Multi-target Compounds Research Articles

RETRACTED: Improvement of extraction from Hericium erinaceus on the gut-brain axis in AD-like mice

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the lead author, Dr. Diling Chen. Dr. Chen alerted the Editor-in-Chief that data previously published in Aging (Albany NY). 2020 Jan 6; 12:260-287 https://doi.org/10.18632/aging.102614 were accidently reused in the above-referenced Brain Research article. Dr. Chen is a co-author on both articles. The reused content pertains to the fecal transplantation data of the model group, represented by Figure 2 in the Aging article and Figure 5 in the Brain Research article. Dr. Chen did not carefully check the data published by the team before the final submission, resulting in repeated use. The lead author states further that it was an honest mistake, and the team had no intention to plagiarize previously published material. All authors were notified and all are in agreement with the retraction. The authors apologize to the scientific community for any inconvenience or challenges resulting from the publication and retraction of this article.

Epigenetic active phytoceuticals activate immune relevant miRNAs important in virus response systems

Background: Viruses significantly affect global health. The few available viricidal and antiviral therapies are expensive and often associated with unwanted side effects. Functional foods as plant extracts (nutraceuticals) are epigenetically active, and multi-target antiviral compounds that affect several steps of the viral life cycle and host proteins. MicroRNAs (miRNAs) post-transcriptionally regulate host and viral gene expression and are responsible for the fine-tuning of gene expression by controlling the expression of their target messenger RNAs (mRNA) in host cells and viruses. Several plant ingredients have been proven to be active against RNA virus infections. Obviously, miRNAs play a central role in the regulation of gene transcription in viral replication and host immune defense. A healthy diet and nutraceuticals can support the fine-tuning of miRNAs. Objectives: The aim of this study was to analyze the effects of epigenetic active phytoceuticals and/or functional foods on immune relevant miRNAs and mRNAs in a healthy human study population. Methods: In a 2-month human intervention study (n=80), a mix of plant extracts (sage extract, green tea extract, berberine, apple extract, onion extract, elderberry extract, and grape skin extract) with proven activity against RNA viruses were examined for the change of miRNA and mRNA patterns involved in virus response systems. Lifestyle and nutritional behavior, including self-reported stress levels, as well as infection frequency as potential cofounders have been raised. Results: The intervention with secondary plant extracts could modulate the expression of miRNAs involved in the virus defense (miR-30e, miR-877, miR-150) and the expression of NF-κB. The intervention also increased miRNA expression patterns associated with a positive lifestyle. The intervention adapted miRNAs that correlate with an increased risk of infection, smoking, stress, and processed meat products.Conclusion: Plant extracts can enhance the beneficial effects of a healthy nutrition and lifestyle by modulating miRNAs. MiRNAs are promising drug targets for maintaining immune homeostasis.Keywords: antiviral, epigenetic active nutraceutical, miRNA, secondary plant extracts, virus response, plant ingredients, functional foods

Virtual screening of lead compounds for the treatment of Alzheimer’s disease based on multi-target strategy

ABSTRACT Alzheimer’s disease (AD) is a neurological illness that develops over time. Although the disease’s origin and pathophysiology remain unclear, acetylcholinesterase (AChE) has been identified as a potential target. Other targets including glycogen synthase kinase 3β (GSK-3β), β-secretase (BACE-1), and others, are also being investigated as possible therapeutic targets. In this work, compounds from the DrugBank and ZINC subset drug-like databases were screened in silico using ligand-based pharmacophore filtering and molecular docking. Two multi-target compounds, ZINC-27 and ZINC-1-4, were discovered utilising a combination of compound profiling, ADMET prediction, and structural modification, which can inhibit AChE, GSK-3β, and BACE-1. Finally, the trustworthiness of the virtual screening findings was confirmed using molecular dynamics simulation, MM-PBSA binding free energy calculation, and principal component analysis. In conclusion, the multi-approach study revealed that ZINC-27 and ZINC-1-4 might be prospective multi-target anti-AD medicines that work concurrently on AChE, GSK-3β, and BACE-1, which merit further investigation.

