Structure-activity Relationship Research Articles

Revealing the antioxidant properties of alkyl gallates: a novel approach through quantum chemical calculations and molecular docking.

This study investigates the antioxidant potential of alkyl gallates (C1-C10), focusing on the impact of alkyl chain length and solvent polarity on their antioxidant properties. Known for their biomedical relevance in mitigating oxidative stress, alkyl gallates' structure-activity relationships, particularly regarding chain length and environmental factors, still need to be explored. Key thermochemical parameters, including bond dissociation enthalpy (BDE), ionization potential (IP), proton affinity (PA), and electron transfer enthalpy (ETE), reveal that shorter alkyl chains (C1-C4) exhibit superior antioxidant activity. In contrast, longer chains (C5-C10) show reduced effectiveness due to steric hindrance and lower solubility in polar solvents. Molecular docking studies also demonstrated favorable binding interactions with vital biological targets, further reinforcing their antioxidant potential. Quantum chemical calculations were performed using Gaussian 16 with the B3LYP/6-311G(dp) basis set for geometry optimizations. Solvent effects were modeled using the integral equation formalism-polarized continuum model (IEF-PCM). Molecular docking studies were conducted using AutoDockTools 4.2, targeting Tyrosine Kinase Hck, Heme Oxygenase, and Human Serum Albumin to evaluate fundamental binding interactions. These computational methods provided insights into alkyl gallates' chemical reactivity and antioxidant efficiency, allowing for the rational design of more potent antioxidant compounds.

Recent Advances in Polysaccharides Derived from the Genus Panax: Preparation Strategies, Structural Profiles, Functional Properties and Structure-Activity Relationships.

Plants from the Panax genus have significant medicinal and nutritional benefits. Many Panax species are traditionally used in Chinese medicine and have gained popularity as food and health products because of their tonic effects and high safety. Their key bioactive components include polysaccharides, which are hydrophilic biomolecules that have demonstrated significant potential in the food and pharmaceutical industries because of their multiple health-promoting qualities, such as immunomodulatory, antitumor, antiaging, blood glucose and blood lipid regulation, antiviral, hepatoprotective, and gastrointestinal protective properties. Additionally, polysaccharides are abundant in health products made from the genus Panax, such as energy drinks and herbal teas. However, compared with more extensively studied components, such as ginsenosides and saponins, polysaccharides from the genus Panax (GPPs) have been the subject of relatively limited research. This review provides a comprehensive overview of the extraction and purification technology, structural characteristics, biological activities, applications, and structure-activity relationships of GPPs. Ultimately, this information establishes a theoretical foundation for the further development and application of GPPs in nutrition and medicine.

Combining a Chemical Language Model and the Structure-Activity Relationship Matrix Formalism for Generative Design of Potent Compounds with Core Structure and Substituent Modifications.

In medicinal chemistry, compound optimization relies on the generation of analogue series (AS) for exploring structure-activity relationships (SARs). Potency progression is a critical criterion for advancing AS. During optimization, a key question is which analogues to synthesize next. We introduce a new computational methodology for the extension of AS with potent compounds containing both core structure and substituent modifications at multiple sites, which has been reported for the first time. The approach combines a transformer chemical language model (CLM) with a SAR matrix (SARM) methodology that identifies and organizes structurally related AS. Therefore, the SARM approach was expanded to cover multisite AS. Consensus series extracted from SARMs representing a potency gradient served as input for CLM training to extend test AS with potent analogues. Different model variants were derived and investigated. Both general and fine-tuned models correctly predicted known potent analogues at high positions in probability-based compound rankings and chemically diversified AS through core structure modifications of the generated candidate compounds and substituent replacements at multiple sites.

