Cheminformatics Analysis Research Articles

Design, Synthesis, and Biological Examination of N‐Phenyl‐6‐fluoro‐4‐hydroxy‐2‐quinolone‐3‐carboxamides as Anticancer Agents

AbstractCancer is one of the leading causes of death worldwide, and it has a major impact on public health. Phosphatidylinositol 3‐kinase (PI3Kα) has been recognized as a promising drug target for developing anticancer agents. Herein, a series of N‐phenyl‐6‐fluoro‐4‐hydroxy‐2‐quinolone‐3‐carboxamides was developed to target PI3Kα. All synthesized compounds were characterized using FT‐IR, NMR (1H and 13C) and elemental analysis. All synthesized chemical analogues exerted distinctive anticancer activity. They inhibited the growth of human epithelial colorectal adenocarcinoma (Caco‐2) with IC50 values between 48.63–378 μM, and human colon cancer (HCT‐116) cell lines with IC50 values between 44–664 μM. Computational modelling studies provided important biological insight. Induced‐fit docking (IFD) studies showed that the synthesized chemical analogues fit the kinase catalytic domains and form a significant H‐bond interaction network with key amino acids at the biding site. Furthermore, cheminformatics analyses indicated that all synthesized compounds were drug‐like permitting further animal testing or clinical development.

Identification of potential andrographolide-based drug candidate against Keap1-Nrf2 pathway through rigorous cheminformatics screening.

The Keap1-Nrf2 [Kelch-like ECH-associated protein-1-Nuclear factor erythroid-2-related factor-2] regulatory pathway plays a vital role in the protection of cells by regulating transcription of antioxidant and detoxification genes. Andrographolide (AGP) regulates the Keap1-Nrf2 pathway by inhibiting the Keap1 protein. To identify a more potent AGP analog as a therapeutic agent against Keap1 protein, in this work, cheminformatics analysis of 237 AGP analogs was carried out. Amongst these, five AGP analogs were screened through virtual screening followed by their molecular docking analysis against Keap1 protein, which revealed greater binding affinities (binding energy = - 4.15 to - 5.59kcal/mol) for the shortlisted AGP analogs compared to AGP (binding energy = - 4.02kcal/mol). Pharmacophore mapping indicated 14 spatial features, including 3 hydrogen bond acceptors and 11 hydrophobic, while ADME analysis established the potential of all five analogs as orally-active drug-like candidates based on Lipinski's rule of five. We also examined the chemical reactivity of AGP and the shortlisted AGP analogs using DFT analysis, which revealed that except for one analog (AGP_A2) all are more chemically reactive than AGP. Further, molecular dynamics simulation analysis and MM/GBSA evidenced that AGP_A1 (PubchemID-123361152), AGP_A3 (PubchemID-58209855) and AGP_A4 (PubchemID-101362374) are the best drug like candidates compared to AGP and have greater potential to activate the Keap1-Nrf2 pathway by inhibiting the Keap1 protein.

Chemotaxonomic investigation of plant terpenoids with an established database (TeroMOL).

Terpenoids constitute the biggest class of plant-derived natural products with diverse chemical structures and extensive biological activities. Interpreting enzyme functions and mining new structures of terpenoids could be inspired by the cheminformatic and chemotaxonomic analysis, whereas it is hampered by the incompleteness of available data for terpenoids. Here a dedicated terpenoids database, TeroMOL, is developed to collect more than 170 000 terpenoids and their derivatives annotated with reported biological sources, along with a user-friendly and freely accessible webserver to visualise and analyse the terpenoids skeletons and organism sources. The quantitative distributions as well as the qualitative trends between terpenoid skeletons and organism sources in plant kingdom are revealed from a chemotaxonomic view, while no comparisons are attempted due to the inherent data biases. Nevertheless, the terpenoid chemomarkers in several organisms are discussed based on the available data with highly enriched and exclusive carbon skeletons. We believe that the TeroMOL database and its accessory computational tools will be very promising for exploring the chemical space and biological sources of terpenoids, and assisting the terpenoid research community in the future.

Chemical Evolution of Natural Product Structure.

