Integrating computational methods guided the discovery of phytochemicals as potential Pin1 inhibitors for cancer: pharmacophore modeling, molecular docking, MM-GBSA calculations and molecular dynamics studies

Pin1 is a pivotal player in interactions with a diverse array of phosphorylated proteins closely linked to critical processes such as carcinogenesis and tumor suppression. Its axial role in cancer initiation and progression, coupled with its overexpression and activation in various cancers render it a potential candidate for the development of targeted therapeutics. While several known Pin1 inhibitors possess favorable enzymatic profiles, their cellular efficacy often falls short. Consequently, the pursuit of novel Pin1 inhibitors has gained considerable attention in the field of medicinal chemistry. In this study, we employed the Phase tool from Schrödinger to construct a structure-based pharmacophore model. Subsequently, 449,008 natural products (NPs) from the SN3 database underwent screening to identify compounds sharing pharmacophoric features with the native ligand. This resulted in 650 compounds, which then underwent molecular docking and binding free energy calculations. Among them, SN0021307, SN0449787 and SN0079231 showed better docking scores with values of −9.891, −7.579 and −7.097 kcal/mol, respectively than the reference compound (−6.064 kcal/mol). Also, SN0021307, SN0449787 and SN0079231 exhibited lower free binding energies (−57.12, −49.81 and −46.05 kcal/mol, respectively) than the reference ligand (−37.75 kcal/mol). Based on these studies, SN0021307, SN0449787, and SN0079231 showed better binding affinity that the reference compound. Further the validation of these findings, molecular dynamics simulations confirmed the stability of the ligand-receptor complex for 100 ns with RMSD ranging from 0.6 to 1.8 Å. Based on these promising results, these three phytochemicals emerge as promising lead compounds warranting comprehensive biological screening in future investigations. These compounds hold great potential for further exploration regarding their efficacy and safety as Pin1 inhibitors, which could usher in new avenues for combating cancer

HEPATOPROTECTIVE ACTIVITY OF COSTUS SPECIOSUS (KOEN. EX. RETZ.) AGAINST PARACETAMOL-INDUCED LIVER INJURY IN MICE

Background: Liver diseases are a common cause of mortality and morbidity over the world. It is caused mainly by toxic chemicals and chemotherapeutic agents. Costus speciosus (Koen ex. Retz.) (Zingiberaceae) is widely employed in various traditional medicines for the prevention and treatment of different aliments. The purpose of this study is to assess the protective effect of C. speciosus rhizomes MeOH extract against the injury of the liver induced by paracetamol (PA) in mice. Material and Methods: The mice were pretreated for seven days with distilled H2O, silymarin 12 mg/kg or 100 and 200 mg/kg MeOH extract. Then, PA (750 mg/kg) was also intra-peritoneal administrated once a day. Animals were euthanatized 24 h after the damage inducement. The levels of the serum enzymes aspartate aminotransferase (AST), alkaline phosphatase (ALP), alanine aminotransferase (ALT), and aspartate aminotransferase, in addition to the tumor necrosis factor-alpha (TNF-α), were determined. Moreover, the histopathological examination was carried out. Results: Administration of the MeOH extract (200 mg/kg) showed improvement in the toxic effects of PA through significant fall on the serum markers enzymes of liver damage: AST, ALT, and ALP, as well as TNF-α, compared to silymarin. In parallel, the histopathological profile in the mice` liver also proved that extract markedly minimized the PA toxicity and maintained the liver tissues` histoarchitecture to near the normal ones more than that achieved by silymarin. Conclusion: The findings suggested that C. speciosus extract acts as a potential hepatoprotective agent against PA-induced liver toxicity. This hepato-protection effect may be due to the existence of steroids, saponins, different glycosides, and phenolic compounds in C. speciosus

Unlocking the potential of approved drugs for the allosteric inhibition of tropomyosin-receptor kinase A using molecular docking and molecular dynamics studies