Initial Development of Automated Machine Learning-Assisted Prediction Tools for Aryl Hydrocarbon Receptor Activators

Background: The aryl hydrocarbon receptor (AhR) plays a crucial role in immune and metabolic processes. The large molecular diversity of ligands capable of activating AhR makes it impossible to determine the structural features useful for the design of new potent modulators. Thus, in the field of drug discovery, the intricate nature of AhR activation necessitates the development of novel tools to address related challenges. Methods: In this study, quantitative structure–activity relationship (QSAR) models of classification and regression were developed with the objective of identifying the most effective method for predicting AhR activity. The initial dataset was obtained by combining the ChEMBL and WIPO databases which contained 978 molecules with EC50 values. The predictive models were developed using the automated machine learning platform mljar according to a 10-fold cross validation (10-CV) testing procedure. Results: The classification model demonstrated an accuracy value of 0.760 and F1 value of 0.789 for the test set. The root-mean-squared error (RMSE) was 5444, and the coefficient of determination (R2) was 0.208 for the regression model. The Shapley Additive Explanations (SHAP) method was then employed for a deeper comprehension of the impact of the variables on the model’s predictions. As a practical application for scientific purposes, the best performing classification model was then used to develop an AhR web application. This application is accessible online and has been implemented in Streamlit. Conclusions: The findings may serve as a foundation in prompting further research into the development of a QSAR model, which could enhance comprehension of the influence of ligand structure on the modulation of AhR activity.

Discovery of Selective PDE1 Inhibitors with Anti-pulmonary Fibrosis Effects by Targeting the Metal Pocket.

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease with no ideal drugs. Our previous research demonstrated that phosphodiesterase 1 (PDE1) could be a promising target for the treatment of IPF. However, only a few selective PDE1 inhibitors are available, and the mechanism of recognition between inhibitors and the PDE1 protein is not fully understood. This study carried out a step-by-step optimization of a dihydropyrimidine hit Z94555858. By targeting the metal pocket of PDE1, a lead compound 3f was obtained, exhibiting an IC50 value of 11 nM against PDE1, moderate selectivity over other PDEs, and significant anti-fibrotic effects in bleomycin-induced pulmonary fibrosis rats. The structure-activity relationship study aided by molecular docking revealed that forming halogen bonds with water in the metal pocket greatly enhanced the PDE1 inhibition, providing a novel strategy for further rational design of PDE1 inhibitors.

EVALUATION OF ANTIOXIDANT ACTIVITY OF NOVEL ORGANOTIN COMPLEXES DERIVED FROM A NEWLY SYNTHESIZED LIGAND AND THEIR STRUCTURAL CHARACTERIZATION

In this work, of New Ligand [(E)-5-hydroxy-4-(3-(4-methoxy phenyl) acryl amido) naphthalene -1- sulfonic acid] (ANS) was prepared by reflexing reaction of 4-amino-5-hydroxy naphthalene sulfonic acid with para methoxy cinnamic acid, this produced and described chemical was employed as ligand to prepare tri and di-organotin complexes by condensation reaction with the salts of organotin chloride (phenyl, butyl, and methyl tin chloride). Specialized methods, including elemental analysis, (tin and proton) magnetic resonance, and infrared spectra, were used to identify the complexes. DPPH (2,2-diphenyl-1-picrylhydrazyl) and CUPRAC (Cupric Reducing Antioxidant Capacity) are both commonly used methods for measuring antioxidant capacity in various samples. Due to the tin moiety, the produced tri and di-tin complexes gave higher percentage inhibition than the ligand in both techniques; also, the triphenyltin complex performed the best when compared to the others. The results of this study are expected to contribute to the understanding of the structure-activity relationship of organotin complexes and their potential as antioxidants, which may have implications for developing novel therapeutic agents with antioxidant properties.

The Underrepresented Quinolinone Alkaloids in Genera Penicillium and Aspergillus: Structure, Biology, and Biosynthetic Machinery.