Umbelliferone and scopoletin target tyrosine kinases on fibroblast-like synoviocytes to block NF-κB signaling to combat rheumatoid arthritis.

Rheumatoid arthritis (RA) is a complex autoimmune condition primarily affecting synovial joints, which targeted synthetic drugs have damaging safety issues. Saussurea laniceps, a reputed anti-rheumatic medicinal herb, is an excellent place to start looking for natural products as safe, effective, targeted therapeutics for RA. Via biomimetic ultrafiltration, umbelliferone and scopoletin were screened as two anti-rheumatic candidates with the highest specific affinities towards the membrane proteomes of rheumatic fibroblast-like synoviocytes (FLS), the pivotal effector cells in RA. In vitro assays confirmed that the two compounds, to varying extents, inhibited RA-FLS proliferation, migration, invasion, and NF-κB signaling. Network pharmacology analysis and molecular docking analysis jointly revealed that umbelliferone and scopoletin act on multiple targets, mostly tyrosine kinases, in combating RA. Taken together, our present study identified umbelliferone and scopoletin as two major anti-rheumatic components from SL that may bind and inhibit tyrosine kinases and subsequently inactivate NF-κB in RA-FLSs. Our integrated drug discovery strategy could be valuable in finding other multi-target bioactive compounds from complex matrices for treating multifactorial diseases.

Gabapentin Antioxidant Derivatives with Anti-Inflammatory and Neuroprotective Potency

Aims: The aim of this work is to investigate the antioxidant and anti-inflammatory potency of novel gabapentin derivatives, which could be proven useful as neuroprotective agents. Background: Alzheimer’s disease (AD) is one of the most common neurodegenerative disorders worldwide. Due to its multi-factorial character, no effective treatment has been obtained yet. In this direction, the multi-targeting compounds approach could be useful for the development of novel, more effective drugs against AD. Oxidative stress and inflammation are highly involved in the progression of neurodegeneration, while gabapentin has been investigated for the treatment of behavioral symptoms in AD. Objective: In this work, derivatives of cinnamic acid, Trolox, and 3,5-di-tertbutyl-4-hydroxybenzoic acid amidated with gabapentin methyl ester were designed and studied. Compounds with these structural characteristics are expected to act in various biochemical pathways, affecting neurodegenerative processes. Methods: The designed compounds were synthesized with classical amidation methods, purified by flash column chromatography, and identified spectrometrically (1H-NMR and 13C-NMR). Their purity was determined by CHN elemental analysis. They were tested in vitro for their antioxidant and antiinflammatory properties and for their inhibitory effect on acetylcholinesterase. Their in vivo antiinflammatory activity was also tested. Results: Molecules that incorporated antioxidant moiety possessed inhibitory activity against rat microsomal membrane lipid peroxidation and oxidative protein glycation, as well as radical scavenging activity. Moreover, most of them presented moderate inhibition towards lipoxygenase (up to 51% at 100μΜ) and acetylcholinesterase (AchE) (IC50 up to 274μΜ) activities. Finally, all synthesized compounds presented in vivo anti-inflammatory activity, decreasing carrageenan-induced rat paw edema up to 53%, and some of them could inhibit cyclooxygenase significantly. Conclusion: These results indicate that the designed compounds could be proven useful as multitargeting molecules against AD since they affect various biochemical pathways associated with neurodegeneration. Thus, more effective drugs can be obtained, and the possible adverse effects of drug combinations can be limited.

