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Metabolites
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Design of Novel Target-Oriented Chemotherapeutic Anti-cancer Agents with ADME Pharmacokinetics
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Design of Novel Target-Oriented Chemotherapeutic Anti-cancer Agents with ADME Pharmacokinetics

A special issue of Metabolites (ISSN 2218-1989). This special issue belongs to the section "Pharmacology and Drug Metabolism".

Deadline for manuscript submissions: closed (31 July 2023) | Viewed by 14745

Special Issue Editors

Dr. Mohamed S. Nafie

E-Mail Website
Guest Editor
Department of Chemistry, Faculty of Science, Suez Canal University, Ismailia 41522, Egypt
Interests: biochemistry; molecular; anti-cancer; natural products
Dr. Ahmed A. Al-karmalawy

E-Mail Website
Guest Editor
Pharmaceutical Chemistry Department, Faculty of Pharmacy, Ahram Canadian University, 6th of October City, Giza 12566, Egypt
Interests: medicinal chemistry; organic chemistry; computational chemistry; drug design; drug repurposing
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cancer, as uncontrolled cell proliferation, is the second-leading cause of death worldwide. The present chemotherapy protocols have significant limitations in selectivity and target efficacy. Hence, anti-cancer activity still presents a promising area of research for finding effective and selective anti-cancer agents, so designing novel chemotherapeutics with target-oriented pathways will be of added value. In the context of updated and continuous drug discovery, the term "computer-aided drug design" (CADD) refers to a wide variety of theoretical and computational methodologies that have been employed in predicting the three-dimensional molecular structures of receptors, enzymes, and nucleic acids as molecular models of drug–receptor complexes for designing novel inhibitors with altered recognition and receptor-affinity properties. CADD helps in finding rationalized synthetic compounds or semisynthetic natural compounds against apoptosis, angiogenesis, and metastasis downstream signaling pathway. Additionally, rationalized design helps in studying drug metabolism, drug–target interactions, and ADME pharmacokinetics.

Therefore, this Special Issue deals with designing novel chemotherapeutic agents (synthetic- or natural-based compounds) against both cellular and molecular pathways as selective anti-cancer agents.

Dr. Mohamed S. Nafie
Dr. Ahmed A. Al-karmalawy
Guest Editors

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Metabolites is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • natural-based compounds
  • anti-cancer
  • target-oriented mechanisms
  • novel synthetic compounds
  • ADME

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Published Papers (5 papers)