Natural products are the result of Nature’s exploration of biologically relevant chemical space through evolution and an invaluable source of bioactive small molecules for chemical biology and medicinal chemistry. Novel concepts for the discovery of new bioactive compound classes based on natural product structure may enable exploration of wider biologically relevant chemical space. The pseudo-natural product concept merges the relevance of natural product structure with efficient exploration of chemical space by means of fragment-based compound development to inspire the discovery of new bioactive chemical matter through de novo combination of natural product fragments in unprecedented arrangements. The novel scaffolds retain the biological relevance of natural products but are not obtainable through known biosynthetic pathways which can lead to new chemotypes that may have unexpected or unprecedented bioactivities. Herein, we cover the workflow of pseudo-natural product design and development, highlight recent examples, and discuss a cheminformatic analysis in which a significant portion of biologically active synthetic compounds were found to be pseudo-natural products. We compare the concept to natural evolution and discuss pseudo-natural products as the human-made equivalent, i.e. the chemical evolution of natural product structure.

Cheminformatic analysis of natural product-based drugs and chemical probes.

Covering: 1981 to 2019Natural products continue to play a major role in drug discovery, with half of new chemical entities based structurally on a natural product. Herein, we report a cheminformatic analysis of the structural and physicochemical properties of natural product-based drugs in comparison to top-selling brand-name synthetic drugs, and a selection of chemical probes recently discovered from diversity-oriented synthesis libraries. In this analysis, natural product-based drugs covered a broad range of chemical space based on size, polarity, and three-dimensional structure. Natural product-based structures were also more prevalent in top-selling drugs of 2018 compared to 2006. Further, the drugs clustered well according to biosynthetic origins, but less so based on therapeutic classes. Macrocycles occupied distinctive and relatively underpopulated regions of chemical space, while chemical probes largely overlapped with synthetic drugs. This analysis highlights the continued opportunities to leverage natural products and their pharmacophores in modern drug discovery.

Cheminformatics analysis of molecular datasets of transcription factors associated with quorum sensing in Pseudomonas aeruginosa.

Transcription factors associated with quorum sensing in P. aeruginosa are promising targets for discovering new adjuvants against infection with this pathogen. Regulation of these transcription factors offers the possibility of controlling multiple virulence factors related to them as biofilm development, proteases, hydrogen cyanide, among others. Numerous molecules have been tested against these targets, however, the keys responsible for antagonistic activity are still unknown. In this work, the structure–activity relationships of active molecules tested against LasR, PqsR, and RhlR transcription factors are analyzed in order to establish the structural characteristics associated. As part of the study, molecular complexity, scaffold, activity cliffs, and chemical space visualization analyses were conducted to find out characteristics associated with biological activity. In this study, several structural features were identified as significant for antagonist activity, highlighting molecular size and hydrogen bond acceptors.

Novel Insights into the Bioactive Metabolites of Macrocybe gigantea (Agaricomycetes), Using Gas Chromatography-Mass Spectrometry Combined with Chemoinformatic Approaches.

Macrocybe gigantea is an edible mushroom and has multiple pharmacological properties, including antibacterial, antioxidant, and antitumor activities. However, only a few reports are currently available on the bioactive compounds and bioactivity of this mushroom. Therefore, the present study aimed to explore the unique chemical diversity of the fruiting body of M. gigantea. Species identification was done accurately with morphological and molecular methods, followed by mycochemical extraction in different solvent systems. The ethanolic extract of the fruiting body gave maximum yield, and gas chromatography-mass spectrometry (GC-MS) analysis was performed along with an assessment of antibacterial activity and cell viability by the MTT assay. The GC-MS analysis revealed 50 metabolites, and further cheminformatics analysis of these metabolites revealed their possible biological activities. In addition, the physicochemical and mineral element analysis of M. gigantea revealed the quality and authenticity of the species. Altogether, the current investigation gives a comprehensive overview of the bioactive metabolites of M. gigantea.

