Cheminformatics Approaches Research Articles

Cheminformatics-aided discovery of potential allosteric site modulators of ubiquitin-specific protease 7

Ubiquitin-specific peptidase 7 (USP7) is a deubiquitinating enzyme that mediates the stability and activity of numerous proteins. At basal expression levels, USP7 stabilizes p53 protein, even in the presence of excess MDM2. However, its overexpression leads to the deubiquitination of MDM2 at a rate faster than p53, leading to p53 degradation and pro-tumorigenic roles. Consequently, it is an attractive target for anticancer drug discovery via the modulation of its allosteric site from which the protein is activated. In this study, molecular modeling techniques and cheminformatics approaches were employed to unravel the potential of eighty compounds to serve as its allosteric site modulators. The compounds were initially subjected to virtual screening. Subsequently, the binding free energies of the top four compounds with the highest binding affinities were calculated, and their drug-likeness, and pharmacokinetic and toxicity profiles were evaluated. Ultimately, the complexes of the protein and hit compounds were subjected to a 100 nanoseconds (ns) molecular dynamics simulation. The results of the study revealed eight compounds from the compound library with docking scores ranging from − 7.491 to -11.43 kcal/mol, compared to P217564, which exhibited a docking score of -5.671 kcal/mol. The top four compounds with the highest affinities possessed drug-like properties, and good pharmacokinetic and toxicity profiles, and their predicted inhibitory potentials showed they will be effective at minimal concentration. Also, molecular dynamics simulation confirmed the stability of the protein-ligand complexes. Conclusively, the compounds identified in this study are worthy of further evaluation for the development of allosteric site modulators of USP7.

Novel efficacy of pregnane and flavonoid glycosides from Desmidorchis flava in in vivo nociceptive and inflammatory paradigms and their target prediction by cheminformatics approach

Inflammation is associated with multiple life-threatening conditions. Desmidorchis flava is an edible plant and traditionally used for managing various diseases. Three novel molecules, namely desmiflavaside-C (1), nizwaside (2), and desmiflanoside (3) were isolated from Desmidorchis flava, and their structures were confirmed by mass spectrometry and through reported literature. These compounds were in vivo examined for antinociceptive (tonic visceral nociception) and anti-inflammatory (carrageenan induced paw edema) activities. Significant antinociceptive potential was demonstrated by compound 1 at 0.5 and 1 mg/kg doses followed by compounds 2 and 3. At similar doses, significant anti-inflammatory activity was noted for all the tested compounds. Their antinociceptive and anti-inflammatory activities were comparable to the reference standards. In silico predicted binding modes suggests that these compounds may target allosteric sites of COX-1 and COX-2 enzymes to elicit their anti-inflammatory activities. These isolated natural products may have therapeutic potential in conditions afflicted with pain and inflammation.

Combining Data-Driven and Structure-Based Approaches in Designing Dual PARP1-BRD4 Inhibitors for Breast Cancer Treatment.

Poly(ADP-ribose) polymerase 1 (PARP1) inhibitors have revolutionized the treatment of many cancers with DNA-repairing deficiencies via synthetic lethality. Advocated by the polypharmacology concept, recent evidence discovered that a significantly synergistic effect in increasing the death of cancer cells was observed by simultaneously perturbating the enzymatic activities of bromodomain-containing protein 4 (BRD4) and PARP1. Here, we developed a novel cheminformatics approach combined with a structure-based method aiming to facilitate the design of dual PARP1-BRD4 inhibitors. Instead of linking pharmacophores, the developed approach first identified merged pharmacophores (a pool of amide-containing ring systems), from which phenanthridin-6(5H)-one was further prioritized. Based on this starting point, several small molecules were rationally designed, among which HF4 exhibited low micromolar inhibitory activity against BRD4 and PARP1, particularly exhibiting strong inhibition of BRD4 BD1 with an IC50 value of 204 nM. Furthermore, it demonstrated potent antiproliferative effects against breast cancer gene-deficient and proficient breast cancer cell lines by arresting cell cycle progression and impeding DNA damage repair. Collectively, our systematic efforts to design lead-like molecules have the potential to open doors for the exploration of dual PARP1-BRD4 inhibitors as a promising avenue for breast cancer treatment. Furthermore, the developed approach can be extended to systematically design inhibitors targeting PARP1 and other related targets.

