucidated the biosynthetic tailoring steps of compound 1, which involve the carboxyl terminal via successive oxidizations by RubU and RubO1/RubO2, O-methylation of the carboxyl terminal by RubX, and reduction of C-3' hydroxyl by RubK. The final tautomerization of the naphthoquinone moiety is mediated by RubO, which anchors the transitional intermediate through O-methylation to form the naphthoquinone tautomer. The structure-activity relationship further revealed the significant influences of the terminal modification status on anticancer activities of rubromycins.

Structural aspects of HIV-1 integrase inhibitors: SAR studies and synthetic strategies.

Acquired immunodeficiency syndrome (AIDS) poses a significant threat to life. Antiretroviral therapy is employed to diminish the replication of the human immunodeficiency virus (HIV), extending life expectancy and improving the quality of patients' lives. These HIV-1 integrase inhibitors form robust covalent interactions with Mg2+ ions, contributing to their tight binding, thereby inhibiting the integration of viral DNA into the CD4 cell DNA. The second-generation INSTIs, the most recently approved, exhibit a higher genetic barrier compared to first-generation drugs. Hence, there is a need to develop novel and safe compounds as inhibitors of HIV-1 integrase. This article presents an overview of the current landscape of anti-HIV-1 integrase inhibitors, emphasizing the structure-activity relationship (SAR) of small molecules. The molecules discussed include monocyclic rings consisting of triazoles moiety, and pyrimidine analog along with bicyclic rings with nitrogen-containing moieties. Researchers are exploring anti-HIV-1 integrase inhibitors from natural sources like marine environments, plant extracts, and microbial products, emphasizing the importance of diverse bioactive compounds in combating the virus, which have also been included in the manuscript. The current manuscript will be helpful to the scientific community engaged in the manipulation of small molecules as anti-HIV integrase inhibitors for designing newer leads.

Regulating the Atomic Active Center by Covalent Organic Framework-Derived Photothermal Nanozyme to Arm Self-Gelling Powder for Bacterial Wound Healing.

Creating simple methods to produce antioxidant nanozymes with clear structure-activity relationships, particularly aiming to improve disinfection and create practical drug formulations for bacterial wound healing, remains a crucial challenge. Herein, we synthesized iron-loaded covalent organic framework nanospheres, which were then controllably transformed into a carbon-based nanozyme with both iron single atoms and iron clusters through simple pyrolysis. We discovered that the gradual growth of iron clusters significantly boosted the nanozyme's adsorption onto the substrate and electron transfer, greatly influencing its activity. The nanozyme, optimized by the coexistence of single iron atoms and Fe4 clusters, exhibited the strongest catalase and superoxide dismutase enzyme activities as well as high photothermal efficiency. Under physiological conditions, its peroxidase and oxidase enzymatic activities, which stimulate oxidative stress, remained low. Furthermore, we created an antibacterial self-gelling powder capable of dispersing the nanozyme using polyacrylamide and poly(acrylic acid). The powder can rapidly gel and adhere to wet wound areas, synergistically sterilizing the wound through the combined actions of the gel's amino groups and the nanozyme's photothermal effect, while leveraging the antioxidant enzymatic effects to mitigate wound inflammation. These properties contribute to the fast healing of infectious wounds, thus promising a clear formulation and treatment.

PARP1 Inhibitors: An Important Part in Cancer Treatment

Abstract: Cancer is a highly fatal disease that is typified by aberrant cells proliferating out of control. The properties of acquired cells, including as genomic instability and mutations, cellular death evasion, and proliferative signaling sustenance, are evidenced by the hallmarks of cancer and contribute to the establishment of malignant tumors. A protein called poly(ADP-ribose) polymerase- 1 (PARP1) is essential for both cell survival and DNA damage repair, two processes that affect cellular control. Since homologous recombination deficient cells exhibit cellular death upon suppression of PARP1, the PARP protein has gained attention as a potential target for anticancer treatments. The Food and Drug Administration (FDA) has already approved a number of effective PARP1 inhibitors, including olaparib and niraparib. The final chemical has a 1,3,4- thiadiazole core in its structure. In fact, heterocyclic moieties have gained attention due to their numerous medicinal advantages, which include their capacity to combat cancer. The compounds derived from these substances have been studied as PARP1 inhibitors, with promising results. Thus, the goal of this study is to go over the importance of PARP1 in cancer as well as its role in cell regulation. It also attempts to offer a comprehensive assessment of the literature that has been published in the previous fifteen years about PARP1 inhibitors, including the different scaffolds, with an emphasis on features of the structure-activity relationship. This will provide vital information for the creation of fresh, more effective PARP1 inhibitors.