A Network Pharmacology Approach to Explore the Potential Mechanism of Ficus religiosa against Alzheimer’s Disease

Background: Ficus religiosa, also known as the peepal tree, is used to treat multiple diseases. It is proved to be effective in treating cognitive impairment. However, the potential targets and pharmacological and molecular mechanisms of its action on the management of Alzheimer’s Disease (AD) are not entirely clear. Therefore, a network pharmacology approach is required to further study and explore its treatment mechanism. Methods: ChEBI database was used to retrieve the active constituents. AD genes were retrieved from the DisGeNet database. SMILES of phytoconstituents were retrieved from PubChem, traced for the positive drug-likeness score, targets were predicted and regulated proteins were enriched to trace probable modulated proteins, pathways, and GO terms. Cytoscape ver. 3.7.2 was used to construct the active ingredient-target-pathway interaction of F. religiosa and network analysis. Molecular docking was also performed. Results: A total of 7 bioactive out of 25 were predicted to possess a positive drug likeliness score. Also, PIK3CA, PIK3RA, AKT1, MAP2K1 and RAF1 were predicted as key gene targets. The results of the GO analysis demonstrated that the somatodendritic compartment, cytoplasm, plasma membrane, and membrane raft are the main cellular components, its molecular functions are mainly catalytic activity, ion binding, protein kinase activity and, identical protein binding. The biological process is focused on biological quality, response to oxygen-contain-compound sound, and metabolic process. Conclusions: This study holistically illuminated possible pharmacological mechanisms of F. religiosa that might be strongly associated with multi-targeting compounds and act on many AD pathways at the same time.

Indole alkaloid ellipticine as efficient multitarget compound

First isolated from the tropical plant Oschrosia elliptica, indole alkaloid ellipticine provoked huge interest since it demonstrated antitumor activity was demonstrated along with limited toxic side effects and a complete lack of hematological toxicity. In this work, a five-step Cranwell and Saxton synthesis was used for obtaining ellipticine (Ell). Ellipticine hydrochloride salt (Ell×HCl) was also synthesized. Detailed in vitro studies of anticancer, antimalarial, and leishmanicidal activities were performed. Antiproliferation assay using DU145 cancer cell line treated with Ell showed a consistent reduction in cell proliferation and cell viability when treated with 5 μmol Ell. Anti-proliferation activity was more pronounced for the Ell×HCl solutions. Both the Ell and Ell×HCl revealed moderate activity in vitro against Leishmania amazonensis promastigotes, which is related to insufficient solubility of the drugs. IC50 values of Ell and Ell×HCl were determined in vitro against multidrug resistant Plasmodium falciparum strain K1. The Ell×HCl was shown to be almost three times more potent than the Ell in DMSO. Upon dilution with water, Ell solubility and activity drops down, while the activity and solubility of Ell×HCl is enhanced up to 10 times in 50:50 aqueous DMSO solutions

Novel Rivastigmine Derivatives as Promising Multi-Target Compounds for Potential Treatment of Alzheimer's Disease.

Alzheimer’s disease (AD) is the most serious and prevalent neurodegenerative disorder still without cure. Since its aetiology is diverse, recent research on anti-AD drugs has been focused on multi-target compounds. In this work, seven novel hybrids (RIV–BIM) conjugating the active moiety of the drug rivastigmine (RIV) with 2 isomeric hydroxyphenylbenzimidazole (BIM) units were developed and studied. While RIV assures the inhibition of cholinesterases, BIM provides further appropriate properties, such as inhibition of amyloid β-peptide (Aβ) aggregation, antioxidation and metal chelation. The evaluated biological properties of these hybrids included antioxidant activity; inhibition of acetylcholinesterase (AChE), butyrylcholinesterase (BChE) and Aβ42 aggregation; as well as promotion of cell viability and neuroprotection. All the compounds are better inhibitors of AChE than rivastigmine (IC50 = 32.1 µM), but compounds of series 5 are better inhibitors of BChE (IC50 = 0.9−1.7 µM) than those of series 4. Series 5 also showed good capacity to inhibit self- (42.1−58.7%) and Cu(II)-induced (40.3−60.8%) Aβ aggregation and also to narrow (22.4−42.6%) amyloid fibrils, the relevant compounds being 5b and 5d. Some of these compounds can also prevent the toxicity induced in SH-SY5Y cells by Aβ42 and oxidative stress. Therefore, RIV–BIM hybrids seem to be potential drug candidates for AD with multi-target abilities.