Cheminformatics approaches to predict the bioactivity and to discover the pharmacophoric traits crucial to block NF-κB

Many human disorders include NF-kB signaling pathways, making IKK a therapeutic target in cancer treatment. Inflammatory illnesses and cancer are examples. COVID-19 is one of several triggers that stimulate NF-kB signaling. The activation of the NF-kB pathway is necessary for COVID-19 to cease its development. To learn more about the mechanism and structural features essential to IKK inhibition (IC50), molecular modeling studies have been undertaken on experimentally reported 503. QSAR analysis explores certain reported and hidden structural features critical for IKKβ inhibition. The OECD guidelines guided the construction of the QSAR model, which achieved all the endorsed threshold values for all validation parameters (R2tr:0.81, R2LMO:0.80, and R2ext:0.78). The present QSAR study shows that IKK inhibitory activity is linked to the following structural features: lipophilic hydrogen atoms within 2 A units of the molecule's center of mass; ring nitrogen atoms within one bond of planar nitrogen atoms; ring carbon atoms exactly four bonds from the non-ring nitrogen atoms; planar nitrogen atoms exactly four bonds from sp2 hybridized carbon atoms; and so on. Pharmacophore modeling highlighted QSAR-identified structural characteristics. To investigate binding, we docked all 503 molecules. The observation indicates that the QSAR and molecular docking/pharmacophore modeling findings are in agreement. Following this, we conducted 200 ns of molecular dynamics simulation to validate the molecular docking protocol. MMGBSA analysis determined the binding energy of the dock complex. Thus, the current study found unique pharmacophoric properties that may assist in optimizing lead/hit compounds for anti-IKKβ activity.

Exploring molecular fragments for fraction unbound in human plasma of chemicals: a fragment-based cheminformatics approach

ABSTRACT Fraction unbound in plasma (f u,p) of drugs is an significant factor for drug delivery and other biological incidences related to the pharmacokinetic behaviours of drugs. Exploration of different molecular fragments for f u,p of different small molecules/agents can facilitate in identification of suitable candidates in the preliminary stage of drug discovery. Different researchers have implemented strategies to build several prediction models for f u,p of different drugs. However, these studies did not focus on the identification of responsible molecular fragments to determine the fraction unbound in plasma. In the current work, we tried to focus on the development of robust classification-based QSAR models and evaluated these models with multiple statistical metrics to identify essential molecular fragments/structural attributes for fractions unbound in plasma. The study unequivocally suggests various N-containing aromatic rings and aliphatic groups have positive influences and sulphur-containing thiadiazole rings have negative influences for the f u,p values. The molecular fragments may help for the assessment of the f u,p values of different small molecules/drugs in a speedy way in comparison to experiment-based in vivo and in vitro studies.

Toxicity reference values (TRVs) for force health protection: Gap identification and TRV prediction

The mission of the Force Health Protection (FHP) program of the U.S. Air Force (USAF), sustaining the readiness of warfighters, relies on determinations of acceptable levels of exposure to a wide array of substances that USAF personnel may encounter. In many cases, exposure details are limited or authoritative toxicity reference values (TRVs) are unavailable. To address some of the TRV gaps, we are integrating several approaches to generate health protective exposure guidelines. Descriptions are provided for identification of chemicals of interest for USAF FHP (467 to date), synthesis of multiple TRVs to derive Operational Exposure Limits (OpELs), and strategies for identifying and developing candidate values for provisional OpELs when authoritative TRVs are lacking. Rodent bioassay-derived long-term Derived No Effect Levels (DNELs) for workers were available only for a minority of the substances with occupational TRV gaps (19 of 84). Additional occupational TRV estimation approaches were found to be straightforward to implement: Tier 1 Occupational Exposure Bands, cheminformatics approaches (multiple linear regression and novel nearest-neighbor approaches), and empirical adjustment of short term TRVs. Risk assessors working in similar contexts may benefit from application of the resources referenced and developed in this work.