Tropomyosin-receptor kinase A (TrkA) is the primary isoform among the tropomyosin-receptor kinases that have been associated with human cancer development, contributing to approximately 7.4% of all cancer cases. TrkA represents an attractive target for cancer treatment; however, currently available TrkA inhibitors face limitations in terms of resistance development and potential toxicity. Hence, the objective of this study was to identify new allosteric-approved inhibitors of TrkA that can overcome these challenges and be employed in cancer therapy. To achieve this goal, a screening of 9,923 drugs from the ChEMBL database was conducted to assess their repurposing potential using molecular docking. The top 49 drug candidates, exhibiting the highest docking scores (−11.569 to −7.962 kcal/mol), underwent MM-GBSA calculations to evaluate their binding energies. Delanzomib and tibalosin, the top two drugs with docking scores of −10.643 and −10.184 kcal/mol, respectively, along with MM-GBSA dG bind values of −67.96 and −50.54 kcal/mol, were subjected to 200 ns molecular dynamic simulations, confirming their stable interactions with TrkA. Based on these findings, we recommend further experimental evaluation of delanzomib and tibalosin to determine their potential as allosteric inhibitors of TrkA. These drugs have the potential to provide more effective and less toxic therapeutic alternatives. The approach employed in this study, which involves repurposing drugs through molecular docking and molecular dynamics, serves as a valuable tool for identifying novel drug candidates with distinct therapeutic uses. This methodology can contribute to reducing the attrition rate and expediting the process of drug discovery

Fungal Depsides—Naturally Inspiring Molecules: Biosynthesis, Structural Characterization, and Biological Activities

Fungi represent a huge reservoir of structurally diverse bio-metabolites. Although there has been a marked increase in the number of isolated fungal metabolites over the past years, many hidden metabolites still need to be discovered. Depsides are a group of polyketides consisting of two or more ester-linked hydroxybenzoic acid moieties. They possess valuable bioactive properties, such as anticancer, antidiabetic, antibacterial, antiviral, anti-inflammatory, antifungal, antifouling, and antioxidant qualities, as well as various human enzyme-inhibitory activities. This review provides an overview of the reported data on fungal depsides, including their sources, biosynthesis, physical and spectral data, and bioactivities in the period from 1975 to 2020. Overall, 110 metabolites and more than 122 references are confirmed. This is the first review of these multi-faceted metabolites from fungi

Thiophenes—Naturally Occurring Plant Metabolites: Biological Activities and In Silico Evaluation of Their Potential as Cathepsin D Inhibitors

Naturally, thiophenes represent a small family of natural metabolites featured by one to five thiophene rings. Numerous plant species belonging to the family Asteraceae commonly produce thiophenes. These metabolites possessed remarkable bioactivities, including antimicrobial, antiviral, anti-inflammatory, larvicidal, antioxidant, insecticidal, cytotoxic, and nematicidal properties. The current review provides an update over the past seven years for the reported natural thiophene derivatives, including their sources, biosynthesis, spectral data, and bioactivities since the last review published in 2015. Additionally, with the help of the SuperPred webserver, an AI (artificial intelligence) tool, the potential drug target for the compounds was predicted. In silico studies were conducted for Cathepsin D with thiophene derivatives, including ADMET (drug absorption/distribution/metabolism/excretion/and toxicity) properties prediction, molecular docking for the binding interaction, and molecular dynamics to evaluate the ligand–target interaction stability under simulated physiological conditions

Bright Side of Fusarium oxysporum: Secondary Metabolites Bioactivities and Industrial Relevance in Biotechnology and Nanotechnology

Fungi have been assured to be one of the wealthiest pools of bio-metabolites with remarkable potential for discovering new drugs. The pathogenic fungi, Fusarium oxysporum affects many valuable trees and crops all over the world, producing wilt. This fungus is a source of different enzymes that have variable industrial and biotechnological applications. Additionally, it is widely employed for the synthesis of different types of metal nanoparticles with various biotechnological, pharmaceutical, industrial, and medicinal applications. Moreover, it possesses a mysterious capacity to produce a wide array of metabolites with a broad spectrum of bioactivities such as alkaloids, jasmonates, anthranilates, cyclic peptides, cyclic depsipeptides, xanthones, quinones, and terpenoids. Therefore, this review will cover the previously reported data on F. oxysporum, especially its metabolites and their bioactivities, as well as industrial relevance in biotechnology and nanotechnology in the period from 1967 to 2021. In this work, 180 metabolites have been listed and 203 references have been cited