Investigating Multi-Target Antiviral Compounds by Screening of Phytochemicals From Neem (Azadirachta indica) Against PRRSV: A Vetinformatics Approach.

Porcine reproductive and respiratory syndrome virus (PRRSV) is a global health problem for pigs. PRRSV is highly destructive and responsible for significant losses to the swine industry. Vaccines are available but incapable of providing adequate and long-term protection. As a result, effective and safe strategies are urgently needed to combat the virus. The scavenger receptor cysteine-rich domain 5 (SRCR5) in porcine CD163, non-structural protein 4 (Nsp4), and Nsp10 are known to play significant roles in PRRSV infection and disease development. Therefore, we targeted these proteins to identify multi-target antiviral compounds. To identify potent inhibitors, molecular docking of neem phytochemicals was conducted; three compounds [7-deacetyl-7-oxogedunin (CID:1886), Kulactone (CID:15560423), and Nimocin (CASID:104522-76-1)] were selected based on the lowest binding energy and multi-target inhibitory nature. The efficacy and safety of the selected compounds were revealed through the pharmacokinetics analysis and toxicity assessment. Moreover, 100 ns molecular dynamics (MD) simulation was performed to evaluate the stability and dynamic behavior of target proteins and their docked complexes with selected compounds. Besides, molecular mechanics Poisson–Boltzmann surface area method was used to estimate the binding free energy of each protein-ligand complex obtained from the MD simulations and validate the affinities of selected compounds to target proteins. Based on our analysis, we concluded that the identified multi-target compounds can be utilized as lead compounds for the development of natural drugs against PRRSV. If further validated in clinical studies, these compounds can be used individually or in combination against the virus.

The multitarget FAAH inhibitor/D3 partial agonist ARN15381 decreases nicotine self-administration in male rats

Tobacco use disorder is a worldwide health problem for which available medications show limited efficacy. Nicotine is the psychoactive component of tobacco responsible for its addictive liability. Similar to other addictive drugs, nicotine enhances mesolimbic dopamine transmission. Inhibition of the fatty acid amide hydrolase (FAAH), the enzyme responsible for the degradation of the endocannabinoid anandamide (AEA), palmitoylethanolamide (PEA) and oleoylethanolamide (OEA), reduces nicotine-enhanced dopamine transmission and acquisition of nicotine self-administration in rats. Down-regulation of dopamine transmission by antagonists or partial agonists of the dopamine D3 receptor (DRD3) also reduced nicotine self-administration and conditioned place preference. Based on these premises, we evaluated the effect of ARN15381, a multitarget compound showing FAAH inhibition and DRD3 partial agonist activity in the low nanomolar range, on nicotine self-administration in rats. Pretreatment with ARN15381 dose dependently decreased self-administration of a nicotine dose at the top of the nicotine dose/response (D/R) curve, while it did not affect self-administration of a nicotine dose laying on the descending limb of the D/R curve. Conversely, pretreatment with the selective FAAH inhibitor URB597 and the DRD3 partial agonist CJB090 failed to modify nicotine self-administration independent of the nicotine dose self-administered. Our data indicates that the concomitant FAAH inhibition and DRD3 partial agonism produced by ARN15381 is key to the observed reduction of nicotine self-administration, demonstrating that a multitarget approach may hold clinical importance for the treatment of tobacco use disorder.

Dual-Hit Model of Parkinson's Disease: Impact of Dysbiosis on 6-Hydroxydopamine-Insulted Mice-Neuroprotective and Anti-Inflammatory Effects of Butyrate.