Chemical spaces of taste and odor

AbstractThe thesis provides a draft map of the chemical space of chemosensory active molecules in foods and enables, by application of cheminformatics approaches, the deduction of general principles of raw material influence and processing on the sensory perception of complex food systems. The summarized data supports the development of analytical methods targeting the efficient quantitation of key compounds, provides a database for screening of chemosensory receptor agonists and facilitates the optimization of in‐silico tools for prediction of receptor activation determining sensory quality and biological function.

Exploring marine-derived bioactive compounds for dual inhibition of Pseudomonas aeruginosa LpxA and LpxD: integrated bioinformatics and cheminformatics approaches.

Pseudomonas aeruginosa can cause serious nosocomial infections. Targeting the biosynthesis of Lipid A, a major structural domain of lipopolysaccharide (LPS) in P. aeruginosa has emerged as a valuable strategy for developing novel therapeutic agents. The biosynthesis of Lipid A involves the activation of homolog enzymes including LpxA and LpxD. LpxA enzyme facilitates the transfer of R-3-hydroxydecanoic fatty acid to uridine diphosphate N-acetylglucosamine in the first step. While LPxD is accountable in third step, wherein R-3-hydroxydodecanoate is transferred to the 2' amine of UDP-3-O-(3-hydroxydecanoyl) utilizing an ACP donor. The exploration of LpxA and LpxD has been largely neglected, as no specific small-molecule inhibitors have been identified, thus far, except for peptide inhibitors. Here, we report the identification of potential dual inhibitors of the lipid A biosynthesis pathway that target both the LpxA and LpxD enzymes as novel antibiotic agents. Among the virtually screened 32,000 marine bioactive compounds Oscillatoxin A, NCI60_041046, and LTS0192263 exhibited optimal docking interactions with LpxA and LpxD, respectively. MD simulation and MMPBSA data showcased stable interactions between selected marine products and LpxA/LpxD. FMO analysis showed that Oscillatoxin A and NCI60_041046 are the most chemically active molecules. MEP analysis data highlighted the possible electrophilic and nucleophilic distribution zones present in the structure. In addition, these bioactive molecules showed acceptable ADMET profiles. These data confirmed that Oscillatoxin A, NCI60_041046, and LTS0192263 could serve as seeds for the development of potential therapeutics to combat P. aeruginosa infection.

Cheminformatics approach to identify andrographolide derivatives as dual inhibitors of methyltransferases (nsp14 and nsp16) of SARS-CoV-2

The Covid-19 pandemic outbreak has accelerated tremendous efforts to discover a therapeutic strategy that targets severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to control viral infection. Various viral proteins have been identified as potential drug targets, however, to date, no specific therapeutic cure is available against the SARS-CoV-2. To address this issue, the present work reports a systematic cheminformatic approach to identify the potent andrographolide derivatives that can target methyltransferases of SARS-CoV-2, i.e. nsp14 and nsp16 which are crucial for the replication of the virus and host immune evasion. A consensus of cheminformatics methodologies including virtual screening, molecular docking, ADMET profiling, molecular dynamics simulations, free-energy landscape analysis, molecular mechanics generalized born surface area (MM-GBSA), and density functional theory (DFT) was utilized. Our study reveals two new andrographolide derivatives (PubChem CID: 2734589 and 138968421) as natural bioactive molecules that can form stable complexes with both proteins via hydrophobic interactions, hydrogen bonds and electrostatic interactions. The toxicity analysis predicts class four toxicity for both compounds with LD50 value in the range of 500–700 mg/kg. MD simulation reveals the stable formation of the complex for both the compounds and their average trajectory values were found to be lower than the control inhibitor and protein alone. MMGBSA analysis corroborates the MD simulation result and showed the lowest energy for the compounds 2734589 and 138968421. The DFT and MEP analysis also predicts the better reactivity and stability of both the hit compounds. Overall, both andrographolide derivatives exhibit good potential as potent inhibitors for both nsp14 and nsp16 proteins, however, in-vitro and in vivo assessment would be required to prove their efficacy and safety in clinical settings. Moreover, the drug discovery strategy aiming at the dual target approach might serve as a useful model for inventing novel drug molecules for various other diseases.