Quinolone alkaloids are N-heterocycles with extensive structural diversity, mainly derived from in fungi from anthranilic acid and amino acids as precursors with a wide range of biological activities as antifungal, antimicrobial, anti-inflammatory, and insecticidal activities. The quinolone basic skeleton comprised of either 2-quinolones or 4-quinolones generated more than one hundred compounds. Several reviews discussed quinolones; particularly, the fluoroquinolones, yet few studies tackled natural quinolones. Many of these quinolones were not assayed for their antimicrobial potential despite their unique stereospecificity, which can supersede synthetic quinolones if their discovery is coupled with OMICS techniques, biochemical and molecular strategies as heterologous expression to maximize their yield. Herein, we conducted a comprehensive review of the quinolone's family in Aspergillus and Penicillium species, the exclusive producers of quinolones whether they are soil, endophytic or marine derived highlighting their isolation, chemical structures, pharmacological effects, structure activity relationships if any, and biosynthetic machinery. We believe that our initiative will pave the way for further development of natural quinolones as future antimicrobial agents.

Structure-activity relationship studies of ME1111, a novel antifungal agent for topical treatment of onychomycosis.

Onychomycosis is a prevalent disease in many areas of the world, affecting approximately 5.5% of the global population. Among several subtypes of onychomycosis, distal-lateral-subungual onychomycosis is the most common, and topical onychomycosis agents effective against this pathogenesis require properties such as high nail penetration and low affinity for keratin, the main component of the nail. To develop novel and highly effective antifungal agents with such properties, we first established an efficient ex vivo evaluation method using bovine hoof slices and human nails, and then used this method to screen an in-house compound library. Using this strategy, we identified 1, a structure with a phenyl-pyrazole skeleton. In subsequent analyses, we investigated the structure-activity relationship of 1, permitting the identification of 28 (Development Code ME1111).

Comprehensive Overview of the Amide Linker Modification in the Succinate Dehydrogenase Inhibitors.

Succinate dehydrogenase inhibitors (SDHIs) have become one of the most important classes of agrochemical fungicides. According to the data from FRAC, the resistance risk for SDHIs had reached up to medium and even to high. In general, the chemical structure of SDHIs mainly contained three fragments: an acid core, a hydrophobic tail, and an amide linker, corresponding to three modification directions for each fragment. Among them, amide linker modification (ALM) has become a research hotspot for the design of novel SDHIs fungicides in recent years. We presented here a detailed review on the ALM strategy in the past decade, and some of them had entered the market. According to their chemical structures, ALM strategy were classified into four parts: (1) linked aliphatic chain between amide bond and hydrophobic tail, (2) introducing substituents to replacing hydrogen atom in the amide bond, (3) reverse extending the amide linker, and (4) changed with other bioisosteres. Moreover, the structure-activity relationship and the interaction mechanism of ALM-SDHI with SDH were discussed. This review aims to provide a global perspective on research and development of novel SDHIs, as well as suggestions for food safety management.

The bioactive constituents from the fruits of Elaeagnus angustifolia L.

Multiple spectroscopic, chromatographic, and chemical reaction methods were combined to investigate the chemical components in the fruits of Elaeagnus angustifolia L. As results, thirty-two compounds were obtained from it as natural products. Six of them, elangphenosides A (1), B (2), C (3) and D (4), elangmegastigmanoside A (5), and elangorganic acid A1 (6) were retrieved by Scifinder as previously undescribed ones. Additionally, a previously undescribed artificial product, elangorganic acid A2, as well as a known artificial one, (3R) 5-ethoxy-3-(ethoxycarbonyl)-3-hydroxy-5-oxopentanoic acid, were yielded. Following the phytochemical investigation, LC-MS analysis was employed to conduct a systematical characterization of the constituents from E. angustifolia fruits. Ultimately, fifty-six compounds, including seventeen phenols, one ionone, twenty-four triterpenes, and fourteen other ones, were unambiguously detected and identified. Moreover, in vitro anti-inflammatory activity screening of forty-four natural compounds presented in E. angustifolia fruits was performed by using the LPS-induced RAW264.7 cell model. Twenty-six compounds, including phenols, organic acids, and other compounds, showed assignable activity. Furthermore, their structure-activity relationships were summarized. Combined with the previous research work in our lab, triterpenes, phenols, and organic acids were speculated to be key components during the E. angustifolia fruits exerting anti-inflammatory activity. In summary, this article fully explored the chemical composition of E. angustifolia fruits, assayed their in vitro NO production inhibitory effects, greatly expanding its material foundation and laying a solid foundation for further research and development.