Recent evidence highlights Parkinson’s disease (PD) initiation in the gut as the prodromal phase of neurodegeneration. Gut impairment due to microbial dysbiosis could affect PD pathogenesis and progression. Here, we propose a two-hit model of PD through ceftriaxone (CFX)-induced dysbiosis and gut inflammation before the 6-hydroxydopamine (6-OHDA) intrastriatal injection to mimic dysfunctional gut-associated mechanisms preceding PD onset. Therefore, we showed that dysbiosis and gut damage amplified PD progression, worsening motor deficits induced by 6-OHDA up to 14 days post intrastriatal injection. This effect was accompanied by a significant increase in neuronal dopaminergic loss (reduced tyrosine hydroxylase expression and increased Bcl-2/Bax ratio). Notably, CFX pretreatment also enhanced systemic and colon inflammation of dual-hit subjected mice. The exacerbated inflammatory response ran in tandem with a worsening of colonic architecture and gut microbiota perturbation. Finally, we demonstrated the beneficial effect of post-biotic sodium butyrate in limiting at once motor deficits, neuroinflammation, and colon damage and re-shaping microbiota composition in this novel dual-hit model of PD. Taken together, the bidirectional communication of the microbiota–gut–brain axis and the recapitulation of PD prodromal/pathogenic features make this new paradigm a useful tool for testing or repurposing new multi-target compounds in the treatment of PD.

Oxidative stress response system in Escherichia coli arising from diphenyl ditelluride (PhTe)2 exposure

The toxicity of diphenyl ditelluride (PhTe)2 is associated with its ability to oxidize sulfhydryl groups from biological molecules. Therefore, we evaluated possible molecular mechanisms of toxicity induced by this organochalcogen in Escherichia coli (E. coli) by evaluating oxidative damage markers, relative expression of genes associated with the cellular redox state in bacteria, such as katG, sodA, sodB, soxS, and oxyR, as well as the activity of enzymes responsible for cellular redox balance. After exposure of (PhTe)2 (6, 12, and 24 μg/mL), there was a decrease in non-protein thiols (NPSH) levels, an increase in protein carbonylation and lipid peroxidation in E. coli. Intra- and extracellular reactive species (RS) was increased at concentrations of 6, 12, and 24 μg/mL. The superoxide dismutase (SOD) activity was increased at the three concentrations tested, while catalase (CAT) activity was higher at 12 and 24 μg/mL. The soxS gene showed lower expression at the three concentrations tested, while the oxyR gene was supressed at 24 μg/mL. The katG antioxidant response gene showed lower expression, and sodA and sodB were positively activated, except for sodB at 6 μg/mL. Our findings demonstrate that exposure to (PhTe)2 induced RS formation, NPSH depletion and changes in transcriptional factors regulation, characterizing it as a multi-target compound, causing disruption in cellular oxidative state, as well as molecular mechanisms associated in E. coli.

Computational investigation of benzalacetophenone derivatives against SARS-CoV-2 as potential multi-target bioactive compounds

Benzalacetophenones, precursors of flavonoids are aromatic ketones and enones and possess the immunostimulant as well as antiviral activities. Thus, benzalacetophenones were screened against the COVID-19 that could be lethal in patients with compromised immunity. We considered ChEBI recorded benzalacetophenone derivative(s) and evaluated their activity against 3C-like protease (3CLpro), papain-like protease (PLpro), and spike protein of SARS-Cov-2 to elucidate their possible role as antiviral agents. The probable targets for each compound were retrieved from DIGEP-Pred at 0.5 pharmacological activity and all the modulated proteins were enriched to identify the probably regulated pathways, biological processes, cellular components, and molecular functions. In addition, molecular docking was performed using AutoDock 4 and the best-identified hits were subjected to all-atom molecular dynamics simulation and binding energy calculations using molecular mechanics Poisson-Boltzmann surface area (MMPBSA). The compound 4-hydroxycordoin showed the highest druglikeness score and regulated nine proteins of which five were down-regulated and four were upregulated. Similarly, enrichment analysis identified the modulation of multiple pathways concerned with the immune system as well as pathways related to infectious and non-infectious diseases. Likewise, 3'-(3-methyl-2-butenyl)-4′-O-β-d-glucopyranosyl-4,2′-dihydroxychalcone with 3CLpro, 4-hydroxycordoin with PLpro and mallotophilippen D with spike protein receptor-binding domain showed highest binding affinity, revealed stable interactions during the simulation, and scored binding free energy of −26.09 kcal/mol, −16.28 kcal/mol, and −39.2 kcal/mol, respectively. Predicted anti-SARS-CoV-2 activities of the benzalacetophenones reflected the requirement of wet lab studies to develop novel antiviral candidates.

