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Computational Molecular Biology of Metabolic Pathways and Signal Transduction Pathways
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Computational Molecular Biology of Metabolic Pathways and Signal Transduction Pathways

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: 20 August 2025 | Viewed by 10722

Special Issue Editor

Dr. Ralf Herwig

E-Mail Website
Guest Editor
Laboratories PD Dr. R. Herwig, 80337 Munich, Germany
Interests: sonography; ELISA; Transmission Electron Microscopy (TEM); flow cytometry; urologic oncology; prostate cancer; cancer immunology; cellular and molecular immunology; antineoplastic agents; rt-PCR

Special Issue Information

Dear Colleagues,

The regulation of metabolic pathways and the associated signal transduction has received immense therapeutic importance due to their key role in major neural disorders and tumor regulations and onco-metabolism. Furthermore, the metabolic pathways and signal transduction are entirely regulated through interactions of small bio-ligands, signaling molecules, neurotransmitters with receptors, proteins, and membrane bilayer proteins. The complete understanding of these interactions, their binding mode, and their associated biological function are dependent on how good we establish or understand the structure–activity relationship that actually helps in comprehension of these biological functions. Computational structural and molecular biology has emerged as an interdisciplinary discipline in combination with theoretical and computational chemistry and biophysics to explore the biological functions at molecular and atomistic levels. Since I have been working in the quoted areas with my colleague Dr. Khair Bux, thus, it would be a great pleasure to work as the Guest editor for this Special Issue of IJMS. I am very hopeful that my contribution will be quality-oriented and will help IJMS to report quality research in this discipline in the future.

Prof. Dr. Ralf Herwig
Guest Editor

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Keywords

  • computational genomics
  • computational structural and molecular biology
  • molecular dynamics simulations
  • artificial intelligence
  • AI-driven drug design and development
  • molecular modeling
  • computer-aided drug design
  • computational proteomics
  • computational and theoretical chemistry

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Published Papers (6 papers)