Synthesis and Antifungal Activity Evaluation of Novel L-Carvone-Based 1,3,4-Thiadiazole-amide Derivatives as a Potential Succinate Dehydrogenase Inhibitor.

In an effort to explore new-type high-efficiency antifungal agents, 25 novel L-carvone-based 1,3,4-thiadiazole-amide derivatives were designed, synthesized, and structurally characterized by IR, 1H NMR, 13C NMR, and high-resolution mass spectrometry (HRMS) analyses. The antifungal activity of the target compounds was preliminarily assayed at a concentration of 50 μg/mL, and boscalid, a commercialized fungicide identified as a succinate dehydrogenase inhibitor (SDHI), was employed as the positive control. It was found that all of the target compounds showed moderate to potent antifungal activity against the tested fungi compared to boscalid. Surprisingly, compound 4b exhibited broad-spectrum and significant inhibition activity against the growth of eight phytopathogenic strains with inhibitory rates of 67-89%. Further, the results of the EC50 value test suggested that the EC50 values of compound 4b against Physalospora piricola and Colletotrichum orbiculare were 16.33 and 18.06 μg/mL, respectively, and both of them were better than those of boscalid (16.64 and >50). Therefore, compound 4b deserves further study as a lead compound for novel fungicides. In addition, the inhibitory activity of compound 4b against succinate dehydrogenase (SDH) was evaluated as well to prove that compound 4b (IC50 = 3.38 μM) displayed higher SDH-inhibition activity than boscalid (IC50 = 7.02 μM). The binding mode of compound 4b and SDH was simulated by molecular docking and found to be similar to that of boscalid. The structure-activity relationships (SARs) of the target compounds were analyzed by establishing a 3D-QSAR model. Besides, a 4b-loaded complex 4b/CSTA on a reported L-carvone-based nanochitosan carrier CSTA containing the 1,3,4-thiadiazole-amide group was constructed, and its sustained release performance was investigated in the EtOH-H2O system (1:9, v/v). The complex 4b/CSTA exhibited preferred sustained release performance, indicating its potential for developing environmentally friendly nanofungicides.

Discovery of highly potent and ALK2/ALK1 selective kinase inhibitors using DNA-encoded chemistry technology

Activin receptor type 1 (ACVR1; ALK2) and activin receptor like type 1 (ACVRL1; ALK1) are transforming growth factor beta family receptors that integrate extracellular signals of bone morphogenic proteins (BMPs) and activins into Mothers Against Decapentaplegic homolog 1/5 (SMAD1/SMAD5) signaling complexes. Several activating mutations in ALK2 are implicated in fibrodysplasia ossificans progressiva (FOP), diffuse intrinsic pontine gliomas, and ependymomas. The ALK2 R206H mutation is also present in a subset of endometrial tumors, melanomas, non-small lung cancers, and colorectal cancers, and ALK2 expression is elevated in pancreatic cancer. Using DNA-encoded chemistry technology, we screened 3.94 billion unique compounds from our diverse DNA-encoded chemical libraries (DECLs) against the kinase domain of ALK2. Off-DNA synthesis of DECL hits and biochemical validation revealed nanomolar potent ALK2 inhibitors. Further structure-activity relationship studies yielded center for drug discovery (CDD)-2789, a potent [NanoBRET (NB) cell IC50: 0.54 μM] and metabolically stable analog with good pharmacological profile. Crystal structures of ALK2 bound with CDD-2281, CDD-2282, or CDD-2789 show that these inhibitors bind the active site through Van der Waals interactions and solvent-mediated hydrogen bonds. CDD-2789 exhibits high selectivity toward ALK2/ALK1 in KINOMEscan analysis and NB K192 assay. In cell-based studies, ALK2 inhibitors effectively attenuated activin A and BMP-induced Phosphorylated SMAD1/5 activation in fibroblasts from individuals with FOP in a dose-dependent manner. Thus, CDD-2789 is a valuable tool compound for further investigation of the biological functions of ALK2 and ALK1 and the therapeutic potential of specific inhibition of ALK2.

