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Synthesis and Theoretical Study of Bioactive Molecules

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

Deadline for manuscript submissions: closed (30 November 2024) | Viewed by 10700

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Guest Editor
Office of Research, The University of Western Australia, Perth, WA 6009, Australia
Interests: medicinal chemistry; pharmaceutical chemistry; physical chemistry; computational chemistry; anticancer drugs
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Special Issue Information

Dear Colleagues,

Not all synthesized compounds exhibit biological activity. Therefore, biological evaluation of synthesized compounds is required, which is unfortunately expensive and time-consuming. To avoid such problems, theoretical studies exploring molecular mechanics, docking, and molecular dynamics can provide info on the physicochemical properties of a compound and its binding interaction with the expected target receptor. Therefore, this Special Issue focuses on the synthesis of bioactive molecules and theoretically studying their binding with target receptor by using different computational tools.

Dr. Muhammad Khattab
Guest Editor

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Keywords

  • synthesis
  • computational study
  • molecular dynamics
  • docking
  • biomolecules
  • molecular mechanics
  • drug discovery
  • drug development

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Published Papers (6 papers)

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Research

16 pages, 1795 KiB  
Article
In Silico Screening of 1,3,4-Thiadiazole Derivatives as Inhibitors of Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2)
by Steven M. Ewell, Hannah Burton and Bereket Mochona
Curr. Issues Mol. Biol. 2024, 46(10), 11220-11235; https://doi.org/10.3390/cimb46100666 - 6 Oct 2024
Cited by 1 | Viewed by 1890
Abstract
Angiogenesis plays a pivotal role in the growth, survival, and metastasis of solid tumors, with Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) being overexpressed in many human solid tumors, making it an appealing target for anti-cancer therapies. This study aimed to identify potential lead [...] Read more.
Angiogenesis plays a pivotal role in the growth, survival, and metastasis of solid tumors, with Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) being overexpressed in many human solid tumors, making it an appealing target for anti-cancer therapies. This study aimed to identify potential lead compounds with azole moiety exhibiting VEGFR-2 inhibitory effects. A ligand-based pharmacophore model was constructed using the X-ray crystallographic structure of VEGFR-2 complexed with tivozanib (PDB ID: 4ASE) to screen the ZINC15 database. Following virtual screening, six compounds demonstrated promising docking scores and drug-likeness comparable to tivozanib. These hits underwent detailed pharmacokinetic analysis to assess their absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. Furthermore, Density Functional Theory (DFT) analysis was employed to investigate the molecular orbital properties of the top hits from molecular docking. Molecular dynamics (MD) simulations were conducted to evaluate the conformational stability of the complexes over a 100 ns run. Results indicated that the compounds (ZINC8914312, ZINC8739578, ZINC8927502, and ZINC17138581) exhibited the most promising lead requirements for inhibiting VEGFR-2 and suppressing angiogenesis in cancer therapy. This integrated approach, combining pharmacophore modeling, molecular docking, ADMET studies, DFT analysis, and MD simulations, provides valuable insights into the identification of potential anti-cancer agents targeting VEGFR-2. Full article
(This article belongs to the Special Issue Synthesis and Theoretical Study of Bioactive Molecules)
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16 pages, 3923 KiB  
Article
Marine Bioactive Molecules as Inhibitors of the Janus Kinases: A Comparative Molecular Docking and Molecular Dynamics Simulation Approach
by Emad A. Ahmed and Salah A. Abdelsalam
Curr. Issues Mol. Biol. 2024, 46(9), 10635-10650; https://doi.org/10.3390/cimb46090631 - 23 Sep 2024
Cited by 2 | Viewed by 1524
Abstract
A treasure trove of naturally occurring biomolecules can be obtained from sea living organisms to be used as potential antioxidant and anti-inflammatory agents. These bioactive molecules can target signaling molecules involved in the severity of chronic autoimmune diseases such as rheumatoid arthritis (RA). [...] Read more.
A treasure trove of naturally occurring biomolecules can be obtained from sea living organisms to be used as potential antioxidant and anti-inflammatory agents. These bioactive molecules can target signaling molecules involved in the severity of chronic autoimmune diseases such as rheumatoid arthritis (RA). The intracellular tyrosine kinases family, Janus kinases (JAKs, includes JAK1, JAK2, and JAK3), is implicated in the pathogenesis of RA through regulating several cytokines and inflammatory processes. In the present study, we conducted molecular docking and structural analysis investigations to explore the role of a set of bioactive molecules from marine sources that can be used as JAKs’ specific inhibitors. Around 200 antioxidants and anti-inflammatory molecules out of thousands of marine molecules found at the Comprehensive Marine Natural Products Database (CMNPD) website, were used in that analysis. The details of the interacting residues were compared to the recent FDA approved inhibitors tofacitinib