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Research

14 pages, 2929 KiB  
Article
9-Methoxyellipticine: Antibacterial Bioactive Compound Isolated from Ochrosia elliptica Labill. Roots
by Rana Elshimy, Wael Y. Khawagi, Ibrahim A. Naguib, Sarah I. Bukhari and Riham A. El-Shiekh
Metabolites 2023, 13(5), 643; https://doi.org/10.3390/metabo13050643 - 9 May 2023
Cited by 4 | Viewed by 2013
Abstract
Antibacterial resistance bears a major threat to human health worldwide, causing about 1.2 million deaths per year. It is noteworthy that carbazole derivatives have shown a potential antibacterial activity, for example, 9-methoxyellipticine, which was isolated from Ochrosia elliptica Labill. roots (Apocynaceae) in the [...] Read more.
Antibacterial resistance bears a major threat to human health worldwide, causing about 1.2 million deaths per year. It is noteworthy that carbazole derivatives have shown a potential antibacterial activity, for example, 9-methoxyellipticine, which was isolated from Ochrosia elliptica Labill. roots (Apocynaceae) in the present study. An in vitro screening of the antibacterial activity of 9-methoxyellipticine was investigated against four multidrug-resistant (MDR) Klebsiella pneumoniae and Shiga toxin-producing Escherichia coli (STEC O157) as Gram-negative bacteria, in addition to Methicillin-resistant Staphylococcus aureus (MRSA) with Bacillus cereus as Gram-positive bacteria. The compound had significant antibacterial activity against the two Gram-negative isolates and lower activity against the Gram-positive ones. The synergistic use of 9-methoxyellipticine and antibiotics was successfully effective in reducing the MDR microorganisms. Lung pneumonia and kidney infection mice models were used to investigate the compound’s efficacy in vivo for the first time. Noteworthy reductions in K. pneumoniae and STEC shedding and the colonization were observed, with a reduction in pro-inflammatory factors and immunoglobulin levels. Other related lesions such as inflammatory cell infiltration, alveolar interstitial congestion, and edema were noticed to occur, lessened to different limits. The anti-STEC and anti-K. pneumoniae activities of 9-methoxyellipticine were revealed, providing a new alternative against MDR nosocomial infections. Full article
(This article belongs to the Special Issue Design of Novel Target-Oriented Chemotherapeutic Anti-cancer Agents with ADME Pharmacokinetics)
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16 pages, 7248 KiB  
Article
Identification of Antimicrobial Metabolites from the Egyptian Soil-Derived Amycolatopsis keratiniphila Revealed by Untargeted Metabolomics and Molecular Docking
by Ahmed A. Hamed, Osama G. Mohamed, Elsayed A. Aboutabl, Fify I. Fathy, Ghada A. Fawzy, Riham A. El-Shiekh, Ahmed A. Al-Karmalawy, Areej M. Al-Taweel, Ashootosh Tripathi and Tarek R. Elsayed
Metabolites 2023, 13(5), 620; https://doi.org/10.3390/metabo13050620 - 30 Apr 2023
Cited by 4 | Viewed by 2400
Abstract
Actinomycetes are prolific producers of bioactive secondary metabolites. The prevalence of multidrug-resistant (MDR) pathogens has prompted us to search for potential natural antimicrobial agents. Herein, we report the isolation of rare actinobacteria from Egyptian soil. The strain was identified as Amycolatopsis keratiniphila DPA04 using [...] Read more.
Actinomycetes are prolific producers of bioactive secondary metabolites. The prevalence of multidrug-resistant (MDR) pathogens has prompted us to search for potential natural antimicrobial agents. Herein, we report the isolation of rare actinobacteria from Egyptian soil. The strain was identified as Amycolatopsis keratiniphila DPA04 using 16S rRNA gene sequencing. Cultivation profiling, followed by chemical and antimicrobial evaluation of crude extracts, revealed the activity of DPA04 ISP-2 and M1 culture extracts against Gram-positive bacteria. Minimum inhibitory concentrations (MIC) values ranged from 19.5 to 39 µg/mL. Chemical analysis of the crude extracts using ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-QTOF) led to the identification of 45 metabolites of different chemical classes. In addition, ECO-0501 was identified in the cultures with significant antimicrobial activity. Multidrug resistance in Staphylococcus aureus is reported to be related to the multidrug efflux pump (MATE). ECO-0501 and its related metabolites were subjected to molecular docking studies against the MATE receptor as a proposed mechanism of action. ECO-0501 and its derivatives (AK_1 and N-demethyl ECO-0501) had better binding scores (−12.93, −12.24, and −11.92 kcal/mol) than the co-crystallized 4HY inhibitor (−8.99 kcal/mol) making them promising candidates as MATE inhibitors. Finally, our work established that natural products from this strain could be useful therapeutic tools for controlling infectious diseases. Full article
