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Drugs: Mechanisms of Action, Molecular Targets and Biological Activities, 2nd Edition

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A special issue of Current Issues in Molecular Biology (ISSN 1467-3045). This special issue belongs to the section "Molecular Pharmacology".

Deadline for manuscript submissions: 31 May 2025 | Viewed by 10541

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Dr. Pratibha Kumari

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System College of Pharmacy, Department of Pharmaceutical Sciences, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
Interests: computation biology; computational chemistry; molecular modeling; protein-drug interaction; free energy estimation; drug design; molecular docking and virtual screening; enhance sampling methods; bio-compatible solvents; steered or targeted MD; CRISPR-Cas systems
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Special Issue Information

Dear Colleagues,

This Special Issue is dedicated to addressing research pertaining to the biological activity, mechanisms of action, and molecular targets of both well-known and novel drugs. Ongoing development in biotechnological cell-based assays and computational investigations have enabled the discovery of biologically active small molecules with great speed. Currently, gene expression profiling and comprehensive gene knockout are being used for target identification. However, drug targets are poorly understood, both for launched and for potential therapeutic agents in discovery and development. Many natural products are identified as bioactive molecules, though their targets and underlying mechanisms of action are still unknown. Target identifications and mechanisms of action can be delineated using experimental and computational interfaces. In many instances, a blend of different methods may need to be applied to thoroughly characterize the molecular actions, target and allosteric response and biological activity of drugs. Recently, drug repurposing methods have used drug–target interaction data extensively. The aim of this Special Issue is to publish high-quality articles, including original research, reviews, short communications and clinical trial studies, to shed light on all the current and past developments that focus on mechanisms of action, biological activity and molecular targets of a drug or a group of drugs at the molecular level.

We look forward to receiving valuable contributions from researchers and academicians all around the world.

Dr. Pratibha Kumari
Guest Editor

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Keywords

molecular target
drug repurposing
gene expression
biological activity
phenotype
genotype
allostery

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Published Papers (8 papers)

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Research

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28 pages, 5671 KiB

Open AccessArticle

Computational Modelling of Tunicamycin C Interaction with Potential Protein Targets: Perspectives from Inverse Docking with Molecular Dynamic Simulation

by Vivash Naidoo, Ikechukwu Achilonu, Sheefa Mirza, Rodney Hull, Jeyalakshmi Kandhavelu, Marushka Soobben and Clement Penny

Curr. Issues Mol. Biol. 2025, 47(5), 339; https://doi.org/10.3390/cimb47050339 - 8 May 2025

Viewed by 285

Abstract

Protein glycosylation plays a crucial role in cancer biology, influencing essential cellular processes such as cell signalling, immune recognition, and tumour metastasis. Therefore, this study highlights the therapeutic potential of targeting glycosylation in cancer treatment, as modulating these modifications could disrupt the fundamental mechanisms driving cancer progression and improve therapeutic outcomes. Recently, Tunicamycin C, a well-known glycosylation inhibitor, has shown promise in breast cancer treatment but remains unexplored in colorectal cancer (CRC). Thus, in this study, we aimed to understand the potential action of Tunicamycin C in CRC using in silico studies to identify possible drug targets for Tunicamycin C. First, we identified two target proteins using the HTDocking algorithm followed by GO and KEGG pathway searches: thymidine kinase 1 (TK1) and cAMP-dependent protein kinase catalytic subunit alpha (PKAc). Following this, molecular dynamics modelling revealed that Tunicamycin C binding induced a conformational perturbation in the 3D structures of TK1 and PKAc, inhibiting their activities. This interaction led to a stable design, promoting optimal binding of Tunicamycin C in the hydrophobic pockets of TK1 and PKAc. Serial validation studies highlighted the role of active site residues in binding stabilisation. Tunicamycin C exhibited high binding affinity with TK1 and PKAc. This study provides a way to explore and repurpose novel inhibitors of TK1 and PKAc and identify new therapeutic targets, which may block glycosylation in cancer treatment. Full article

(This article belongs to the Special Issue Drugs: Mechanisms of Action, Molecular Targets and Biological Activities, 2nd Edition)

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22 pages, 6932 KiB

Open AccessArticle

Antiviral Activity of Rhamnolipids Nano-Micelles Against Rhinoviruses—In Silico Docking, Molecular Dynamic Analysis and In-Vitro Studies

by Lila Touabi, Nasser S. M. Ismail, Marwa R. Bakkar, Gary R. McLean and Yasmin Abo-zeid

Curr. Issues Mol. Biol. 2025, 47(5), 333; https://doi.org/10.3390/cimb47050333 - 6 May 2025