Development and Biological Evaluation of New Diphenyl Ether Formylhydrazide Compounds as Potent Inhibitors of Succinate Dehydrogenase.

Succinate dehydrogenase (SDH), also recognized as succinate ubiquinone oxidoreductase (SQR), is considered one of the most promising targets for fungicide development, garnering significant international interest. We have focused on the development of highly effective, broad-spectrum-targeted SDH inhibitors. Using an active scaffold combining strategy, we designed and synthesized a series of novel diphenyl ether formylhydrazine derivatives, and most compounds have demonstrated broad-spectrum antifungal activity. Notably, compound M8 exhibited antifungal activity of more than 93% against four tested pathogen types at a concentration of 10 μg/mL, with an EC50 value below 0.3 μg/mL for each pathogen, outperforming boscalid. Additionally, compound M8 exhibited a control efficacy of 83% against Sclerotinia sclerotiorum on rapeseed leaves at a concentration of 200 μg/mL and demonstrated an 87% efficacy in controlling Fusarium graminearum on wheat ears when applied at 400 μg/mL. Structure-activity relationship research suggested that para-substituted benzene rings are more effective, offering stronger and more extensive antifungal potency. Further investigation, including enzyme inhibition assays, mycelial morphology observations, and molecular docking studies, suggests that the antifungal potency of M8 is due to the inhibition of its SDH activity. Therefore, our research positions compound M8 as a highly promising lead compound with broad-spectrum antifungal properties, potentially introducing a new class of fungicide.

Resveratrol and Its Derivatives Diminish Lipid Accumulation in Adipocytes In Vitro—Mechanism of Action and Structure–Activity Relationship

Background and Objectives: Expansion of white adipose tissue causes systemic inflammation and increased risk of metabolic diseases due to its endocrine function. Resveratrol was suggested to be able to prevent obesity-related disorders by mimicking caloric restriction; however, its structure–activity relationships and molecular targets are still unknown. We aimed to compare the effects of resveratrol and its analogues on adipocyte metabolism and lipid accumulation in vitro. Methods: Mouse embryonic fibroblasts were differentiated to adipocytes in the absence or presence of resveratrol or its derivatives (oxyresveratrol, monomethylated resveratrol, or trimethylated resveratrol). Intracellular lipid content was assessed by Oil Red O staining. Glucose uptake and its response to insulin were estimated by 2-NBDG, and mitochondrial activity was assayed via resazurin reduction. Involvement of potential molecular pathways was investigated by concurrent treatment with their inhibitors. Results: Although lipid accumulation was significantly reduced by all analogues without altering protein content, oxyresveratrol was the most potent (IC50 = 4.2 μM), while the lowest potency was observed with trimethylated resveratrol (IC50 = 27.4 μM). Increased insulin-stimulated glucose uptake was restored by each analogue with comparable efficiency. The enhanced mitochondrial activity was normalized by resveratrol and its methylated derivatives, while oxyresveratrol had a minor impact on it. Among the examined pathways, inhibition of SIRT1, PGC-1α, and JNK diminished the lipid-reducing effect of the compounds. Autophagy appeared to play a key role in the effect of all compounds but oxyresveratrol. Conclusions: Resveratrol and its analogues can mimic caloric restriction with complex mechanisms, including activation of SIRT1, PGC-1α, and JNK, making them possible drug candidates to treat obesity-related diseases.

