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Drug Discovery of Compounds by Structural Design

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

Deadline for manuscript submissions: 30 August 2024 | Viewed by 3541

Special Issue Editor

Special Issue Information

Dear Colleagues,

Structural information on macromolecules is of great importance for understanding the underlying mechanisms of various types of diseases.

The computational design of drugs against these diseases is based on the knowledge of the active center or allosteric sites of enzymes to find chemical compounds that can bind in a stable way to the amino acids present in them, thus inhibiting or modulating their activity.

The inhibitors discovered will undoubtedly have a social and positive impact in the fight against various diseases. Even those inhibitors that are designed, and for various reasons cannot be optimized as drugs in patients, can be used as new research tools to study cellular function.

This special issue welcomes papers that use 3D screening strategies and computational design of new drugs and therapies, useful in the understanding and treatment of diseases, whether of tumor type, genetic origin, or related to viral or bacterial infections.

Dr. Paulino Gómez-Puertas
Guest Editor

Manuscript Submission Information

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Keywords

  • drug discovery
  • virtual screening
  • molecular dynamics
  • computational biology
  • drug repurposing

Published Papers (3 papers)

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Research

26 pages, 9017 KiB  
Article
In Vitro and In Silico Studies on Cytotoxic Properties of Oxythiamine and 2′-Methylthiamine
by Marta Malinowska, Magdalena Czerniecka, Izabella Jastrzebska, Artur Ratkiewicz, Adam Tylicki and Natalia Wawrusiewicz-Kurylonek
Int. J. Mol. Sci. 2024, 25(8), 4359; https://doi.org/10.3390/ijms25084359 - 15 Apr 2024
Viewed by 294
Abstract
It is important to search for cytostatic compounds in order to fight cancer. One of them could be 2′-methylthiamine, which is a thiamine antimetabolite with an additional methyl group at the C-2 carbon of thiazole. So far, the cytostatic potential of 2′-methylthiamine has [...] Read more.
It is important to search for cytostatic compounds in order to fight cancer. One of them could be 2′-methylthiamine, which is a thiamine antimetabolite with an additional methyl group at the C-2 carbon of thiazole. So far, the cytostatic potential of 2′-methylthiamine has not been studied. We have come forward with a simplified method of synthesis using commercially available substrates and presented a comparison of its effects, as boosted by oxythiamine, on normal skin fibroblasts and HeLa cancer cells, having adopted in vitro culture techniques. Oxythiamine has been found to inhibit the growth and metabolism of cancer cells significantly better than 2′-methylthiamine (GI50 36 and 107 µM, respectively), while 2′-methylthiamine is more selective for cancer cells than oxythiamine (SI = 180 and 153, respectively). Docking analyses have revealed that 2′-methylthiamine (ΔG −8.2 kcal/mol) demonstrates a better affinity with thiamine pyrophosphokinase than thiamine (ΔG −7.5 kcal/mol ) and oxythiamine (ΔG −7.0 kcal/mol), which includes 2′-methylthiamine as a potential cytostatic. Our results suggest that the limited effect of 2′-methylthiamine on HeLa arises from the related arduous transport as compared to oxythiamine. Given that 2′-methylthiamine may possibly inhibit thiamine pyrophosphokinase, it could once again be considered a potential cytostatic. Thus, research should be carried out in order to find the best way to improve the transport of 2′-methylthiamine into cells, which may trigger its cytostatic properties. Full article
(This article belongs to the Special Issue Drug Discovery of Compounds by Structural Design)
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16 pages, 26655 KiB  
Article
VSpipe-GUI, an Interactive Graphical User Interface for Virtual Screening and Hit Selection
by Rashid Hussain, Andrew Scott Hackett, Sandra Álvarez-Carretero and Lydia Tabernero
Int. J. Mol. Sci. 2024, 25(4), 2002; https://doi.org/10.3390/ijms25042002 - 07 Feb 2024
Viewed by 617
Abstract
Virtual screening of large chemical libraries is essential to support computer-aided drug development, providing a rapid and low-cost approach for further experimental validation. However, existing computational packages are often for specialised users or platform limited. Previously, we developed VSpipe, an open-source semi-automated pipeline [...] Read more.
Virtual screening of large chemical libraries is essential to support computer-aided drug development, providing a rapid and low-cost approach for further experimental validation. However, existing computational packages are often for specialised users or platform limited. Previously, we developed VSpipe, an open-source semi-automated pipeline for structure-based virtual screening. We have now improved and expanded the initial command-line version into an interactive graphical user interface: VSpipe-GUI, a cross-platform open-source Python toolkit functional in various operating systems (e.g., Linux distributions, Windows, and Mac OS X). The new implementation is more user-friendly and accessible, and considerably faster than the previous version when AutoDock Vina is used for docking. Importantly, we have introduced a new compound selection module (i.e., spatial filtering) that allows filtering of docked compounds based on specified features at the target binding site. We have tested the new VSpipe-GUI on the Hepatitis C Virus NS3 (HCV NS3) protease as the target protein. The pocket-based and interaction-based modes of the spatial filtering module showed efficient and specific selection of ligands from the virtual screening that interact with the HCV NS3 catalytic serine 139. Full article
(This article belongs to the Special Issue Drug Discovery of Compounds by Structural Design)
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20 pages, 5533 KiB  
Article
Identification of Catechins’ Binding Sites in Monomeric Aβ42 through Ensemble Docking and MD Simulations
by Rohoullah Firouzi, Shahin Sowlati-Hashjin, Cecilia Chávez-García, Mitra Ashouri, Mohammad Hossein Karimi-Jafari and Mikko Karttunen
Int. J. Mol. Sci. 2023, 24(9), 8161; https://doi.org/10.3390/ijms24098161 - 03 May 2023
Cited by 1 | Viewed by 2085
Abstract
The assembly of the amyloid-β peptide (Aβ) into toxic oligomers and fibrils is associated with Alzheimer’s disease and dementia. Therefore, disrupting amyloid assembly by direct targeting of the Aβ monomeric form with small molecules or antibodies is a promising [...] Read more.
The assembly of the amyloid-β peptide (Aβ) into toxic oligomers and fibrils is associated with Alzheimer’s disease and dementia. Therefore, disrupting amyloid assembly by direct targeting of the Aβ monomeric form with small molecules or antibodies is a promising therapeutic strategy. However, given the dynamic nature of Aβ, standard computational tools cannot be easily applied for high-throughput structure-based virtual screening in drug discovery projects. In the current study, we propose a computational pipeline—in the framework of the ensemble docking strategy—to identify catechins’ binding sites in monomeric Aβ42. It is shown that both hydrophobic aromatic interactions and hydrogen bonding are crucial for the binding of catechins to Aβ42. Additionally, it has been found that all the studied ligands, especially EGCG, can act as potent inhibitors against amyloid aggregation by blocking the central hydrophobic region of Aβ. Our findings are evaluated and confirmed with multi-microsecond MD simulations. Finally, it is suggested that our proposed pipeline, with low computational cost in comparison with MD simulations, is a suitable approach for the virtual screening of ligand libraries against Aβ. Full article
(This article belongs to the Special Issue Drug Discovery of Compounds by Structural Design)
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