QSAR, Pharmacophore and Molecular Docking Studies for the Design of Novel Arylamide-derived Inhibitors of Mycobacterium tuberculosis

Tuberculosis is an infectious disease caused by the bacterium Mycobacterium tuberculosis. It remains a significant public health challenge worldwide. In 2022, approximately 10.6 million people were diagnosed with tuberculosis, and 1.3 million individuals lost their lives to the disease. This manuscript presents our research focused on designing new inhibitors for the enoyl acyl carrier protein reductase (InhA) of Mycobacterium tuberculosis. This enzyme is vital as it plays a key role in the type II fatty acid biosynthesis pathway of M. tuberculosis. To conduct our study, we utilized computer simulations, specifically docking and quantitative structure-activity relationship (QSAR) analysis on free molecules. We applied these methods to a series of arylamide-derived inhibitors, the efficacy of which was proposed by He et al. The results obtained from our docking and QSAR analyses confirm the robustness of the molecules identified by He et al., based on their experimental activities. Furthermore, the docking results facilitated the generation of a pharmacophore model, which was instrumental in designing a new inhibitor of Mycobacterium tuberculosis InhA. This new compound demonstrates enhanced activity compared to previously identified inhibitors. Such advancements could significantly contribute to the development of novel treatments for tuberculosis and help address this critical global health issue.

PFAS (per- and polyfluorinated alkyl substances) as EDCs (endocrine-disrupting chemicals) - Identification of compounds with high potential to bind to selected terpenoids NHRs (nuclear hormone receptors).

The objective of the subsequent study was to examine the probability of PFAS (per- and polyfluorinated alkyl substances) binding to various NHRs (nuclear hormone receptors) and to identify their structural features that contribute most to the binding score (BS). We evaluated the BS for PFAS in relation to 7 selected NHRs - 4 with additional antagonist forms (Retinoid X receptor alpha - RXRα, Liver X receptor alpha - LXRα, Liver X receptor beta - LXRβ, Estrogen receptor alpha - ERα, Estrogen receptor alpha antagonist - anti-ERα, Estrogen receptor beta - ERβ, Estrogen receptor beta antagonist - anti-ERβ, Glucocorticoid receptor - GR, Glucocorticoid receptor antagonist - anti-GR, Androgen receptor - AR, Androgen receptor antagonist - anti-AR). We based our study on the results of molecular docking, which we used to develop MLR-QSAR (Multiple Linear Regression - Quantitative Structure-Activity Relationship) models. The models we developed allowed us to predict the BS for an extensive set of PFAS compounds from the NORMAN database (more than 4,000) - virtual screening. The probability of PFAS binding to selected receptors was determined by structural features such as particle size, branching, and fluorine content. These variables were also identified in the literature reports of experimental studies as the most important for this group of compounds. The research focused on receptors from the terpenoid group. The RXRα, LXRα and β, GR, and anti-GR receptors were shown to be the group less likely to be affected by PFAS. Sex hormones such as AR, anti-AR, ERα and ERβ with their antagonist forms are the most affected.

Transformation behavior and toxicity assessment of beaytlmethodeyammonNium chbride (BAC-12) disinfectant during hospital wastewater treatment.

This work focused on the transformation behavior of the emerging beaytlmethodeyammonium chbride (BAC-12) disinfectant existed in the treatment of medical sewage during its disinfection treatment. The degradation ability of ozone (O3) to BAC-12 was the best, followed by UV/NaOCl, UV, and NaOCl. The enhancement of BAC-12 in UV/NaOCl system is caused by the combined effect of UV photolysis, reactive chlorine species (RCS), and •OH. The transformation products of BAC-12 in the disinfection treatment were detected, and the chemical structure of products was rationalized by frontier molecular orbital and transition state theory methodologies. According to the ecological structure-activity relationship (ECOSAR) assessment, the intermediates of BAC-12 in UV, NaOCl, and UV/NaOCl treatments had lower half lethal concentration (LC50) and chronic toxicity (ChV) values with a higher ecotoxicity than BAC-12. O3 disinfection treatment of these toxic intermediates can significantly reduce the toxicity of the BAC-12 solution. This work provides necessary information on the potential environmental risks of BAC-12 arising from different disinfection methods in the treatment of medical wastewater.