Electrophilic thymol isobutyrate from Inula nervosa Wall. (Xiaoheiyao) ameliorates steatosis in HepG2 cells via Nrf2 activation

• Electrophilic components from Xiaoheiyao are knocked out using magnetic GSH probe. • Electrophilic components have the potential to ameliorate steatosis in HepG2 cells. • 10-Isobutyryloxy-8,9-epoxythymol isobutyrate is discovered as a bioactive compound. • 10-Isobutyryloxy-8,9-epoxythymol isobutyrate improves steatosis via Nrf2 activation. Xiaoheiyao , the rhizomes of Inula nervosa Wall., is a culinary spice known to contain some electrophilic Nrf2 activators that could potentially intervene in nonalcoholic fatty liver disease (NAFLD). In this study, the electrophilic components from Xiaoheiyao were annotated by comprehensive cheminformatics analyses on UHPLC-MS/MS data after being knocked out with glutathione (GSH)-immobilized magnetic microspheres. Their intervention effects against hepatic steatosis were investigated in free fatty acid (FFA)-treated HepG2 cells. The electrophilic components in Xiaoheiyao were found to be the major bioactive components preventing hepatic steatosis in FFA-treated HepG2 cells. In particular, 10-isobutyryloxy-8,9-epoxythymol isobutyrate (XHY-1) improved hepatic lipid metabolism disorder, Krebs cycle activity, oxidative phosphorylation, and the cellular and mitochondrial redox status. Moreover, XHY-1 activates the Nrf2-ARE signaling pathway through the up-regulation of Nrf2 expression and promotion of Nrf2 nuclear translocation. Molecular docking further showed that XHY-1 could conjugate with Cys151 in the BTB domain of Keap1 through the epoxy group. In conclusion, the electrophilic components of Xiaoheiyao , especially XHY-1, attenuated hepatic steatosis in FFA-treated HepG2 cells through activation of the Nrf2-ARE signaling pathway.

N-([1,1'-biaryl]-4-yl)-1-naphthamide-based scaffolds synthesis, their cheminformatics analyses, and screening as bacterial biofilm inhibitor.

Naphthamides have pharmacological potential as they express strong activities against microorganisms. The commercially available naphthoyl chloride and 4-bromoaniline were condensed in dry dichloromethane (DCM) in the presence of Et3 N to form N-(4-bromophenyl)-1-naphthamide (86%) (3). Using a Pd(0) catalyzed Suzuki-Miyaura Cross-Coupling reaction of (3) and various boronic acids, a series of N-([1,1'-biaryl]-4-yl)-1-naphthamide derivatives (4a-h) were synthesized in moderate to good yields. The synthesized derivatives were evaluated for cytotoxicity haemolytic assay and biofilm inhibition activity through in silico and in vitro studies. Molecular docking, ADME (absorption, distribution, metabolism, and excretion), toxicity risk, and other cheminformatics predict synthesized molecules as biologically active moieties, further validated through in vitro studies in which compounds (4c) and (4f) showed significant haemolytic activity whereas (4e) exhibited an efficient biofilm inhibition activity against Gram-negative bacteria Escherichia coli and Gram-positive bacteria Bacillus subtilis. When forming biofilms, bacteria become resistant to various antimicrobial treatments. Currently, research is focused on the development of agents that inhibit biofilm formation, thus the present work is valuable for preventing future drug resistance.

In silico insights into potential gut microbial modulation of NAD+ metabolism and longevity

Recent evidence has prompted the notion of gut-microbial signatures as an indirect marker of aging and aging-associated decline in humans. However, the underlying host-symbiont molecular interactions contributing to these signatures remain poorly understood. In this study, we address this gap using cheminformatic analyses to elucidate potential gut microbial metabolites that may perturb the longevity-associated NAD+ metabolic network. In silico ADMET, KEGG interaction analysis, molecular docking, molecular dynamics simulation, and molecular mechanics calculation predict a large number of safe and bioavailable microbial metabolites to be direct and/or indirect activators of NAD+-dependent sirtuin proteins. Our simulation results suggest dihydropteroate, phenylpyruvic acid, indole-3-propionic acid, phenyllactic acid, all-trans-retinoic acid, and multiple deoxy-, methyl-, and cyclic nucleotides from intestinal microbiota as the best-performing regulators of NAD+ metabolism. Retracing these molecules to their source microorganisms also suggest commensal Escherichia, Bacteroides, Bifidobacteria, and Lactobacilli to be associated with the highest number of pro-longevity metabolites. These findings from our early-stage study, therefore, provide an informatics-based context for previous evidence in the area and grant novel insights for future clinical investigation intersecting anti-aging drug discovery, probiotics, and gut microbial signatures.