Treating neurodegenerative diseases with multitarget drugs: an interview with Maria João Matos.

Neurodegenerative diseases are one of the leading causes of death, disability and dependency worldwide. Since the etiology of these complex pathologies is not completely known, the available therapeutic options can only cause temporary relief of the symptoms, but cannot cure them. Life-changing therapeutic solutions are urgently needed, as the number of people suffering from these pathologies has been increasing quickly over the last few decades. Recent studies regarding the paradigm of using multitarget compounds to treat both Alzheimer's and Parkinson's diseases have been analyzed and included in the review entitled "Multitarget therapeutic approaches for Alzheimer's and Parkinson's diseases: an opportunity or an illusion?". This interview is based on this previously published overview, highlighting some of the most important aspects.

Integrated Whole-Transcriptome Profiling and Bioinformatics Analysis of the Polypharmacological Effects of Ganoderic Acid Me in Colorectal Cancer Treatment.

Ganoderic acid Me (GA-Me) is a natural bioactive compound derived from Ganoderma lucidum. Our present results suggested that GA-Me inhibited proliferation, induced DNA fragmentation and significantly activated caspase-9 and caspase-3 in HCT116 cells. As shown in our previous studies, GA-Me targets several genes to prevent cancer, including colorectal cancer (CRC). Thus, we hypothesized that GA-Me might be a multitarget ligand against cancer. However, its exact mechanism in CRC remains unclear. Here, whole-transcriptome sequencing was employed to assess the long noncoding RNA (lncRNA), circular RNA (circRNA), microRNA (miRNA), and messenger RNA (mRNA) profiles of GA-Me-treated HCT116 cells. In total, 1572 differentially expressed (DE) lncRNAs, 123 DEcircRNAs, 87 DEmiRNAs, and 1508 DEmRNAs were identified. DCBLD2 and RAPGEF5 were validated as two core mRNAs in the DElncRNA, DEcircRNA, and DEmiRNA networks. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed the biological functions and potential mechanisms of TCONS-00008997, XR-925056.2, circRNA-07908, hsa-miR-100-3p, hsa-miR-1257, hsa-miR-3182, NAV3, ADAM20, and STARD4, which were altered after GA-Me treatment. The regulatory relationships of the XR-925056.2-hsa-miR-3182-NAV3/ADAM20/STARD4, circRNA-07908|Chr22:38986298-39025349-hsa-miR-3182-NAV3/ADAM20, ENST00000414039/ENST00000419190-novel874_mature-MMP9 and circRNA-00314|Chr1:35470863-35479212/circRNA-05460|Chr17:72592203-72649268-novel874_mature-MMP9 immune-regulatory networks involved both noncoding RNAs (ncRNAs) and mRNAs. Molecular docking studies showed that Zn2+ and the His201, His205, His211, Glu202, and Ala165 residues of MMP2 contributed to its high affinity for GA-Me. Zn2+ and the Glu402 and Gly186 residues of MMP9 are important for its interaction with GA-Me. Our results suggested and confirmed that GA-Me is a potential multitarget lead compound for CRC treatment with unique polypharmacological advantages.