Extraction, purification, structural characterization, bioactivities, modifications and structure–activity relationship of polysaccharides from Ophiopogon japonicus: a review

Ophiopogon japonicus (Thunb.) Ker Gawl., is a traditional Chinese medicine (TCM) with a history of thousands of years. O. japonicus polysaccharides (OJPs), as one of the main active ingredient, are a kind of representative pharmacological bioactive macromolecules and mainly composed of Glc and Fru with molecular weight between 2.48 and 325 kDa. OJPs have a variety of biological activities, such as hypoglycemic, cardioprotective, immunomodulatory, improvement of obesity, and renal protective activity. In this review, the extraction, purification and structural characterization of OJPs were systematically reviewed, and its biological function, molecular mechanism and structure–activity relationship were analyzed. Additionally, this review summarized and found that structural modifications such as liposome modification, sulfation modification, and polyethylene glycol modification have improved the pharmacological activity and bioavailability of OJPs. Overall, this work will help to better understand OJPs and provide a theoretical review of their further development and utilization in the field of medicine and health food.

Halogen-based quinazolin-4(3H)-one derivatives as MCF-7 breast cancer inhibitors: Current developments and structure-activity relationship.

Currently, cancer is a serious health challenge with predominance beyond restrictions. Breast cancer remains one of the major contributors to cancer-related morbidity and mortality in women. Chemotherapy continues to be crucial in the treatment of all variants of cancer. Several antitumor drugs are presently in different phases of clinical trials, whereas many more have been approved for clinical use. However, these drugs have the potential to cause adverse effects, and certain individuals may become resistant to them, which would eventually reduce the drug's efficacy. Therefore, it is essential to discover, develop, and improve newer anticancer drug molecules that could potentially inhibit proliferative pathways. In recent years, quinazolinone derivatives, more specifically halogen-substituted 4(3H)-quinazolinone, have drawn attention as a promising new class of chemotherapeutic agents. In addition, these molecules showed significant inhibition in micromolar ranges when tested in vitro against the MCF-7 cell line. Therefore, this study aims to emphasize the intriguing versatility of halogen atoms, providing an in-depth summary and highlighting recent developments in the anticancer properties of halogenated 4(3H)-quinazolinones. It also features a detailed discussion of the structure-activity relationship (SAR) of various functional groups and their interaction with amino acid residues utilizing molecular docking studies. The intent is to foster novel discoveries that can inspire innovative investigations in this domain. Hence, this study simplifies the drug design and development strategies by prolonging the array of pharmacologically active candidates.

Pyrrolo[2,3-D]Pyrimidines as EGFR and VEGFR Kinase Inhibitors: A Comprehensive SAR Review.

Tyrosine kinases are implicated in a wide array of cellular physiological processes, including cell signaling. The discovery of the BCR-ABL tyrosine kinase inhibitor imatinib and its FDA approval in 2001 paved the way for the development of small molecule chemical entities of diverse structural backgrounds as tyrosine kinase inhibitors for the treatment of various ailments. Two of the most prominent tyrosine kinases as drug targets are the epidermal growth factor receptor (EGFR) and the vascular endothelial growth factor receptor (VEGFR), as evidenced by the clinical success of their many inhibitors in the drug market. Among several other physiological roles, EGFR regulates epithelial tissue development and homeostasis, while VEGFR regulates tumor-induced angiogenesis. The pyrrolo[2,3-d]pyrimidine nucleus represents a deaza-isostere of adenine, the nitrogenous base of ATP. The recent introduction of many pyrrolo[2,3-d]pyrimidines to the drug market as tyrosine kinase inhibitors makes them a hot topic in the medicinal chemistry research area at the present time. This review article comprehensively sheds light on the structure-activity relationship (SAR) of pyrrolo[2,3-d]pyrimidines as EGFR and VEGFR tyrosine kinase inhibitors, aiming to provide help medicinal chemists in the design of future pyrrolopyrimidine kinase inhibitors.