Viewed by 636

Abstract

Hospital-acquired infections (HAIs) previously focused mainly on multidrug-resistant (MDR) bacteria, with less attention on viruses. The COVID-19 pandemic highlighted the importance of controlling viral infections. Human rhinoviruses (HRVs) are among the viruses responsible for HAIs. HRVs are non-enveloped viruses that infect the upper airways after airborne or direct transmission. Due to their lack of a membrane envelope, HRVs exhibit moderate resistance to commonly applied alcoholic disinfectants. Therefore, there is a significant need to develop alternative disinfection and hand sanitation strategies to control HRV infections in healthcare settings without posing a risk to human health. The antimicrobial activity and safety of rhamnolipids and rhamnolipids nano-micelles (RMN) against MDR-bacteria and several viruses, including SARS-CoV-2, were confirmed recently. Also, we previously demonstrated the superior antimicrobial activity of RMN over rhamnolipids. In the current study, molecular docking demonstrated the weak interactions of rhamnolipids with HRV-1A (minor group) compared to HRV-14 (major group), suggesting a superior antiviral activity of rhamnolipids towards major group rhinoviruses. To biologically validate these data, RMN was prepared and characterized, and then antiviral activity against HRV-16 (major group) and HRV-1B (minor group) infection of HeLa cells was assessed. RMN showed a complete inhibition of HRV-16 infection with recovery of 100% of HeLa cell viability. In contrast, only partial inhibition of HRV-1B infection with approximately 50% protection against infection was observed. Therefore, RMN might be recommended as a disinfectant and/or a hand sanitizer component to control the spread of RVs in hospital care settings or elsewhere to reduce the incidence of respiratory infections. Full article

(This article belongs to the Special Issue Drugs: Mechanisms of Action, Molecular Targets and Biological Activities, 2nd Edition)

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20 pages, 2975 KiB

Open AccessArticle

Molecular Docking and Pharmacological In Silico Evaluation of Camptothecin and Related Ligands as Promising HER2-Targeted Therapies for Breast Cancer

by Elmer Joel Millan-Casarrubias, Yunia Verónica García-Tejeda, Claudia Haydée González-De la Rosa, Lucero Ruiz-Mazón, Yazmín Mariela Hernández-Rodríguez and Oscar Eduardo Cigarroa-Mayorga

Curr. Issues Mol. Biol. 2025, 47(3), 193; https://doi.org/10.3390/cimb47030193 - 15 Mar 2025

Viewed by 1009

Abstract

Breast cancer is one of the leading causes of cancer-related mortality in women worldwide, highlighting the importance of effective therapies. This study evaluates the interaction between camptothecin, a potent anticancer agent, and two key receptors implicated in breast cancer progression: HER2 (human epidermal growth factor receptor 2) and EGFR (epidermal growth factor receptor), using molecular docking. The results reveal a stronger binding affinity between camptothecin and HER2 than EGFR, in contrast to neratinib, which demonstrated affinity exclusively for HER2. Camptothecin exhibits significant hydrophobic and pi-alkyl interactions with HER2, whereas its interactions with EGFR are primarily mediated by hydrogen bonds. Molecular dynamics (MD) simulations of the camptothecin-HER2 complex indicate stable binding, with minimal fluctuations observed over 100 nanoseconds, confirming the stability of the ligand–receptor interaction. Pharmacokinetic evaluations, based on Lipinski’s rule of five, demonstrate that camptothecin adheres to essential drug-likeness parameters, suggesting favorable bioavailability. Furthermore, the analysis comparing the pharmacological properties of camptothecin with other well-known anticancer compounds, such as neratinib, shows that camptothecin exhibited superior compliance with drug-likeness rules. Despite its low solubility, the binding stability and pharmacokinetic profile suggest its potential as an effective therapeutic agent for breast cancer, particularly when combined with drug delivery systems that enhance solubility. This work underscores the importance of receptor-specific ligand interactions in drug design and highlights the need for further studies into camptothecin’s clinical applications, especially in HER2-positive breast cancer treatment. Full article

(This article belongs to the Special Issue Drugs: Mechanisms of Action, Molecular Targets and Biological Activities, 2nd Edition)

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16 pages, 3191 KiB

Open AccessArticle

Triterpenoids from Chios Mastiha Resin Against MASLD—A Molecular Docking Survey

by Nataša Milošević, Maja Milanović, Milica Medić Stojanoska, Varomyalin Tipmanee, Ilias Smyrnioudis, George V. Dedoussis and Nataša Milić

Curr. Issues Mol. Biol. 2025, 47(1), 51; https://doi.org/10.3390/cimb47010051 - 15 Jan 2025