The discovery of multi-target compounds with anti-inflammation activity from traditional Chinese medicine by TCM-target effects relationship spectrum

Ethnopharmacological relevanceRhei Radix et Rhizoma, Lonicerae Japonicae Flos and Zingiberis Rhizoma was widely used in the treatment of inflammatory disease. The discovery of new multi-target compounds for new drug from the TCM was a possible direction.Aim of the study: Multi-target compounds screening based on polypharmacology was an effective method. As an interdisciplinary field, polypharmacology screen multi-target compounds by various methods. So, a flexible screening framework to avoid the disadvantage of single methods is considered to have great significance. Materials and methodsThe research propose a common framework called Traditional Chinese medicine target-effect relationship spectrum (TCM-TERS). TCM-TERS was constructed based on the pharmacophore and molecular docking models, which provided predicted activity by compounds screening. TCM-TERS merge the results of different models and visualize the targeted activity of each compounds. Then the TCM-TERS were analyzed by the analytic hierarchy process and active components were chosen by the contributing factors. The activity of components was verified on the RAW264.7 by RT-PCR. ResultsThis article constructed TCM-TERS of Rhei Radix et Rhizoma, Lonicerae Japonicae Flos and Zingiberis Rhizoma with the COX-2, mPGES-1, 5-LOX and SPLA2-IIA. Seven compounds were chosen with multiple targeted activity based on the TCM-TERS, which showed remarkable activity in RT-PCR. ConclusionThe TCM-TERS was an efficient interdisciplinary method for drug discovery of the TCM, which provide a flexible method to the researcher that can screen specific compounds with multiple screening methods.

3β-Acetoxy-21α-H-hop-22(29)ene, a novel multitargeted phytocompound against SARS-CoV-2: in silico screening

The present pandemic disease COVID-19 demands an urgent need for more efficient antiviral drugs against SARS-CoV-2. Computational drug designing and discovery enable us to explore ethnomedicinal plants as a source of various lead molecules that can be used against present and future pathogens. Adiantum latifolium Lam., a common fern, is resistant to pathogens mainly due to the presence of various phytochemicals having antimicrobial properties. In our previous study, 3β-acetoxy-21α-H-hop-22(29)ene, a terpenoid has been characterized from the methanol extract of leaves of A. latifolium. The manuscript evaluates the antiviral potency of the compound against SARS-CoV-2 through molecular docking method. Proteins essential for SARS-CoV-2 multiplication in host cells are the target sites. The study revealed strong binding affinity of the compound for all the ten proteins selected, including seven nonstructural proteins, two structural proteins and one receptor protein, with a binding energy of −4.67 to −8.76 kcal/mol. MDS and MMPBSA analysis of the best ranked complex further confirmed the results. The multitargeted compound can be considered as a natural lead molecule in drug designing against COVID-19, but requires wet-lab experimentation and clinical trials. Communicated by Ramaswamy H. Sarma

A New Strategy for Multitarget Drug Discovery/Repositioning Through the Identification of Similar 3D Amino Acid Patterns Among Proteins Structures: The Case of Tafluprost and its Effects on Cardiac Ion Channels.

The identification of similar three-dimensional (3D) amino acid patterns among different proteins might be helpful to explain the polypharmacological profile of many currently used drugs. Also, it would be a reasonable first step for the design of novel multitarget compounds. Most of the current computational tools employed for this aim are limited to the comparisons among known binding sites, and do not consider several additional important 3D patterns such as allosteric sites or other conserved motifs. In the present work, we introduce Geomfinder2.0, which is a new and improved version of our previously described algorithm for the deep exploration and discovery of similar and druggable 3D patterns. As compared with the original version, substantial improvements that have been incorporated to our software allow: (i) to compare quaternary structures, (ii) to deal with a list of pairs of structures, (iii) to know how druggable is the zone where similar 3D patterns are detected and (iv) to significantly reduce the execution time. Thus, the new algorithm achieves up to 353x speedup as compared to the previous sequential version, allowing the exploration of a significant number of quaternary structures in a reasonable time. In order to illustrate the potential of the updated Geomfinder version, we show a case of use in which similar 3D patterns were detected in the cardiac ions channels NaV1.5 and TASK-1. These channels are quite different in terms of structure, sequence and function and both have been regarded as important targets for drugs aimed at treating atrial fibrillation. Finally, we describe the in vitro effects of tafluprost (a drug currently used to treat glaucoma, which was identified as a novel putative ligand of NaV1.5 and TASK-1) upon both ion channels’ activity and discuss its possible repositioning as a novel antiarrhythmic drug.