Cheminformatics and QSAR‐Based Identification of Natural Bioactive Compounds as Potent Inhibitors of SARS‐CoV‐2 N‐7 Methyltransferases

AbstractEver since the emergence of the COVID‐19 pandemic, to date, no specific and efficient therapeutic cure is available for the SARS‐CoV‐2 viral infection. Few reports have been observed with the late cardiovascular or neurodegenerative disorders that are associated with altered immunity. The nsp14 protein of SARS‐CoV‐2 is a key target for antiviral drug development as it controls replication of virus and evasion of host immune system. In this study, a consensus of cheminformatics approaches involving virtual screening, molecular docking, ADMET profiling, molecular dynamics simulations, free‐energy landscape, MM‐GBSA, DFT and 2D‐QSAR analysis is employed to discover the inhibitor of nsp14 protein. Our investigation reveals four natural bioactive compounds, i. e. ZINC2132169, ZINC8791872, ZINC8952607 and ZINC6624334 that possess enhanced binding affinity towards nsp14 protein with no predicted toxicity. Molecular docking, MD simulations and MM‐GBSA analysis established that all hit compounds strongly bind at the same pocket through hydrophobic interactions and hydrogen bonding. DFT analysis revealed greater reactivity of hit compounds and their stable complex formation with nsp14 protein, while the 2D‐QSAR (R2=0.92) predicted their pIC50 value in the range of 5.30–6.71 nM. These findings imply that hit compounds would be potent drug candidates in controlling the SARS‐CoV‐2 by inhibiting nsp14 protein.

Small molecule drug discovery for glioblastoma treatment based on bioinformatics and cheminformatics approaches.

Background: Glioblastoma (GBM) is a common and highly aggressive brain tumor with a poor prognosis for patients. It is urgently needed to identify potential small molecule drugs that specifically target key genes associated with GBM development and prognosis. Methods: Differentially expressed genes (DEGs) between GBM and normal tissues were obtained by data mining the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Gene function annotation was performed to investigate the potential functions of the DEGs. A protein-protein interaction (PPI) network was constructed to explore hub genes associated with GBM. Bioinformatics analysis was used to screen the potential therapeutic and prognostic genes. Finally, potential small molecule drugs were predicted using the DGIdb database and verified using chemical informatics methods including absorption, distribution, metabolism, excretion, toxicity (ADMET), and molecular docking studies. Results: A total of 429 DEGs were identified, of which 19 hub genes were obtained through PPI analysis. The hub genes were confirmed as potential therapeutic targets by functional enrichment and mRNA expression. Survival analysis and protein expression confirmed centromere protein A (CENPA) as a prognostic target in GBM. Four small molecule drugs were predicted for the treatment of GBM. Conclusion: Our study suggests some promising potential therapeutic targets and small molecule drugs for the treatment of GBM, providing new ideas for further research and targeted drug development.

Enhancing the Small-Scale Screenable Biological Space beyond Known Chemogenomics Libraries with Gray Chemical Matter─Compounds with Novel Mechanisms from High-Throughput Screening Profiles.

Phenotypic assays have become an established approach to drug discovery. Greater disease relevance is often achieved through cellular models with increased complexity and more detailed readouts, such as gene expression or advanced imaging. However, the intricate nature and cost of these assays impose limitations on their screening capacity, often restricting screens to well-characterized small compound sets such as chemogenomics libraries. Here, we outline a cheminformatics approach to identify a small set of compounds with likely novel mechanisms of action (MoAs), expanding the MoA search space for throughput limited phenotypic assays. Our approach is based on mining existing large-scale, phenotypic high-throughput screening (HTS) data. It enables the identification of chemotypes that exhibit selectivity across multiple cell-based assays, which are characterized by persistent and broad structure activity relationships (SAR). We validate the effectiveness of our approach in broad cellular profiling assays (Cell Painting, DRUG-seq, and Promotor Signature Profiling) and chemical proteomics experiments. These experiments revealed that the compounds behave similarly to known chemogenetic libraries, but with a notable bias toward novel protein targets. To foster collaboration and advance research in this area, we have curated a public set of such compounds based on the PubChem BioAssay dataset and made it available for use by the scientific community.