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Research

27 pages, 11242 KiB  
Article
Bioinformatics Analysis of the Anti-Inflammatory Mechanism and Potential Therapeutic Efficacy of Kezimuke granules in Treating Urinary Tract Infections by Inhibiting NLRP3 Inflammasome Activation
by Alhar Baishan, Alifeiye Aikebaier, Dilihuma Dilimulati, Nuerbiye Nueraihemaiti, Yipaerguli Paerhati, Sendaer Hailati, Nulibiya Maihemuti and Wenting Zhou
Int. J. Mol. Sci. 2025, 26(4), 1764; https://doi.org/10.3390/ijms26041764 - 19 Feb 2025
Viewed by 747
Abstract
Kezimuke granules (KZMK), derived from traditional Kazakh folk medicine, exhibit a variety of pharmacological properties. Long-term clinical studies have demonstrated their efficacy in clearing heat, detoxifying, promoting qi circulation, and alleviating gonorrhea. However, their specific pharmacological effects on urinary tract infections remain unclear. [...] Read more.
Kezimuke granules (KZMK), derived from traditional Kazakh folk medicine, exhibit a variety of pharmacological properties. Long-term clinical studies have demonstrated their efficacy in clearing heat, detoxifying, promoting qi circulation, and alleviating gonorrhea. However, their specific pharmacological effects on urinary tract infections remain unclear. This study employed UHPLC-MS/MS technology to identify the blood components of KZMK and integrated network pharmacology with bioinformatics analysis for molecular docking validation. The anti-inflammatory activity of KZMK was further evaluated using a rat model of LPS-induced cystitis. A total of 17 components in KZMK were identified as capable of entering the bloodstream. Predictive analysis revealed that its primary targets include Caspase-1, NLRP3, STAT1, TLR4, and TNF, with the NLRP3 inflammasome signaling pathway emerging as the key mechanism. In vivo studies showed that KZMK effectively reduced the white blood cell (WBC) count and bladder index in urine sediments of rats with cystitis. Additionally, KZMK alleviated bladder congestion, edema, and histopathological changes in the animals. Treatment with KZMK led to decreased levels of IL-18 and IL-1β cytokines. KZMK significantly inhibited the expression of NLRP3, GSDMD, and Caspase-1 in LPS-induced cystitis, further confirming its anti-inflammatory effects. These findings indicate that KZMK provides protection against LPS-induced cystitis, primarily by inhibiting the activation of the NLRP3 inflammasome. Collectively, the results suggest that KZMK holds promise as a potential therapeutic option for urinary tract infections. Full article
(This article belongs to the Special Issue Computational Molecular Biology of Metabolic Pathways and Signal Transduction Pathways)
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19 pages, 5699 KiB  
Article
Molecular Docking Studies and In Vitro Activity of Pancreatic Lipase Inhibitors from Yak Milk Cheese
by Peng Wang, Xuemei Song and Qi Liang
Int. J. Mol. Sci. 2025, 26(2), 756; https://doi.org/10.3390/ijms26020756 - 17 Jan 2025
Cited by 1 | Viewed by 872
Abstract
Pancreatic lipase serves as a primary trigger for hyperlipidemia and is also a crucial target in the inhibition of hypercholesterolemia. By synthesizing anti-hypercholesterolemic drugs such as atorvastatin, which are used to treat hypercholesterolemia, there were some side effects associated with the long-term use [...] Read more.
Pancreatic lipase serves as a primary trigger for hyperlipidemia and is also a crucial target in the inhibition of hypercholesterolemia. By synthesizing anti-hypercholesterolemic drugs such as atorvastatin, which are used to treat hypercholesterolemia, there were some side effects associated with the long-term use of statins. Based on this idea, in the present study, we identified peptides that inhibited PL by virtual screening and in vitro activity assays. In addition, to delve into the underlying mechanisms, we undertook a dual investigative approach involving both molecular docking analyses and molecular dynamics simulations. The results showed that peptides RK7, KQ7, and TL9, all with molecular weights of <1000 Da and a high proportion of hydrophobic amino acids, inhibited PL well. Molecular docking and molecular dynamics showed that peptides RK7, KQ7, and TL9 bound to important amino acid residues of PL, such as Pro and Leu, through hydrogen bonding, hydrophobic interactions, salt bridges, and π-π stacking to occupy the substrate-binding site, which inhibited PL and identified them as potential PL inhibitors. In vitro tests showed that the IC50 of RK7 and KQ7 on PL were 0.690 mg/mL and 0.593 mg/mL, respectively, and the inhibitory effects of RK7 and KQ7 on PL were significantly enhanced after simulated gastrointestinal digestion. Our results suggested that peptides RK7 and KQ7 from yak milk cheese can be identified as a novel class of potential PL inhibitors. Full article