Novel Meta-Diamide Derivatives Bearing Triazole: Design, Synthesis, and Bioactivity.

In searching for novel insecticide lead, 20 new meta-diamide compounds containing triazole were designed and synthesized regarding cyproflanilide as lead compound. All the compounds were characterized by 1H NMR, 13C NMR, and High-resolution mass spectra (HR MS). In preliminary bioassay, we found that one of the compounds: N-(cyclopropylmethyl)-N-(5-((2,6-dibromo-4-(1,2,2,2-tetrafluoro-1-(trifluoromethyl)ethyl)phenyl)carbamoyl)-2-(1H-1,2,4-triazol-1-yl)phenyl)-6-(trifluoromethyl) nicotinamide (16a) had high activity against the target organism Plutella xylostella at 1mg/L and against the target organism Mythimna separata at 2mg/L. It is obviously superior to the known compounds Ia and Ib, and it is equivalent to cyproflanilide, and the LC50 values of the compound against P. xylostella and M. separata were 0.90mg/L and 0.64mg/L, respectively. It is providing important clues for subsequent structure-activity relationship (SAR) studies. From this, we explored the SAR of these compounds. Through comprehensive analysis of their structural characteristics and insecticidal activity data, we found that different halogen substituents on benzene ring and different aromatic substituents on amino group in the compound had significant effects on insecticidal activity. This has certain guiding significance for further structural optimization and activity enhancement.

Deciphering the Comprehensive Structure-Activity Relationship of Sunshinamide for Breast Cancer Therapy through Dual Modulation of Apoptotic and Ferroptotic Pathways via TrxR1 and Gpx4 Inhibition.

Sunshinamide, a cyclodepsipeptide, has demonstrated significant potential in inhibiting cancer cell proliferation. Our prior research established the total synthesis and anticancer properties of sunshinamide. However, a deeper understanding of the structure-activity relationship (SAR) of sunshinamide remained imperative. In this study, we aimed to elucidate the SAR and mechanistic insights underlying sunshinamide action, both in vitro and in vivo. SAR studies confirm the crucial roles of both the bicyclic-ring and disulfide moiety in the anticancer activity of sunshinamide. Our recent findings unveil that sunshinamide targets TrxR1, leading to ROS generation and ER-stress-mediated apoptosis, while also promoting lipid peroxidation by targeting Gpx4, rendering cancer cells vulnerable to ferroptosis. In vivo, experiments demonstrated the effectiveness of sunshinamide in reducing tumor growth by inducing both apoptosis and ferroptosis. The dual efficacy of sunshinamide in eliciting apoptosis and ferroptosis positions it as a promising candidate for breast cancer therapy, addressing the challenge of chemoresistance.

Tandem Electroreduction of CO2 to C2+ Products Based on M-SACs/Cu Catalysts.

Electrochemical CO2 reduction reaction (ECO2RR) is considered a highly promising method to produce high-value chemicals and fuels, contributing significantly the artificial carbon balance. Plenty catalysts can facilitate the conversion of CO2 into mono-carbon (C1) products. Among these catalysts, Cu species exhibit a distinct role in the formation of multi-carbon (C2+) products characterized by enhanced energy density. However, the limited selectivity of C2+ products, along with the inferior stability, and high overpotential demonstrated by single-component Cu catalysts, hinders their applicability in industrial-scale production. The implementation of a tandem strategy, which involves coupling the CO2-to-CO pathway using Ag, Au, metal single-atom catalysts (M-SACs), etc., with the CO-to-C2+ conversion on Cu, represents a novel approach for the efficient generation of C2+ products. Given the high cost and restricted availability of noble metals, M-SACs have attracted substantial interest in tandem systems due to their cost-effectiveness and efficient atom utilization. The systematic analysis of the design principles and structure-activity relationship is essential for the advancement of M-SACs/Cu-based tandem catalysts. Here we first introduce various prevalent design strategies of M-SACs/Cu-based tandem catalysts for ECO2RR and then systematically summarize the latest advancements of M-SACs/Cu-based tandem system, encompassing metal-organic frameworks/Cu (MOFs/Cu), covalent organic frameworks/Cu (COFs/Cu), and nitrogen-doped carbon support transition metal single atomic materials/Cu (M-N-C/Cu). Lastly, we discuss the challenges and opportunities with the design and construction of M-SACs/Cu-based tandem catalysis for ECO2RR.