(This article belongs to the Special Issue Design of Novel Target-Oriented Chemotherapeutic Anti-cancer Agents with ADME Pharmacokinetics)
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17 pages, 6585 KiB  
Article
Design of Novel Letrozole Analogues Targeting Aromatase for Breast Cancer: Molecular Docking, Molecular Dynamics, and Theoretical Studies on Gold Nanoparticles
by Alaa Edris, Mohammed Abdelrahman, Wadah Osman, Asmaa E. Sherif, Ahmed Ashour, Elrashied A. E. Garelnabi, Sabrin R. M. Ibrahim, Rawan Bafail, Waad A. Samman, Kholoud F. Ghazawi, Gamal A. Mohamed and Abdulrahim A. Alzain
Metabolites 2023, 13(5), 583; https://doi.org/10.3390/metabo13050583 - 23 Apr 2023
Cited by 9 | Viewed by 3251
Abstract
The use of aromatase inhibitors is an established therapy for estrogen-dependent breast cancer in postmenopausal women. However, the only commercially available aromatase inhibitor, letrozole, is not highly selective; in addition to aromatase, it has an affinity for binding to desmolase, an enzyme involved [...] Read more.
The use of aromatase inhibitors is an established therapy for estrogen-dependent breast cancer in postmenopausal women. However, the only commercially available aromatase inhibitor, letrozole, is not highly selective; in addition to aromatase, it has an affinity for binding to desmolase, an enzyme involved in steroidogenesis, which explains the main side effects. Therefore, we designed new compounds based on the structure of letrozole. More than five thousand compounds were constructed based on the letrozole structure. Then, these compounds were screened for their binding ability toward the target protein, aromatase. Quantum docking, Glide docking, and ADME studies showed 14 new molecules with docking scores of ≤−7 kcal/mol, compared to the docking score of −4.109 kcal/mol of the reference, letrozole. Moreover, molecular dynamics (MD) and post-MD MM-GBSA calculations were calculated for the top three compounds, and the results supported in their interaction’s stability. Finally, the density-functional theory (DFT) study applied to the top compound to study the interaction with gold nanoparticles revealed the most stable position for the interaction with the gold nanoparticles. The results of this study confirmed that these newly designed compounds could be useful starting points for lead optimization. Further in vitro and in vivo studies are recommended for these compounds to verify these promising results experimentally. Full article
(This article belongs to the Special Issue Design of Novel Target-Oriented Chemotherapeutic Anti-cancer Agents with ADME Pharmacokinetics)
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16 pages, 4992 KiB  
Article
Integrating Metabolomics and Gene Expression Underlying Potential Biomarkers Compounds Associated with Antioxidant Activity in Southern Grape Seeds
by Ahmed G. Darwish, Md Moniruzzaman, Violeta Tsolova and Islam El-Sharkawy
Metabolites 2023, 13(2), 210; https://doi.org/10.3390/metabo13020210 - 31 Jan 2023
Cited by 7 | Viewed by 2652
Abstract
Different southern grape (Muscadine) genotypes (Muscadinia rotundifolia Michx.) were evaluated for their contents of metabolites in ripe berries. The metabolome study identified 331 metabolites in ripening skin and seed tissues. The major chemical groups were organic acids, fatty acyls, polyketides, and organic [...] Read more.
Different southern grape (Muscadine) genotypes (Muscadinia rotundifolia Michx.) were evaluated for their contents of metabolites in ripe berries. The metabolome study identified 331 metabolites in ripening skin and seed tissues. The major chemical groups were organic acids, fatty acyls, polyketides, and organic heterocycle compounds. The metabolic pathways of the identified metabolite were mainly arginine biosynthesis, D-glutamine, D-glutamate metabolism, alanine, aspartate metabolism, aminoacyl-tRNA biosynthesis, and citrate cycle. Principal component analysis indicated that catechin, gallic acid, and epicatechin-3-gallate were the main metabolites existing in muscadine seed extracts. However, citramalic and malic acids were the main metabolites