Flexible scaffold-based cheminformatics approach for polypharmacological drug design

Effective treatments for complex central nervous system (CNS) disorders require drugs with polypharmacology and multifunctionality, yet designing such drugs remains a challenge. Here, we present a flexible scaffold-based cheminformatics approach (FSCA) for the rational design of polypharmacological drugs. FSCA involves fitting a flexible scaffold to different receptors using different binding poses, as exemplified by IHCH-7179, which adopted a "bending-down" binding pose at 5-HT2AR to act as an antagonist and a "stretching-up" binding pose at 5-HT1AR to function as an agonist. IHCH-7179 demonstrated promising results in alleviating cognitive deficits and psychoactive symptoms in mice by blocking 5-HT2AR for psychoactive symptoms and activating 5-HT1AR to alleviate cognitive deficits. By analyzing aminergic receptor structures, we identified two featured motifs, the "agonist filter" and "conformation shaper," which determine ligand binding pose and predict activity at aminergic receptors. With these motifs, FSCA can be applied to the design of polypharmacological ligands at other receptors.

Antimicrobial phytoconstituents from Azadirachta indica (neem) with potential inhibitor against FtsZ protein of Pseudomonas aeruginosa

Pseudomonas aeruginosa is a well-known pathogen for its rapid development of multi-drug antibiotic resistance. This pathogen is responsible for numerous human diseases, particularly affecting immunocompromised and elderly patients. Hence, discovering novel therapeutics has become necessary in the fight against antimicrobial resistance. This study is focused on evaluating the potential inhibitory activity of eleven phytocompounds from Azadirachta indica against the nucleotide-binding site of the FtsZ protein of P. aeruginosa through a cheminformatics approach. FtsZ is an indispensable and highly conserved protein in prokaryotic cell division. Docking studies revealed favourable binding energies (ΔG= − 8.3 to − 5.4 kcal/mol) for all selected phytoconstituents. Finally, we selected Nimbiol (CID 11119228), as a lead compound, exhibiting a binding energy (ΔG= −7.8 kcal/mol) for the target. Based on our findings, Nimbiol shows potential as an anti-FtsZ compound, making it a promising candidate for further in vitro and in vivo investigations to assess its antimicrobial activity.

Natural products in neuroprotective therapies: Experimental and cheminformatics approaches to manage neurological disorders

Neurological disorders (NDs) such as Alzheimer’s disease (AD), Parkinson’s disease (PD), epilepsy, despondency, and dementia have been evidenced as a rising concern among diverse geographical regions. Brain-related diseases are currently the main concern because they increase mortality and morbidity in the elderly. Regardless of the continual efforts by modern scientists to develop a promising pharmacological or surgical management, the outcome has not been satisfactory. Also, due to synthetic drugs’ associated side effects, scientists have taken the initiative to consider using natural compounds as an alternative. Hence, they obtain pretty effective results by using natural compounds. Natural ingredients are synthesized from a variety of plant and animal sources. These natural ingredients cure brain diseases through a variety of mechanisms. For effective medication advancement, the molecules must go through preliminary clinical systems that require some investment and significant speculation. In this situation, cheminformatics is fundamental in diminishing time and venture. Cheminformatics methods play a significant role in these issues, including 3-dimensional quantitative structure-activity relationship 3D-(QSAR), virtual screening, docking, molecular dynamic studies, and quantum chemical studies. The vital purpose of this study is to disclose different types of NDs and the neuroprotective effect of several natural products for experimental and cheminformatics-based therapy. Natural products like green tea, flavonoids, and ginseng are discussed as effective neuroprotective products. However, more investigation is expected to comprehend the better utilization of regular items in future exploratory and cheminformatics-based treatment for NDs.

Synthesis, characterization and larvicidal studies of ethyl 3-benzoyl-7-(piperidin-1-yl)indolizine-1-carboxylate analogues against Anopheles arabiensis and cheminformatics approaches