Cited by 2 | Viewed by 1000

Abstract

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease without an approved pharmacological approach for its prevention/treatment. Based on the modified Delphi process, NAFLD was redefined as metabolic dysfunction-associated steatotic liver disease (MASLD) to highlight the metabolic aspect of liver pathogenesis. Chios mastiha (Pistacia lentiscus var. Chia, Anacardiaceae) resin demonstrated promising results in MASLD treatment. In this paper, molecular docking was applied to test 16 compounds from Chios mastiha as potential ligands for the receptors GR, LXRα, LXRβ, PPARα PPARγ, MC4R, AMPK, and VEGFR2, whose up- and down-regulation interfere with MASLD development and progression. The observed compounds had moderate and high affinity for LXR, GR, MC4R, and PPARγ in comparison to proven ligands, while their affinity for PPARα, AMPK, and VEGFR was less pronounced. The combination of active compounds from Chios mastiha rather than a single molecule may have a superior ability to control the intertwined MASLD metabolic pathways. Full article

(This article belongs to the Special Issue Drugs: Mechanisms of Action, Molecular Targets and Biological Activities, 2nd Edition)

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12 pages, 2055 KiB

Open AccessArticle

Phospho-Chitooligosaccharides below 1 kDa Inhibit HIV-1 Entry In Vitro

by Fatih Karadeniz and Se-Kwon Kim

Curr. Issues Mol. Biol. 2024, 46(4), 3729-3740; https://doi.org/10.3390/cimb46040232 - 22 Apr 2024

Viewed by 1510

Abstract

Despite present antiviral agents that can effectively work against HIV-1 replication, side effects and drug resistance have pushed researchers toward novel approaches. In this context, there is a continued focus on discovering new and more effective antiviral compounds, particularly those that have a natural origin. Polysaccharides are known for their numerous bioactivities, including inhibiting HIV-1 infection and replication. In the present study, phosphorylated chitosan oligosaccharides (PCOSs) were evaluated for their anti-HIV-1 potential in vitro. Treatment with PCOSs effectively protected cells from HIV-1-induced lytic effects and suppressed the production of HIV-1 p24 protein. In addition, results show that PCOSs lost their protective effect upon post-infection treatment. According to the results of ELISA, PCOSs notably disrupted the binding of HIV-1 gp120 protein to T cell surface receptor CD4, which is required for HIV-1 entry. Overall, the results point out that PCOSs might prevent HIV-1 infection at the entry stage, possibly via blocking the viral entry through disruption of virus–cell fusion. Nevertheless, the current results only present the potential of PCOSs, and further studies to elucidate its action mechanism in detail are needed to employ phosphorylation of COSs as a method to develop novel antiviral agents. Full article

(This article belongs to the Special Issue Drugs: Mechanisms of Action, Molecular Targets and Biological Activities, 2nd Edition)

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17 pages, 1483 KiB

Open AccessArticle

In Vitro Hepatotoxicity of Routinely Used Opioids and Sedative Drugs

by Katharina Haller, Sandra Doß and Martin Sauer

Curr. Issues Mol. Biol. 2024, 46(4), 3022-3038; https://doi.org/10.3390/cimb46040189 - 30 Mar 2024

Cited by 3 | Viewed by 2261

Abstract

A hepatocyte cell line was used to determine the hepatotoxicity of sedatives and opioids, as the hepatotoxicity of these drugs has not yet been well characterized. This might pose a threat, especially to critically ill patients, as they often receive high cumulative doses for daily analgosedation and often already have impaired liver function due to an underlying disease or complications during treatment. A well-established biosensor based on HepG2/C3A cells was used for the determination of the hepatotoxicity of commonly used sedatives and opioids in the intensive care setting (midazolam, propofol, s-ketamin, thiopental, fentanyl, remifentanil, and sufentanil). The incubation time was 2 × 3 days with clinically relevant (Cmax) and higher concentrations (C5× and C10×) of each drug in cell culture medium or human plasma. Afterward, we measured the cell count, vitality, lactate dehydrogenase (LDH), mitochondrial dehydrogenase activity, cytochrome P 450 1A2 (CYP1A2), and albumin synthesis. All tested substances reduced the viability of hepatocyte cells, but sufentanil and remifentanil showed more pronounced effects. The cell count was diminished by sufentanil in both the medium and plasma and by remifentanil only in plasma. Sufentanil and remifentanil also led to higher values of LDH in the cell culture supernatant. A reduction of mitochondrial dehydrogenase activity was seen with the use of midazolam and s-ketamine. Microalbumin synthesis was reduced in plasma after its incubation with higher concentrations of sufentanil and remifentanil. Remifentanil and s-ketamine reduced CYP1A2 activity, while propofol and thiopental increased it. Our findings suggest that none of the tested sedatives and opioids have pronounced hepatotoxicity. Sufentanil, remifentanil, and s-ketamine showed moderate hepatotoxic effects in vitro. These drugs should be given with caution to patients vulnerable to hepatotoxic drugs, e.g., patients with pre-existing liver disease or liver impairment as part of their underlying disease (e.g., hypoxic hepatitis or cholestatic liver dysfunction in sepsis). Further studies are indicated for this topic, which may use more complex cell culture models and global pharmacovigilance reports, addressing the limitation of the used cell model: HepG2/C3A cells have a lower metabolic capacity due to their low levels of CYP enzymes compared to primary hepatocytes. However, while the test model is suitable for parental substances, it is not for toxicity testing of metabolites. Full article