Garcixanthone E and Garcimangophenone C: New Metabolites from <i>Garcinia mangostana</i> and Their Cytotoxic and Alpha Amylase Inhibitory Potential

Garcinia mangostana (Clusiaceae) is a rich pool of metabolites with diversified bioactivities. A new xanthone, garcixanthone E (1), and a new benzophenone, rhamnoside, as well as garcimangophenone C (9) together with garcinone E (2), α-mangostin (3), γ-mangostin (4), garcinone C (5), garcixanthone C (6), gartanin (7), and 2,4,6,3′,5′-pentahydroxybenzophenone (8) were purified from G. mangostana EtOAc extract. Their structural verification was accomplished utilizing assorted spectral tools and relating to the literature. The in vitro cytotoxic potential versus MCF-7, A549, and HCT-116 cell lines demonstrated the moderate potential of 1 (IC50s 8.5, 5.4, and 5.7 µM, respectively) in comparison to doxorubicin (IC50s 0.18, 0.6 and 0.2 µM, respectively) using a sulforhodamine B (SRB) assay. Additionally, 1 and 9 had AAI (α-amylase inhibition) with IC50s 17.8 and 12.9 µM, respectively, compared to acarbose (IC50 6.7 µM). Further, their AAI mechanisms were inspected utilizing molecular-docking evaluation by employing the crystal structure of the human α-amylase (PDB-ID: 5EOF). Compound 9 possessed a reasonable docking score of −7.746 kcal/mol compared with the native ligand 7JR which had a docking score of −9.932 kcal/mol. These results could further provide new insight into the potential usage of G. mangostana as a functional food for regulating postprandial hyperglycemia via suppressing AA

Lansium domesticum&mdash;A Fruit with Multi-Benefits: Traditional Uses, Phytochemicals, Nutritional Value, and Bioactivities

Lansium domesticum (Langsat, Meliaceae) is a tropical fruit mainly found in Southeast Asian countries, particularly in Thailand, Malaysia, Indonesia, and the Philippines. Traditionally, it is utilized as a folk treatment for eye inflammation, ulcers, diarrhea, dysentery, fever, spasms, flatulence, worms, insect bites, scorpion stings, and malaria. Additionally, it is utilized as a mosquito repellent, skin moisturizer and whitening agent. Pharmacological research showed that the plant has a wide array of bioactivities, including antimalarial, antifeedant, anti-aging, wound healing, antioxidant, cytotoxic, analgesic, antibacterial, antimutagenic, insecticidal, and larvicidal. The most commonly described activities were attributed to the presence of terpenoids and phenolics. Further, some studies reported the preparation of nanoparticles and pharmaceutical formulations from the plant. This review highlights the potential of L. domesticum as herbal medicine. It provides an overview about the reported data on L. domesticum from 1931 to November 2021, including nutritional value, traditional uses, phytoconstituents, and bioactivities, as well as nanoparticles and pharmaceutical formulations

Thiotagetin A, a new cytotoxic thiophene from <i>Tagetes minuta</i>

<p>Phytochemical investigation of the <i>n</i>-hexane fraction of the methanolic extract of <i>Tagetes minuta</i> L. (Asteraceae) aerial parts afforded a new thiophene derivative: thiotagetin A (<b>3</b>), together with β-sitosterol (<b>1</b>) and stigmasterol (<b>2</b>). The structure of the new thiophene was identified by UV, IR, 1D (¹H and ¹³C), 2D (¹H–¹H COSY, HSQC and HMBC) NMR and HRESIMS spectral data. Compound <b>3</b> displayed cytotoxic activity against KB and MCF7 cancer cell lines with ED₅₀ values of 2.03 and 3.88 μg/mL, respectively, compared to adriamycin (0.26 and 0.07 μg/mL, respectively).</p