Structure-Activity Relationships and Molecular Pharmacology of Positive Allosteric Modulators of the Mu-Opioid Receptor.

Positive allosteric modulation of the mu-opioid receptor is a promising strategy to address the ever-growing problem of acute and chronic pain management. Positive allosteric modulators (PAMs) of the mu-opioid receptor could be employed to enhance the efficacy of endogenous opioid peptides to a degree that provides pain relief without the need for traditional opioid drugs. Alternatively, PAMs might be used to enhance the action of opioid drugs and so provide an opioid-sparing effect, allowing for the use of lower doses of opioid agonists and potentially decreasing associated side effects. BMS-986122 (2-(3-bromo-4-methoxyphenyl)-3-[(4-chlorophenyl)-sulfonyl]-thiazolidine) has been previously identified as a PAM of the mu-opioid receptor. In the present work, we have designed and synthesized 33 analogs of BMS-986122 to explore the structure-activity relationships of this scaffold and confirm its allosteric mechanism of action. Among several newly identified modulators, the most promising compound (14b) had improved activity to increase the in vitro potency of the standard mu-opioid agonist DAMGO and showed in vivo activity in mice to enhance the antinociceptive action of morphine.

Structure-activity relationships between nitrile analogues and acaricidal activities against Haemaphysalis longicornis.

A recent increase in severe fever with thrombocytopaenia syndrome (SFTS) virus cases in Korea has been observed. This virus attacks humans and animals, and no drug is available for its treatment. This study is investigating potential control measures targeting the causative agent, Haemaphysalis longicornis. Lepidium meyenii oil was ≈8.3-, 4.2- and 4.1-fold more active than diethyltoluamide against H. longicornis larvae, nymphs and adults, respectively. The major components of L. meyenii oil were identified as benzyl nitrile (71.64%), followed by ethyl linoleic acid (13.32%), ethyl palmitate (7.81%) and 3-methoxybenzyl nitrile (2.10%). In testing individual components of the oil were tested against H. longicornis adults, the half-maximal lethal dose (LD50) values for benzaldehyde, benzyl nitrile and benzyl isothiocyanate were found to be 9.21, 9.19 and 18.26 μg cm-3, respectively. The acaricidal component was isolated and identified as benzyl nitrile. To establish the structure-activity relationships between nitrile analogues and acaricidal activities, benzyl nitrile (LD50: 0.56, 6.38 and 9.19 μg cm-3) exhibited the highest acaricidal activities against H. longicornis larvae, nymphs and adults, followed by benzoyl nitrile (3.24, 8.36 and 15.47 μg cm-3), phenyl nitrile (5.45, 9.35 and 17.48 μg cm-3) and diethyltoluamide (7.95, 14.81 and 22.12 μg cm-3). However, the presence of allyl, methyl or vinyl functional groups bound to the nitrile group abolished the acaricidal activity. These results demonstrate that L. meyenii oil, benzyl nitrile, benzoyl nitrile and phenyl nitrile represent suitable options for the secure management of H. longicornis. Nevertheless, additional research is essential to develop formulations that enhance the efficacy and safety of the aforementioned acaricides. © 2024 Society of Chemical Industry.

Advances in antitumor effects of pterostilbene and its derivatives.

Pterostilbene (PT) is a naturally occurring small molecule stilbenoid that has garnered significant attention due to its potential therapeutic effects in tumor diseases. In this review, we conducted a comprehensive analysis of the antitumor effects of PT and its derivatives on various cancer types, including colon, breast, liver, lung, and pancreatic cancers in recent 20 years. We have succinctly summarized the PT derivatives that exhibit superior anti-tumor efficacy compared to PT. Additionally, we reviewed the potential structure-activity relationship (SAR) rules and clinical application methods to establish a foundation for chemical modification and clinical utilization of stilbene compounds.