(This article belongs to the Special Issue Computational Molecular Biology of Metabolic Pathways and Signal Transduction Pathways)
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12 pages, 3096 KiB  
Article
Enhancement of Stress Granule Formation by a Chiral Compound Targeting G3BP1 via eIF2α Phosphorylation
by Yoon Ho Park, Hyun Suh Cho, Sungjin Moon, Sim Namkoong and Hyun Suk Jung
Int. J. Mol. Sci. 2024, 25(19), 10571; https://doi.org/10.3390/ijms251910571 - 30 Sep 2024
Viewed by 1381
Abstract
The chirality of a chemical differentiates it from its mirror-image counterpart. This unique property has significant implications in chemistry, biology, and drug discovery, where chiral chemicals display high selectivity and activity in achieving target specificity and reducing attrition rates in drug development. Stress [...] Read more.
The chirality of a chemical differentiates it from its mirror-image counterpart. This unique property has significant implications in chemistry, biology, and drug discovery, where chiral chemicals display high selectivity and activity in achieving target specificity and reducing attrition rates in drug development. Stress granules (SGs) are dynamic assemblies of proteins and RNA that form in the cytoplasm of cells under stress conditions. Modulating their formation or disassembly could offer a novel approach to treating a wide range of diseases. This has led to significant interest in SGs as potential therapeutic targets. This study examined the NTF2-like domain of G3BP1 as a possible target for SG modulation. Molecular docking was used to simulate the interactions of compounds with the domain, and a potential candidate with a chiral structure was identified. The experiments showed that the compound induced the formation of SG-like granules. Importantly, the ability of this compound to modulate SG offers valuable insights into a new mechanism underlying the dynamics and promoting the assembly of SGs, and this new mechanism, in turn, holds potential for the development of drugs with diverse mechanisms of action and potentially synergistic effects. Full article
(This article belongs to the Special Issue Computational Molecular Biology of Metabolic Pathways and Signal Transduction Pathways)
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14 pages, 3587 KiB  
Article
The Discovery of Novel α2a Adrenergic Receptor Agonists Only Coupling to Gαi/O Proteins by Virtual Screening
by Peilan Zhou, Fengfeng Lu, Huili Zhu, Beibei Shi, Xiaoxuan Wang, Shiyang Sun, Yulei Li and Ruibin Su
Int. J. Mol. Sci. 2024, 25(13), 7233; https://doi.org/10.3390/ijms25137233 - 30 Jun 2024
Viewed by 1739
Abstract
Most α2-AR agonists derived from dexmedetomidine have few structural differences between them and have no selectivity for α2A/2B-AR or Gi/Gs, which can lead to side effects in drugs. To obtain novel and potent α2A-AR agonists, we performed [...] Read more.
Most α2-AR agonists derived from dexmedetomidine have few structural differences between them and have no selectivity for α2A/2B-AR or Gi/Gs, which can lead to side effects in drugs. To obtain novel and potent α2A-AR agonists, we performed virtual screening for human α2A-AR and α2B-AR to find α2A-AR agonists with higher selectivity. Compound P300–2342 and its three analogs significantly decreased the locomotor activity of mice (p < 0.05). Furthermore, P300–2342 and its three analogs inhibited the binding of [3H] Rauwolscine with IC50 values of 7.72 ± 0.76 and 12.23 ± 0.11 μM, respectively, to α2A-AR and α2B-AR. In α2A-AR-HEK293 cells, P300–2342 decreased forskolin-stimulated cAMP production without increasing cAMP production, which indicated that P300–2342 activated α2A-AR with coupling to the Gαi/o pathway but without Gαs coupling. P300–2342 exhibited no agonist but slight antagonist activities in α2B-AR. Similar results were obtained for the analogs of P300–2342. The docking results showed that P300–2342 formed π-hydrogen bonds with Y394, V114 in α2A-AR, and V93 in α2B-AR. Three analogs of P300–2342 formed several π-hydrogen bonds with V114, Y196, F390 in α2A-AR, and V93 in α2B-AR. We believe that these molecules can serve as leads for the further optimization of α2A-AR agonists with potentially few side effects. Full article
(This article belongs to the Special Issue Computational Molecular Biology of Metabolic Pathways and Signal Transduction Pathways)
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21 pages, 1734 KiB  
Article
Reprogramming of Energy Metabolism in Human PKD1 Polycystic Kidney Disease: A Systems Biology Analysis