and baricitinib for data validation. The shortlisted critical amino acids residues of our pharmacophore-based virtual screening were LYS905, GLU957, LEU959, and ASP1003 at JAK1, GLU930 and LEU932 at JAK2, and GLU905 and CYS909 of JAK3. Interestingly, marine biomolecules such as Sargachromanol G, Isopseudopterosin E, Seco-Pseudopterosin, and CID 10071610 showed specific binding and significantly higher binding energy to JAK1 active/potential sites when being compared with the approved inhibitors. In addition, Zoanthoxanthin and Fuscoside E bind to JAK2′s critical residues, GLU930 and LEU932. Moreover, Phorbaketal and Fuscoside E appear to be potential candidates that can inhibit JAK3 activity. These results were validated using molecular dynamics simulation for the docked complexes, JAK1(6sm8)/SG, JAK2 (3jy9)/ZAX, and JAK3 (6pjc)/Fuscoside E, where stable and lower binding energy were found based on analyzing set of parameters, discussed below (videos are attached). A promising role of these marine bioactive molecules can be confirmed in prospective preclinical/clinical investigations using rheumatoid arthritis models. Full article
(This article belongs to the Special Issue Synthesis and Theoretical Study of Bioactive Molecules)
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20 pages, 5801 KiB  
Article
Evaluation of Potential Furin Protease Inhibitory Properties of Pioglitazone, Rosiglitazone, and Pirfenidone: An In Silico Docking and Molecular Dynamics Simulation Approach
by Ahtziri Socorro Carranza-Aranda, Carlos Daniel Diaz-Palomera, Eduardo Lepe-Reynoso, Anne Santerre, José Francisco Muñoz-Valle and Oliver Viera-Segura
Curr. Issues Mol. Biol. 2024, 46(8), 8665-8684; https://doi.org/10.3390/cimb46080511 - 8 Aug 2024
Cited by 1 | Viewed by 1319
Abstract
Furin (Fur) is a member of the protease convertase family; its expression is crucial for cleaving and maturing many proteins. Fur also represents a therapeutic target in cancer, autoimmune diseases, and viral infections. Pioglitazone (PGZ) and rosiglitazone (RGZ) are thiazolidinediones prescribed to type [...] Read more.
Furin (Fur) is a member of the protease convertase family; its expression is crucial for cleaving and maturing many proteins. Fur also represents a therapeutic target in cancer, autoimmune diseases, and viral infections. Pioglitazone (PGZ) and rosiglitazone (RGZ) are thiazolidinediones prescribed to type 2 diabetes patients and are structurally similar to the known Fur inhibitors naphthofluorescein (NPF) and pirfenidone (PFD). Thus, this study used molecular docking and molecular dynamics to assess and compare the affinities and the molecular interactions of these four ligands with the Fur active site (FurAct) and the recently described Fur allosteric site (FurAll). The 7QXZ Fur structure was used for molecular dockings, and for the best pose complexes, molecular dynamics were run for 100 ns. The best affinities of the ligand/FurAct and ligand/FurAll complexes were with NPF, PGZ, and RGZ, while PFD presented the lowest affinity. Asp154 was the central residue involved in FurAct complex formation, while Glu488 and Asn310 were the central residues involved in FurAll complex formation. This study shows the potential of RGZ, PGZ, and PFD as Fur competitive (FurAct) and non-competitive (FurAll) inhibitors. Therefore, they are candidates for repurposing in response to future emerging diseases through the modulation of Fur activity. Full article
(This article belongs to the Special Issue Synthesis and Theoretical Study of Bioactive Molecules)
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13 pages, 5074 KiB  
Article
Docking, MD Simulations, and DFT Calculations: Assessing W254’s Function and Sartan Binding in Furin
by Nikitas Georgiou, Thomas Mavromoustakos and Demeter Tzeli
Curr. Issues Mol. Biol. 2024, 46(8), 8226-8238; https://doi.org/10.3390/cimb46080486 - 30 Jul 2024
Cited by 1 | Viewed by 1269
Abstract
Furins are serine endoproteases that are involved in many biological processes, where they play important roles in normal metabolism, in the activation of various pathogens, while they are a target for therapeutic intervention. Dichlorophenyl-pyridine “BOS” compounds are well known drugs that are used [...] Read more.
Furins are serine endoproteases that are involved in many biological processes, where they play important roles in normal metabolism, in the activation of various pathogens, while they are a target for therapeutic intervention. Dichlorophenyl-pyridine “BOS” compounds are well known drugs that are used as inhibitors of human furin by an induced-fit mechanism, in which tryptophan W254 in the furin catalytic cleft acts as a molecular transition energy gate. The binding of “BOS” drug into the active center of furin has been computationally studied using the density functional theory (DFT) and ONIOM multiscaling methodologies. The binding enthalpies of the W254 with the furin-BOS is −32.8 kcal/mol (“open”) and −18.8 kcal/mol (“closed”), while the calculated torsion barrier was found at 30 kcal/mol. It is significantly smaller than the value of previous MD calculations due to the relaxation of the environment, i.e., nearby groups of the W254, leading to the reduction of the energy demands. The significant lower barrier explains the experimental finding that the dihedral barrier of W254 is overcome. Furthermore, sartans were studied to evaluate their potential as furin inhibitors. Sartans are AT1 antagonists, and they effectively inhibit the hypertensive effects induced by the peptide hormone Angiotensin II. Here, they have been docked into the cavity to evaluate their effect on the BOS ligand via docking and molecular dynamics simulations. A consistent binding of sartans within the cavity during the simulation was found, suggesting that they could act as furin inhibitors. Finally, sartans interact with the same amino acids as W254, leading to a competitive binding that may influence the pharmacological efficacy and potential drug interactions of sartans. Full article