According to WHO, in 2021, there was an estimation of 247 million malaria cases from 84 malaria-endemic countries. Globally an estimated count of 2 billion malaria cases and 11.7 million deaths due to malaria were recorded in the past two decades. Further, the emergence of drug-resistant mosquitos threatens mankind. Therefore, the development of newer larvicidal agents is the need of the hour. This research identifies a new series of variably substituted indolizines for their effectiveness in controlling Anopheles arabiensis larvae through larvicidal activity. The series of Ethyl 3-benzoyl-7-(piperidin-1-yl)indolizine-1-carboxylate analogues (4a-j) were synthesized by reacting 4-(piperidin-1-yl)pyridine, phenacyl bromides with ethyl propiolate via 1, 3-dipolar cycloaddition and the green metrics of the process are reported. All the newly synthesized compounds were characterized by spectroscopic techniques such as 1H NMR,13C NMR, FT-IR, and HRMS. The larvicidal effectiveness of the newly synthesized compounds was assessed against Anopheles arabiensis. Among the compounds studied, namely 4c, 4d, 4e, and 4f, displayed the most notable larval mortality rates within the series, reaching 73%, 81%, 76%, and 71% respectively, in contrast with the negative control acetone. In comparison, the standard Temephos exhibited a mortality rate of 99% at the same concentration. Furthermore, computational approaches including molecular docking and molecular dynamics simulations identified the potential targets of the series compounds as the larval Acetylcholinesterase (AChE) enzyme and the Sterol Carrier Protein-2 (SCP-2) protein. However, it is essential for these computational predictions to undergo experimental validation. Communicated by Ramaswamy H. Sarma

Alcohol-free synthesis, biological assessment, in vivo toxicological evaluation, and in silico analysis of novel silane quaternary ammonium compounds differing in structure and chain length as promising disinfectants

Quaternary ammonium compounds (QACs) are commonly used as disinfectants for industrial, medical, and residential applications. However, adverse health outcomes have been reported. Therefore, biocompatible disinfectants must be developed to reduce these adverse effects. In this context, QACs with various alkyl chain lengths (C12–C18) were synthesized by reacting QACs with the counterion silane. The antimicrobial activities of the novel compounds against four strains of microorganisms were assessed. Several in vivo assays were conducted on Drosophila melanogaster to determine the toxicological outcomes of Si-QACs, followed by computational analyses (molecular docking, simulation, and prediction of skin sensitization). The in vivo results were combined using a cheminformatics approach to understand the descriptors responsible for the safety of Si-QAC. Si-QAC-2 was active against all tested bacteria, with minimal inhibitory concentrations ranging from 13.65 to 436.74 ppm. Drosophila exposed to Si-QAC-2 have moderate-to-low toxicological outcomes. The molecular weight, hydrophobicity/lipophilicity, and electron diffraction properties were identified as crucial descriptors for ensuring the safety of the Si-QACs. Furthermore, Si-QAC-2 exhibited good stability and notable antiviral potential with no signs of skin sensitization. Overall, Si-QAC-2 (C14) has the potential to be a novel disinfectant.

Cheminformatics-Based Design and Synthesis of Hydroxyapatite/Collagen Nanocomposites for Biomedical Applications.

This paper presents a novel cheminformatics approach for the design and synthesis of hydroxyapatite/collagen nanocomposites, which have potential biomedical applications in tissue engineering, drug delivery, and orthopedic and dental implants. The nanocomposites are synthesized by the co-precipitation method with different ratios of hydroxyapatite and collagen. Their mechanical, biological, and degradation properties are analyzed using various experimental and computational techniques. Attenuated total reflection-Fourier-transform infrared spectroscopy, thermogravimetric analysis, and X-ray diffraction unveil the low crystallinity and nanoscale particle size of hydroxyapatite (22.62 nm) and hydroxyapatite/collagen composites (14.81 nm). These findings are substantiated by scanning electron microscopy with energy-dispersive X-ray spectroscopy, confirming the Ca/P ratio between 1.65 and 1.53 and attesting to the formation of non-stoichiometric apatites in all samples, further validated by molecular simulation. The antimicrobial activity of the nanocomposites is evaluated in vitro against several bacterial and fungal strains, demonstrating their medical potential. Additionally, in silico analyses are performed to predict the absorption, distribution, metabolism, and excretion properties and the bioavailability of the collagen samples. This study paves the way for the development of novel biomaterials using chemoinformatics tools and methods, facilitating the optimization of design and synthesis parameters, as well as the prediction of biological outcomes. Future research directions should encompass the investigation of in vivo biocompatibility and bioactivity of the nanocomposites, while exploring further applications and functionalities of these innovative materials.