by Xuewen Song, Lauren Pickel, Hoon-Ki Sung, James Scholey and York Pei
Int. J. Mol. Sci. 2024, 25(13), 7173; https://doi.org/10.3390/ijms25137173 - 29 Jun 2024
Cited by 2 | Viewed by 3018
Abstract
Multiple alterations of cellular metabolism have been documented in experimental studies of autosomal dominant polycystic kidney disease (ADPKD) and are thought to contribute to its pathogenesis. To elucidate the molecular pathways and transcriptional regulators associated with the metabolic changes of renal cysts in [...] Read more.
Multiple alterations of cellular metabolism have been documented in experimental studies of autosomal dominant polycystic kidney disease (ADPKD) and are thought to contribute to its pathogenesis. To elucidate the molecular pathways and transcriptional regulators associated with the metabolic changes of renal cysts in ADPKD, we compared global gene expression data from human PKD1 renal cysts, minimally cystic tissues (MCT) from the same patients, and healthy human kidney cortical tissue samples. We found gene expression profiles of PKD1 renal cysts were consistent with the Warburg effect with gene pathway changes favoring increased cellular glucose uptake and lactate production, instead of pyruvate oxidation. Additionally, mitochondrial energy metabolism was globally depressed, associated with downregulation of gene pathways related to fatty acid oxidation (FAO), branched-chain amino acid (BCAA) degradation, the Krebs cycle, and oxidative phosphorylation (OXPHOS) in renal cysts. Activation of mTORC1 and its two target proto-oncogenes, HIF-1α and MYC, was predicted to drive the expression of multiple genes involved in the observed metabolic reprogramming (e.g., GLUT3, HK1/HK2, ALDOA, ENO2, PKM, LDHA/LDHB, MCT4, PDHA1, PDK1/3, MPC1/2, CPT2, BCAT1, NAMPT); indeed, their predicted expression patterns were confirmed by our data. Conversely, we found AMPK inhibition was predicted in renal cysts. AMPK inhibition was associated with decreased expression of PGC-1α, a transcriptional coactivator for transcription factors PPARα, ERRα, and ERRγ, all of which play a critical role in regulating oxidative metabolism and mitochondrial biogenesis. These data provide a comprehensive map of metabolic pathway reprogramming in ADPKD and highlight nodes of regulation that may serve as targets for therapeutic intervention. Full article
(This article belongs to the Special Issue Computational Molecular Biology of Metabolic Pathways and Signal Transduction Pathways)
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17 pages, 7214 KiB  
Article
Enhanced Sampling Molecular Dynamics Simulations Reveal Transport Mechanism of Glycoconjugate Drugs through GLUT1
by Zhuo Liu, Xueting Cao, Zhenyu Ma, Limei Xu, Lushan Wang, Jian Li, Min Xiao and Xukai Jiang
Int. J. Mol. Sci. 2024, 25(10), 5486; https://doi.org/10.3390/ijms25105486 - 17 May 2024
Cited by 2 | Viewed by 1931
Abstract
Glucose transporters GLUT1 belong to the major facilitator superfamily and are essential to human glucose uptake. The overexpression of GLUT1 in tumor cells designates it as a pivotal target for glycoconjugate anticancer drugs. However, the interaction mechanism of glycoconjugate drugs with GLUT1 remains [...] Read more.
Glucose transporters GLUT1 belong to the major facilitator superfamily and are essential to human glucose uptake. The overexpression of GLUT1 in tumor cells designates it as a pivotal target for glycoconjugate anticancer drugs. However, the interaction mechanism of glycoconjugate drugs with GLUT1 remains largely unknown. Here, we employed all-atom molecular dynamics simulations, coupled to steered and umbrella sampling techniques, to examine the thermodynamics governing the transport of glucose and two glycoconjugate drugs (i.e., 6-D-glucose-conjugated methane sulfonate and 6-D-glucose chlorambucil) by GLUT1. We characterized the specific interactions between GLUT1 and substrates at different transport stages, including substrate recognition, transport, and releasing, and identified the key residues involved in these procedures. Importantly, our results described, for the first time, the free energy profiles of GLUT1-transporting glycoconjugate drugs, and demonstrated that H160 and W388 served as important gates to regulate their transport via GLUT1. These findings provide novel atomic-scale insights for understanding the transport mechanism of GLUT1, facilitating the discovery and rational design of GLUT1-targeted anticancer drugs. Full article
(This article belongs to the Special Issue Computational Molecular Biology of Metabolic Pathways and Signal Transduction Pathways)
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