(This article belongs to the Special Issue Synthesis and Theoretical Study of Bioactive Molecules)
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15 pages, 2230 KiB  
Article
Antioxidant and Neuroprotective Effects of Fucoxanthin and Its Metabolite Fucoxanthinol: A Comparative In Vitro Study
by Letizia Pruccoli, Martina Balducci, Barbara Pagliarani and Andrea Tarozzi
Curr. Issues Mol. Biol. 2024, 46(6), 5984-5998; https://doi.org/10.3390/cimb46060357 - 14 Jun 2024
Cited by 6 | Viewed by 2136
Abstract
Fucoxanthin is the most abundant carotenoid found in marine brown algae that exhibits several healthy properties. Dietary fucoxanthin is metabolized in the intestine, plasma, and other tissues to various metabolites, including fucoxanthinol. In this regard, the contribution of fucoxanthinol to the healthy properties [...] Read more.
Fucoxanthin is the most abundant carotenoid found in marine brown algae that exhibits several healthy properties. Dietary fucoxanthin is metabolized in the intestine, plasma, and other tissues to various metabolites, including fucoxanthinol. In this regard, the contribution of fucoxanthinol to the healthy properties of its precursor, fucoxanthin, against pathogenetic events associated with neurodegenerative diseases remains unexplored. Here, we evaluated and compared the antioxidant and neuroprotective effects of the carotenoids fucoxanthin and fucoxanthinol in in vitro models of Alzheimer’s (AD) and Parkinson’s (PD) disease. Neuronal SH-SY5Y cells were used to evaluate the antioxidant properties of the carotenoids against ABTS radical in the membrane and cytoplasm and oxidative stress elicited by tert-butyl hydroperoxide using the 2′,7′-dichlorodihydrofluorescein diacetate probe. We also assessed the ability of the carotenoids to increase the glutathione (GSH) and activate the Nrf2/Keap1/ARE pathway using the monochlorobimane probe and western blotting method, respectively. The neuroprotective effects of the carotenoids against the neurotoxicity generated by oligomers of Beta-Amyloid (1–42) peptide (OAβ) and 6-hydroxydopamine (6-OHDA), which are neurotoxins of AD and PD, respectively, were finally evaluated in the same neuronal cells using the thiazolyl blue tetrazolium bromide assay. Both carotenoids could reach the cytoplasm, which explains the mainly free radical scavenging activity at this level. Notably, fucoxanthinol had higher and lower antioxidant activity than fucoxanthin at extracellular and cellular levels. Although studied carotenoids exerted the ability to activate the Nrf2/Keap1/ARE pathway, leading to an increase of intracellular GSH, our results suggested that the antioxidant activity of the carotenoids could be mainly attributed to their radical scavenging activity in neuronal membrane and cytoplasm, where they accumulate. Fucoxanthinol also shared similar neuroprotective effects as fucoxanthin against the neurotoxicity generated by OAβ and 6-OHDA, suggesting a potential neuroprotective contribution to the action of fucoxanthin administered as a food supplement in in vivo experimental models. These results encourage further research to evaluate the bioavailability of fucoxanthinol and other metabolites of fucoxanthin at the brain level to elucidate the dietary neuroprotective potential of fucoxanthin. Full article
(This article belongs to the Special Issue Synthesis and Theoretical Study of Bioactive Molecules)
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14 pages, 3221 KiB  
Article
Succinimide Derivatives as Acetylcholinesterase Inhibitors—In Silico and In Vitro Studies
by Błażej Grodner, Dariusz Maciej Pisklak and Łukasz Szeleszczuk
Curr. Issues Mol. Biol. 2024, 46(6), 5117-5130; https://doi.org/10.3390/cimb46060307 - 22 May 2024
Viewed by 1492
Abstract
We studied the effect of succinimide derivatives on acetylcholinesterase activity due to the interest in compounds that influence this enzyme’s activity, which could help treat memory issues more effectively. The following parameters were established for this purpose based on kinetic investigations of the [...] Read more.
We studied the effect of succinimide derivatives on acetylcholinesterase activity due to the interest in compounds that influence this enzyme’s activity, which could help treat memory issues more effectively. The following parameters were established for this purpose based on kinetic investigations of the enzyme in the presence of succinimide derivatives: the half-maximal inhibitory concentration, the maximum rate, the inhibition constant, and the Michaelis–Menten constant. Furthermore, computational analyses were performed to determine the energy required for succinimide derivatives to dock with the enzyme’s active site. The outcomes acquired in this manner demonstrated that all compounds inhibited acetylcholinesterase in a competitive manner. The values of the docking energy parameters corroborated the kinetic parameter values, which indicated discernible, albeit slight, variations in the inhibitory intensity among the various derivatives. Full article
(This article belongs to the Special Issue Synthesis and Theoretical Study of Bioactive Molecules)
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