(This article belongs to the Special Issue Drugs: Mechanisms of Action, Molecular Targets and Biological Activities, 2nd Edition)

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17 pages, 4164 KiB

Open AccessArticle

Investigating Carvedilol’s Repurposing for the Treatment of Non-Small Cell Lung Cancer via Aldehyde Dehydrogenase Activity Modulation in the Presence of β-Adrenergic Agonists

by Balqis A. Ikhmais, Alaa M. Hammad, Osama H. Abusara, Lama Hamadneh, Hamza Abumansour, Qasem M. Abdallah, Ali I. M. Ibrahim, Lina Elsalem, Mariam Awad and Rahaf Alshehada

Curr. Issues Mol. Biol. 2023, 45(10), 7996-8012; https://doi.org/10.3390/cimb45100505 - 29 Sep 2023

Cited by 4 | Viewed by 1771

Abstract

Repurposing existing drugs appears to be a potential solution for addressing the challenges in the treatment of non-small cell lung cancer (NSCLC). β-adrenoceptor antagonist drugs (β-blockers) have tumor-inhibiting effects, making them promising candidates for potential NSCLC treatment. This study investigates the anticancer potential of a subset of β-blockers in NSCLC cell lines; A549 and H1299. Additionally, it investigates the underlying mechanism behind β-blockers’ anticancer effect by influencing a potential novel target named aldehyde dehydrogenase (ALDH). The MTT assay assessed β-blockers’ cytotoxicity on both cell lines, while Western blot and NADH fluorescence assays evaluated their influence on ALDH protein expression and activity. Carvedilol (CAR) was the most effective blocker in reducing cell survival of A549 and H1299 with IC₅₀ of 18 µM and 13.7 µM, respectively. Significantly, CAR led to a 50% reduction in ALDH expression and 80% decrease in ALDH activity in A549 cells, especially when combined with β-agonists, in comparison to the control. This effect might be attributed to β-agonist blockade or an alternative pathway. This novel finding adds to our understanding of CAR’s multifaceted anticancer properties, implying that combining CAR with β-agonists could be a useful strategy for lung cancer treatment. Full article

(This article belongs to the Special Issue Drugs: Mechanisms of Action, Molecular Targets and Biological Activities, 2nd Edition)

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Review

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29 pages, 3950 KiB

Open AccessReview

Multi-Pathway Study for Oxaliplatin Resistance Reduction

by Tong Ye, Chen Wu, Jintong Na, Xiyu Liu and Yong Huang

Curr. Issues Mol. Biol. 2025, 47(3), 172; https://doi.org/10.3390/cimb47030172 - 4 Mar 2025

Viewed by 994

Abstract

Chemotherapy for cancer frequently uses platinum-based medications, including oxaliplatin, carboplatin, and cisplatin; however, due to their high systemic toxicity, lack of selectivity, drug resistance, and other side effects, platinum-based medications have very limited clinical application. As a first-line medication in antitumor therapy, oxaliplatin must be administered to minimize side effects while achieving anticancer objectives. A new CDC7 inhibitor called XL413 has demonstrated promising antitumor therapeutic effects in a variety of malignant tumors and may have anticancer properties. This offers a fresh viewpoint on how to lessen oxaliplatin resistance and, specifically, increase the potency of already prescribed anticancer therapies. In this paper, the current developments in anticancer therapy are discussed, along with the many mechanisms of oxaliplatin’s antitumor effects, clinical treatment challenges, and related approaches. We conducted more research on oxaliplatin resistance that arose during chemotherapy and searched for ways to lessen it in order to enhance its chemotherapeutic performance. Ultimately, we studied how distinct resistance routes relate to one another. Meanwhile, XL413, a novel CDC7 inhibitor, offers a perspective on the possibilities for developing treatment approaches for this innovation point. The search terms “Oxaliplatin, XL413, drug resistance, cancer treatment,” etc., were applied in the X-MOL and PubMed databases for this review’s literature search. Boolean logic was then employed to maximize the search approach. These databases can offer thorough research data and cover a broad range of biological publications. Excluded publications were works of low relevance, duplicates, or those with insufficient information. The mechanism of oxaliplatin’s anticancer effect, oxaliplatin resistance and its amelioration, and the role of XL413 in oxaliplatin treatment were the main topics of the 140 publications that were ultimately included for analysis. Full article

(This article belongs to the Special Issue Drugs: Mechanisms of Action, Molecular Targets and Biological Activities, 2nd Edition)

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