Zinc Bioinspired Catalytic System for the Valorization of CO2 Into Cyclic Carbonates

AbstractCyclic organic carbonates are defined as key compounds for a sustainable chemical economy. Their synthesis from CO2 under mild conditions is a useful way to valorise this greenhouse gas as carbon source. Even if a wide range of catalysts were described to promote the carbon dioxide cycloaddition into epoxides, only few ones concern enzymatic systems. The zinc–l‐histidine active site of carbonic anhydrase inspired the present work, pointing out that the imidazole moiety of the amino acid ligand has a crucial role. An extensive study was undertaken to establish the structure–activity relationship of imidazole derivatives, zinc salts, and their respective catalytic activity in the CO2 cycloaddition reaction. The effect of aromatic, alkyl, or iodine substituents and their position in N‐heterocycles were highlighted. A synergic effect was noted when combining imidazole compounds with zinc salts. The optimization of reaction conditions emphasised the in situ ZnI2–1‐methylimidazole catalytic system, which is selective toward cyclic styrene carbonates and efficient under solvent‐free mild conditions (50 °C, atmospheric CO2 pressure). Once reusing tests confirmed the catalytic system robustness, the reaction scope was enlarged to several epoxides resulting in 84%–99% yields of their corresponding cyclic carbonates.

Quantitative Structure-Activity Relationship Models to Predict Cardiac Adverse Effects.

Drug-induced cardiotoxicity represents one of the most common causes of attrition of drug candidates in preclinical and clinical development. For this reason, the evaluation of cardiac toxicity is essential during drug development and regulatory review. In the present study, drug-induced postmarket adverse event combinations from the FDA Adverse Event Reporting System were extracted for 2002 drugs using 243 cardiac toxicity-related preferred terms (PTs). These PTs were combined into 12 groups based on their clinical relevance to serve as training sets. The optimal classification scheme was determined using a combination of data sources that included drug labeling information, published literature, clinical study data, and postmarket surveillance data. Two commercial QSAR platforms were used to construct 12 models, including general cardiac toxicity, cardiac ischemia, heart failure, cardiac valve disease, myocardial disease, pericardial disease, structural heart disease, cardiac arrhythmia, Torsades de Pointes, long QT syndrome, atrial fibrillation and ventricular arrhythmia, and cardiac arrest. The cross-validated performance for the new models reached a sensitivity of up to 80% and negative predictivity of up to 80%. These new models covering a wide range of cardiac endpoints will provide fast, reliable, and comprehensive predictions of potential cardiotoxic compounds in drug discovery and regulatory safety assessment.

Medicinal Chemistry Insights in Neuronal Nitric Oxide Synthase Inhibitors Containing Nitrogen Heterocyclic Compounds: A Mini Review.

Many scientific reports over the last two decades have focused on the discovery and development of novel nNOS inhibitors. The structural identity of isoforms, bioavailability, pharmacokinetic, and safety profile issues remain major obstacles in the discovery of more potent and selective nNOS inhibitors. This review aims to provide an in-depth overview of the molecular interaction patterns between nNOS active site and inhibitors containing structurally diverse nitrogen heterocyclic compounds and highlight the structural properties needed to develop selective nNOS inhibitors. Previously published data allowed the usage of the structure-driven approach in the designing of selective nNOS inhibitors, which relies on the specific structural features required to achieve isoform-selectivity towards nNOS. The incorporation of chiral pyrrolidine ring, two aminopyridine heads, or a specific amino tail group, along with the inhibitor's capacity to adopt the curled conformation in the nNOS environment significantly strengthens the molecular interaction between the inhibitor and nNOS residues by forming specific electrostatic interactions and non-bonded contacts that are vital for isoform selectivity. Additional structure-activity relationship investigations are necessary to elucidate more structural characteristics that will ultimately resolve the exact structural basis required for isoform-selective inhibition of nNOS.