Abstract 11966: Translational Cardioinformatics: Neutrophil-Derived Translocator Protein as a Novel Regulator of Myocarditis and Coronary Artery Aneurysm in Kawasaki Disease and Multisystem Inflammatory Syndrome in Children

Introduction: Cardiovascular disease (CVD) in Kawasaki disease (KD) and multisystem inflammatory syndrome in children (MIS-C) lead to increased mortality through myocardial infarction. Hypothesis: Since KD and MIS-C are shaped by the same immune continuum, the cardiac pathologies and lethal complications may be averted by targeting a key regulator controlling both diseases; however, the pathogenic drivers are largely undefined. Methods: Through integrated, multi-cohort, single-cell meta-analysis of KD and MIS-C PBMC scRNA-seq profiles, we investigated the immunological drivers associated with systemic damage and cardiac pathologies, compared with other pediatric diseases, and validated across independent cohorts of KD, MIS-C, and myocardial infarction. Via cheminformatics approaches, we identified FDA-approved drugs for repurposing. Results: We found the expansion and hyperactivation of CD177 + neutrophils in KD and MIS-C, but not in other pediatric diseases. CD177 + neutrophils overexpressed markers and causal mediators of CVD development, supported by activation of prognostic CVD gene signatures (acute CVD, major adverse cardiovascular and limb events, and myocardial infarction). CD177 + neutrophils’ overactivated effector repertoire may mediate systemic inflammation and molecular damage via a vascular homing mechanism. We identified a dysfunctional SPI1-dependent regulatory network shared by KD and MIS-C during neutrophil hyperactivation, as well as key regulators which may induce cardiac disorders. Importantly, we found that TSPO is associated with myocarditis and coronary artery aneurysm, disease severity, IVIG treatment, and patient recovery. Via independent cohorts analyses, we validated TSPO as a prime target against KD and MIS-C pathologies. Murine myocardial infarction model confirmed the cardiac hyper-infiltration of hyperactivated CD177 + neutrophils. Lastly, we identified FDA-approved drugs against KD and MIS-C neutrophil hyperactivation. Conclusions: Collectively, CD177 + neutrophils have a pivotal role in KD/MIS-C systemic pathologies, clinical severity, and prognosis. We suggest drugs that can be developed as a single therapeutic strategy against either KD or MIS-C for clinical translation.

Cheminformatics approach for identification of N-HyMenatPimeMelly as a novel potential ligand against RAS and renal chloride channel

Some angiotensin receptor (AR) blockers interfere with the renal chloride channel (ClC-K), which plays an important role in urine concentration. Identifying ligands targeting this channel, whether activating or blocking, is highly desirable because it could open the way for interventions that modulate their activity. In this study, the Asinex (BioDesign) complete library was screened to identify a compound with favorable physicochemical and pharmacokinetic properties, which have both AR blocking and ClC‐Ka-modulating activities to present it as a novel potential oral candidate which could be useful for treatment of salt-sensitive hypertension without major ClC‐K affection. A compound, N-{[4-Hydroxy-1-(2-methyl-1,6-naphthyridin-4-yl)-4-piperidinyl]methyl}-N-methyl-L-lysinamide (N-HyMenatPimeMelly) (Chem Spider ID 68416221), was identified as a potent potential oral ligand of the renin-angiotensin system (RAS) and ClC-Ka with docking scores ranging from −10.978 to −7.324 with the four selected proteins (4YAY: AR type 1, 2PFI: Cytoplasmic domain of ClC-Ka, 6JOD: AR type 2 and 6M0J: Angiotensin-converting enzyme 2). The protein-ligand complex was used to perform molecular dynamics (MD) simulation for 100 ns. The QikProp and SwissADME tools’ results showed that the compound has ADME/T and drug-likeness properties, which are within the permissible ranges for 95% of known drugs. The density functional theory (DFT) analysis and MD simulation extended the study toward computational validation. Throughout the study, N-HyMenatPimeMelly has shown good interactions and stable performance in MD simulation and DFT analysis. The whole analysis has produced promising results, and N-HyMenatPimeMelly can be treated as a novel potential RAS and ClC-K oral ligand, however, experimental validation is needed before human use. Communicated by Ramaswamy H. Sarma