A Catalog of Natural Products Occurring in Watermelon-Citrullus lanatus.

Sweet dessert watermelon (Citrullus lanatus) is one of the most important vegetable crops consumed throughout the world. The chemical composition of watermelon provides both high nutritional value and various health benefits. The present manuscript introduces a catalog of 1,679 small molecules occurring in the watermelon and their cheminformatics analysis for diverse features. In this catalog, the phytochemicals are associated with the literature describing their presence in the watermelon plant, and when possible, concentration values in various plant parts (flesh, seeds, leaves, roots, rind). Also cataloged are the chemical classes, molecular weight and formula, chemical structure, and certain physical and chemical properties for each phytochemical. In our view, knowing precisely what is in what we eat, as this catalog does for watermelon, supports both the rationale for certain controlled feeding studies in the field of precision nutrition, and plant breeding efforts for the development of new varieties with enhanced concentrations of specific phytochemicals. Additionally, improved and comprehensive collections of natural products accessible to the public will be especially useful to researchers in nutrition, cheminformatics, bioinformatics, and drug development, among other disciplines.

Design and construction of a stereochemically diverse piperazine-based DNA-encoded chemical library

Here we report the successful construction of a novel, stereochemically diverse DNA-Encoded Chemical Library (DECL) by utilizing 24 enantiomerically pure trifunctional 2, 6- di-substituted piperazines as central cores. We introduce the concept of positional diversity by placing the DNA attachment at either of two possible sites on the piperazine scaffold. Using a wide range of building blocks, a diverse library of 77 million compounds was produced. Cheminformatic analysis demonstrates that this library occupies a wide swath of chemical space, and that the piperazine scaffolds confers different shape diversity compared to the commonly used triazine core.

Synthesis of Indofulvin Pseudo-Natural Products Yields a New Autophagy Inhibitor Chemotype.

Chemical and biological limitations in bioactive compound design based on natural product (NP) structure can be overcome by the combination of NP‐derived fragments in unprecedented arrangements to afford “pseudo‐natural products” (pseudo‐NPs). A new pseudo‐NP design principle is described, i.e., the combination of NP‐fragments by transformations that are not part of current biosynthesis pathways. A collection of indofulvin pseudo‐NPs is obtained from 2‐hydroxyethyl‐indoles and ketones derived from the fragment‐sized NP griseofulvin by means of an iso‐oxa‐Pictet‐Spengler reaction. Cheminformatic analysis indicates that the indofulvins reside in an area of chemical space sparsely covered by NPs, drugs, and drug‐like compounds and they may combine favorable properties of these compound classes. Biological evaluation of the compound collection in different cell‐based assays and the unbiased high content cell painting assay reveal that the indofulvins define a new autophagy inhibitor chemotype that targets mitochondrial respiration.

Newly Identified Chemicals Preserve Mitochondrial Capacity and Decelerate Loss of Photoreceptor Cells in Murine Retinal Degeneration Models.

Purpose: Metabolic stress and associated mitochondrial dysfunction are implicated in retinal degeneration irrespective of the underlying cause. We identified seven unique chemicals from a Chembridge DiverSET screen and tested their protection against photoreceptor cell death in cell- and animal-based approaches. Methods: Calcium overload (A23187) was triggered in 661W murine photoreceptor-derived cells, and changes in redox potential and real-time changes in cellular metabolism were assessed using the MTT and Seahorse Biosciences XF assay, respectively. Cheminformatics to compare structures, and biodistribution in the living pig eye aided in selection of the lead compound. In-situ, retinal organ cultures of rd1 mouse and S334ter-line-3 rat were tested, in-vivo the light-induced retinal degeneration in albino Balb/c mice was used, assessing photoreceptor cell numbers histologically. Results: Of the seven chemicals, six were protective against A23187- and IBMX-induced loss of mitochondrial capacity, as measured by viability and respirometry in 661W cells. Cheminformatic analyses identified a unique pharmacophore with 6 physico-chemical features based on two compounds (CB11 and CB12). The protective efficacy of CB11 was further shown by reducing photoreceptor cell loss in retinal explants from two retinitis pigmentosa rodent models. Using eye drops, CB11 targeting to the pig retina was confirmed. The same eye drops decreased photoreceptor cell loss in light-stressed Balb/c mice. Conclusions: New chemicals were identified that protect from mitochondrial damage and lead to improved mitochondrial function. Using ex-vivo and in-vivo models, CB11 decreased the loss of photoreceptor cells in murine models of retinal degeneration and may be effective as treatment for different retinal dystrophies.