contributing to muscadine skin extracts. Partial least-squares discriminant analysis (VIP > 1) described 25 key compounds indicating the metabolome in muscadine tissues (skin and seed). Correlation analysis among the 25 compounds and oxidation inhibition activities identified five biomarker compounds that were associated with antioxidant activity. Catechin, gallic acid, epicatechin-3-gallate, fertaric acid, and procyanidin B1 were highly associated with DPPH, FRAP, CUPRAC, and ABTS. The five biomarker compounds were significantly accumulated in the seed relative to the skin tissues. An evaluation of 15 antioxidant-related genes represented by the 3-dehydroquinate dehydratase (DHD), shikimate kinase (SK), chalcone synthase (CHS), anthocyanidin reductase (ANR), laccase (LAC), phenylalanine ammonia-lyase (PAL), dihydroflavonol 4-reductase (DFR), 3-dehydroquinate synthase (DHQS), chorismate mutase (CM), flavanone-3-hydroxylase (F3H), cinnamoyl-CoA reductase (CCR), cinnamyl alcohol dehydrogenase (CAD), leucoanthocyanidin reductase (LAR), gallate 1-β-glucosyltransferase (UGT), and anthocyanidin 3-O-glucosyltransferase (UFGT) encode critical enzymes related to polyphenolics pathway throughout four developmental stages (fruit-set FS, véraison V, ripe-skin R, and ripe-seed; S) in the C5 genotype demonstrated the dramatic accumulation of all transcripts in seed tissue or a developmental stage-dependent manner. Our findings suggested that muscadine grape seeds contain essential metabolites that could attract the attention of those interested in the pharmaceutical sector and the plant breeders to develop new varieties with high nutraceutical value. Full article
(This article belongs to the Special Issue Design of Novel Target-Oriented Chemotherapeutic Anti-cancer Agents with ADME Pharmacokinetics)
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15 pages, 31825 KiB  
Article
Novel Hybrid Indole-Based Caffeic Acid Amide Derivatives as Potent Free Radical Scavenging Agents: Rational Design, Synthesis, Spectroscopic Characterization, In Silico and In Vitro Investigations
by Ahmed Elkamhawy, Na Kyoung Oh, Noha A. Gouda, Magda H. Abdellattif, Saud O. Alshammari, Mohammed A. S. Abourehab, Qamar A. Alshammari, Amany Belal, Minkyoung Kim, Ahmed A. Al-Karmalawy and Kyeong Lee
Metabolites 2023, 13(2), 141; https://doi.org/10.3390/metabo13020141 - 17 Jan 2023
Cited by 10 | Viewed by 2810
Abstract
Antioxidant small molecules can prevent or delay the oxidative damage caused by free radicals. Herein, a structure-based hybridization of two natural antioxidants (caffeic acid and melatonin) afforded a novel hybrid series of indole-based amide analogues which was synthesized with potential antioxidant properties. A [...] Read more.
Antioxidant small molecules can prevent or delay the oxidative damage caused by free radicals. Herein, a structure-based hybridization of two natural antioxidants (caffeic acid and melatonin) afforded a novel hybrid series of indole-based amide analogues which was synthesized with potential antioxidant properties. A multiple-step scheme of in vitro radical scavenging assays was carried out to evaluate the antioxidant activity of the synthesized compounds. The results of the DPPH assay demonstrated that the indole-based caffeic acid amides are more active free radical scavenging agents than their benzamide analogues. Compared to Trolox, a water-soluble analogue of vitamin E, compounds 3a, 3f, 3h, 3j, and 3m were found to have excellent DPPH radical scavenging activities with IC50 values of 95.81 ± 1.01, 136.8 ± 1.04, 86.77 ± 1.03, 50.98 ± 1.05, and 67.64 ± 1.02 µM. Three compounds out of five (3f, 3j, and 3m) showed a higher capacity to neutralize the radical cation ABTS•+ more than Trolox with IC50 values of 14.48 ± 0.68, 19.49 ± 0.54, and 14.92 ± 0.30 µM, respectively. Compound 3j presented the highest antioxidant activity with a FRAP value of 4774.37 ± 137.20 μM Trolox eq/mM sample. In a similar way to the FRAP assay, the best antioxidant activity against the peroxyl radicals was demonstrated by compound 3j (10,714.21 ± 817.76 μM Trolox eq/mM sample). Taken together, compound 3j was validated as a lead hybrid molecule that could be optimized to maximize its antioxidant potency for the treatment of oxidative stress-related diseases. Full article
(This article belongs to the Special Issue Design of Novel Target-Oriented Chemotherapeutic Anti-cancer Agents with ADME Pharmacokinetics)
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