Design, Synthesis, and Bioevaluation of Indole Core Containing 2-Arylidine Derivatives of Thiazolopyrimidine as Multitarget Inhibitors of Cholinesterases and Monoamine Oxidase A/B for the Treatment of Alzheimer Disease.

In continuation of our previous study to identify multitarget inhibitors of cholinesterases (ChEs) and monoamine oxidase (MAOs) isoforms, we synthesized and evaluated 2-arylidine derivatives of thiazolopyrimidine for the treatment of Alzheimer disease. Three series of compounds with different linker size and target-anchoring functional groups were synthesized. Compounds 34–37 showed excellent to good AChE and BChE inhibition potential at nanomolar to low micromolar concentration. While all the compounds showed excellent MAO-B inhibition and selectivity relative to MAO-A, compounds 25 and 36 emerged as the most potent MAO-B inhibitors of all the series of synthesized compounds with IC50 values of 0.13 μM and 0.10 μM, respectively. Furthermore, kinetic studies of inhibitor 35 showed mixed inhibition mode. Exploration of structure activity relationship (SAR) revealed the role of functionalities and length of linkers on potency. Acute toxicity evaluation showed the safety of tested compounds up to 2000 mg/kg dose. PAMPA-BBB evaluation showed BBB permeability of the tested compounds, while MTT assay performed on neuroblastoma SHSY5Y cells showed that all the tested compounds are non-neurotoxic in the tested concentrations. Docking studies showed a strong correlation with experimental in vitro results via binding orientations and interaction patterns of the synthesized compounds into the binding sites of target enzymes. We have successfully identified safe, non-neurotoxic, and blood brain barrier permeable multitarget lead compounds for the treatment of AD.

An Integrated Strategy for Rapid Screening of Multi-target Lead Compounds for the Treatment of Alzheimer's Disease from Traditional Chinese Medicines by UHPLC Combined with High-throughput Screening: A Case Study on Salviae miltiorrhizae Radix et Rhizoma

Background: Salviae Miltiorrhizae Radix et Rhizoma (Red Sage root) is widely used in traditional Chinese medicine (TCM) for the treatment of Alzheimer’s disease (AD) with demonstrated curative effects, based on the concept of "one drug with multiple therapeutic targets," which appears to be a good strategy for AD treatment. Objective: This study aimed to develop of high-throughput screening (HTS) method for multitherapeutic target components found in complex TCMs, which are active against AD, using Red Sage root as the case study. Method: Acetylcholinesterase (AChE) inhibitors (AChEIs) from Red Sage root extracts were pre-screened by ultrafiltration-HPLC (UF-HPLC) analysis, in which AChE was added to the extract and then ultrafiltered to remove non-binding compounds. Potential AChEIs were identified by HPLC analysis of compounds bound to AChE. A microplate-based HTS was then used to quantify the AChE inhibitory activity and antioxidant activity of the pre-screened compounds. Results: Pre-screening found ten potential inhibitors, which were identified by ESI-TOF/MS; six of these were purified by semi-preparative HPLC: Oleoyl neocryptotanshinone (1), Dihydrotanshinone Ⅰ (2), Cryptotanshinone (3), Tanshinone Ⅰ (4), Tanshinone ⅡA (5) and Miltirone (6). All six compounds had good AChE inhibitory activity and weak DPPH scavenging capacity. Conclusion: This study provides a platform and technology support for the rapid discovery of multi-target components, potentially active against AD, from complex TCMs and with strong potential for adaptation to the discovery of treatments for other diseases.