An interpreted atlas of biosynthetic gene clusters from 1,000 fungal genomes

Fungi are prolific producers of natural products, compounds which have had a large societal impact as pharmaceuticals, mycotoxins, and agrochemicals. Despite the availability of over 1,000 fungal genomes and several decades of compound discovery efforts from fungi, the biosynthetic gene clusters (BGCs) encoded by these genomes and the associated chemical space have yet to be analyzed systematically. Here, we provide detailed annotation and analyses of fungal biosynthetic and chemical space to enable genome mining and discovery of fungal natural products. Using 1,037 genomes from species across the fungal kingdom (e.g., Ascomycota, Basidiomycota, and non-Dikarya taxa), 36,399 predicted BGCs were organized into a network of 12,067 gene cluster families (GCFs). Anchoring these GCFs with reference BGCs enabled automated annotation of 2,026 BGCs with predicted metabolite scaffolds. We performed parallel analyses of the chemical repertoire of fungi, organizing 15,213 fungal compounds into 2,945 molecular families (MFs). The taxonomic landscape of fungal GCFs is largely species specific, though select families such as the equisetin GCF are present across vast phylogenetic distances with parallel diversifications in the GCF and MF. We compare these fungal datasets with a set of 5,453 bacterial genomes and their BGCs and 9,382 bacterial compounds, revealing dramatic differences between bacterial and fungal biosynthetic logic and chemical space. These genomics and cheminformatics analyses reveal the large extent to which fungal and bacterial sources represent distinct compound reservoirs. With a >10-fold increase in the number of interpreted strains and annotated BGCs, this work better regularizes the biosynthetic potential of fungi for rational compound discovery.

Synthesis, Antiprotozoal Activity, and Cheminformatic Analysis of 2-Phenyl-2H-Indazole Derivatives.

Indazole is an important scaffold in medicinal chemistry. At present, the progress on synthetic methodologies has allowed the preparation of several new indazole derivatives with interesting pharmacological properties. Particularly, the antiprotozoal activity of indazole derivatives have been recently reported. Herein, a series of 22 indazole derivatives was synthesized and studied as antiprotozoals. The 2-phenyl-2H-indazole scaffold was accessed by a one-pot procedure, which includes a combination of ultrasound synthesis under neat conditions as well as Cadogan’s cyclization. Moreover, some compounds were derivatized to have an appropriate set to provide structure-activity relationships (SAR) information. Whereas the antiprotozoal activity of six of these compounds against E. histolytica, G. intestinalis, and T. vaginalis had been previously reported, the activity of the additional 16 compounds was evaluated against these same protozoa. The biological assays revealed structural features that favor the antiprotozoal activity against the three protozoans tested, e.g., electron withdrawing groups at the 2-phenyl ring. It is important to mention that the indazole derivatives possess strong antiprotozoal activity and are also characterized by a continuous SAR.

New derivatives of sulfonylhydrazone as potential antitumor agents: Design, synthesis and cheminformatics evaluation.

Phosphoinositide 3-kinase α (PI3Kα) is a propitious target for designing anticancer drugs. A series of new N'-(diphenylmethylene)benzenesulfonohydrazide was synthesized and characterized using FT-IR, NMR (1H and 13C), HRMS, and elemental analysis. Target compounds exhibited an antiproliferative effect against the human colon carcinoma (HCT-116) cell line. Our cheminformatics analysis indicated that the para-tailored derivatives [p-NO2 (3) and p-CF3 (7)] have better ionization potentials based on calculated Moran autocorrelations and ionization potentials. Subsequent in vitro cell proliferation assays validated our cheminformatics results by providing experimental evidence that both derivatives 3 and 7 exhibited improved antiproliferative activities against HCT-116. Hence, our results emphasized the importance of electron-withdrawing groups and hydrogen bond-acceptors in the rational design of small-molecule chemical ligands targeting PI3Kα. These results agreed with the induced-fit docking against PI3Kα, highlighting the role of p-substituted aromatic rings in guiding the ligand-PI3Kα complex formation, by targeting a hydrophobic pocket in the ligand-binding site and forming π-stacking interactions with a nearby tryptophan residue.