Molecular modeling studies, in vitro antioxidant and antimicrobial assay and BSA affinity of novel benzyl-amine derived scaffolds as CYP51B inhibitors.

New scaffolds derived from benzylamine were prepared, characterized, and tested for their antimicrobial, antioxidant activities and binding interactions with BSA. Structure-activity relationship analysis revealed that compounds incorporating both benzylamine and quinoline or pyridine moieties (specifically 3a and 3d) demonstrated potent antifungal activity, surpassing that of the standard drug Ketoconazole against Penicillium italicum. Molecular docking studies confirmed significant inhibitory activity against the CYP51B enzyme-an essential component of fungal cell walls. In addition, compounds 3h, 3d and 3b displayed promising DPPH radical scavenging activity, indicating its strong potential as an antioxidant source. Thermodynamic parameters of standard antiradical mechanisms confirmed antiradical capacity expressed via formal hydrogen atom transfer (FHT). The results of spectrofluorometric assays and molecular docking studies on the affinity of the tested compounds for the BSA enzyme confirmed that all compounds show significant binding affinity for active site III, with compound 3d demonstrating the highest binding affinity. Key pharmacokinetic parameters were assessed using ADMET analysis, ensuring the viability of these compounds for potential therapeutic applications.

Synthesis, anticancer evaluation, preliminary mechanism study of novel 1, 2, 3-triazole-piperlongumine derivatives.

Piperlongumine, a natural product from traditional Chinese medicine, shows promising antitumor effects but suffers from high toxicity. In this study, X and Q series Piperlongumine derivatives containing 1, 2, 3-triazole were designed and synthesized using the principle of molecular hybridization. The antitumor activity of these target compounds was evaluated, revealing significant activity compared to piperlongumine across four cancer cell lines. The structure-activity relationship of these compounds was analyzed using 3D-QSAR. Among these derivatives, compound 6Q demonstrated the highest antitumor activity against human chronic myeloid leukemia (K562) cells, with an IC50 value of 0.31 μM, low toxicity to normal cells, and a selectivity index (SI) of 11.2. Further in vitro experiments confirmed that 6Q induced apoptosis in K562 cells by disrupting mitochondrial membrane potential, activating the MAPK signaling pathway, and causing cell cycle arrest in the G2/M phase. These findings underscored the potential of the natural product derivative 6Q as a promising candidate for further development in cancer therapy.

Human-in-the-loop active learning for goal-oriented molecule generation

Machine learning (ML) systems have enabled the modelling of quantitative structure–property relationships (QSPR) and structure-activity relationships (QSAR) using existing experimental data to predict target properties for new molecules. These property predictors hold significant potential in accelerating drug discovery by guiding generative artificial intelligence (AI) agents to explore desired chemical spaces. However, they often struggle to generalize due to the limited scope of the training data. When optimized by generative agents, this limitation can result in the generation of molecules with artificially high predicted probabilities of satisfying target properties, which subsequently fail experimental validation. To address this challenge, we propose an adaptive approach that integrates active learning (AL) and iterative feedback to refine property predictors, thereby improving the outcomes of their optimization by generative AI agents. Our method leverages the Expected Predictive Information Gain (EPIG) criterion to select additional molecules for evaluation by an oracle. This process aims to provide the greatest reduction in predictive uncertainty, enabling more accurate model evaluations of subsequently generated molecules. Recognizing the impracticality of immediate wet-lab or physics-based experiments due to time and logistical constraints, we propose leveraging human experts for their cost-effectiveness and domain knowledge to effectively augment property predictors, bridging gaps in the limited training data. Empirical evaluations through both simulated and real human-in-the-loop experiments demonstrate that our approach refines property predictors to better align with oracle assessments. Additionally, we observe improved accuracy of predicted properties as well as improved drug-likeness among the top-ranking generated molecules.Scientific contributionWe present an adaptable framework that integrates AL and human expertise to refine property predictors for goal-oriented molecule generation. This approach is robust to noise in human feedback and ensures that navigating chemical space with human-refined predictors leverages human insights to identify molecules that not only satisfy predicted property profiles but also score highly on oracle models. Additionally, it prioritizes practical characteristics such as drug-likeness, synthetic accessibility, and a favorable balance between exploring diverse chemical space and exploiting similarity to existing training data.