Natural product fragment combination to performance-diverse pseudo-natural products

Natural product structure and fragment-based compound development inspire pseudo-natural product design through different combinations of a given natural product fragment set to compound classes expected to be chemically and biologically diverse. We describe the synthetic combination of the fragment-sized natural products quinine, quinidine, sinomenine, and griseofulvin with chromanone or indole-containing fragments to provide a 244-member pseudo-natural product collection. Cheminformatic analyses reveal that the resulting eight pseudo-natural product classes are chemically diverse and share both drug- and natural product-like properties. Unbiased biological evaluation by cell painting demonstrates that bioactivity of pseudo-natural products, guiding natural products, and fragments differ and that combination of different fragments dominates establishment of unique bioactivity. Identification of phenotypic fragment dominance enables design of compound classes with correctly predicted bioactivity. The results demonstrate that fusion of natural product fragments in different combinations and arrangements can provide chemically and biologically diverse pseudo-natural product classes for wider exploration of biologically relevant chemical space.

Pseudo Natural Products-Chemical Evolution of Natural Product Structure.

Pseudo‐natural products (PNPs) combine natural product (NP) fragments in novel arrangements not accessible by current biosynthesis pathways. As such they can be regarded as non‐biogenic fusions of NP‐derived fragments. They inherit key biological characteristics of the guiding natural product, such as chemical and physiological properties, yet define small molecule chemotypes with unprecedented or unexpected bioactivity. We iterate the design principles underpinning PNP scaffolds and highlight their syntheses and biological investigations. We provide a cheminformatic analysis of PNP collections assessing their molecular properties and shape diversity. We propose and discuss how the iterative analysis of NP structure, design, synthesis, and biological evaluation of PNPs can be regarded as a human‐driven branch of the evolution of natural products, that is, a chemical evolution of natural product structure.

Exploring the regulatory mechanism of Nao Tai Fang on vascular Dementia's biological network based on cheminformatics and transcriptomics strategy

Ethnopharmacological relevanceNao Tai Fang (NTF) is modified from Buyang Huanwu Decoction. Modern pharmacological research showed that NTF has a good anti-cerebral ischemic effect and can improve the learning and memory ability of cerebrovascular disease. AimThe purpose of this study is to explore the regulation mechanism of NTF on the regulation mechanism of vascular dementia (VD)'s biological network based on chemoinformatics and transcriptomics strategies. MethodFirst, the bilateral common carotid artery ligation method was used to create a rat VD model. After NTF intervention for 30 days, the treatment effect was evaluated by HE staining and water maze experiment. Then, the Agilent mRNA expression profiling chip was used to obtain mRNA expression data of hippocampal tissues of VD model rats before and after NTF intervention, and microarray analysis was used to screen for genes with significant differential expression. The BATMAN database was utilized to obtain the potential targets of NTF and the Genecards and OMIM were utilized to collect the VD potential genes. The cytoscape was utilized to construct and analyze the networks. ResultThe animal experiments showed that NTF can improve VD. A total of 180 up-regulated proteins and 289 down-regulated proteins were identified. The top 20 up- and down-regulated differentially expressed genes were utilized to construct differentially expressed gene's protein-protein interaction (PPI) network. A total of 677 NTF potential targets and 550 VD genes were obtained and were utilized to construct NTF-VD PPI network. The cheminformatics analysis showed that NTF can regulate a lot of biological processes and signaling pathways (such as inflammation modules, vasodilation and contraction modules, hypoxia modules, angiogenesis, coagulation, neurovascular unit modules, Neuroactive ligand-receptor interaction, Calcium signaling pathway, Serotonergic synapse). ConclusionNTF may play a role in the treatment of VD through the targets, signaling pathways and biological processes discovered in this study.