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Molecules
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Small-Molecule Inhibitors: Insights into Drug Design from Structure
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Small-Molecule Inhibitors: Insights into Drug Design from Structure

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 August 2023) | Viewed by 7378

Special Issue Editors

Dr. Huanxiang Liu

E-Mail Website
Guest Editor
School of Applied Science, Macao Polytechnic Institute, Macao, China
Interests: structure-based drug design; molecular dynamics simulation; molecular generation; virtual screening; deep learning
Special Issues, Collections and Topics in MDPI journals
Dr. Jiazhong Li

E-Mail Website
Guest Editor
School of Pharmacy, Lanzhou University, Lanzhou, China
Interests: drug design; molecular simulations; molecular modeling; network pharmacology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Among the drugs approved by the FDA for clinical use, small-molecule drugs account for a large proportion. Whether in pharmaceutical enterprises or in scientific research institutions, many research groups are dedicated to the search for active small-molecule inhibitors from chemical databases, or deeply study the interaction mechanisms between a drug and the target.

This Special Issue of Molecules focuses on small-molecule inhibitors, especially insights from the structural aspect. The enclosed topics of this Special Issue include, but are not limited to, the following: structure-based drug design, molecular generation, virtual screening, molecular docking, molecular dynamics, interaction studies between small molecules and macromolecules, pharmacogenomics and CADD methodology. All articles on drug design and discovery relating to target structures are welcomed. Cell-based or animal experiments involving any disease model are particularly encouraged.

Dr. Huanxiang Liu
Dr. Jiazhong Li
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • structure-based drug design
  • molecular generation
  • virtual screening
  • molecular docking
  • molecular dynamics
  • deep learning
  • pharmacogenomics
  • CADD methodology

Published Papers (3 papers)

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Research

9 pages, 1907 KiB  
Article
Virtual Screening and Biological Activity Evaluation of New Potent Inhibitors Targeting Hexokinase-II
by Ruijuan Liu and Xuewei Liu
Molecules 2022, 27(21), 7555; https://doi.org/10.3390/molecules27217555 - 04 Nov 2022
Cited by 5 | Viewed by 1918
Abstract
Hexokinase-II (HK-II), the rate-limiting step enzyme in the glycolysis pathway, expresses high levels of cancer cells compared with normal cells. Due to its pivotal role in the different aspects of cancer physiology including cellular proliferation, metastasis, and apoptosis, HK-II provides a new therapeutic [...] Read more.
Hexokinase-II (HK-II), the rate-limiting step enzyme in the glycolysis pathway, expresses high levels of cancer cells compared with normal cells. Due to its pivotal role in the different aspects of cancer physiology including cellular proliferation, metastasis, and apoptosis, HK-II provides a new therapeutic target for cancer therapy. The structure-based virtual screening targeting HK-II was used to hit identifications from small molecule databases, and the select compounds were further evaluated in biological assays. Forty-seven compounds with the lowest binding energies were identified as potential HK-II inhibitors. Among them, nine compounds displayed the highest cytotoxicity to three different cancer cells. Based on the mechanism study, compounds 4244-3659 and K611-0094 showed an obvious inhibitory effect on the HK-II enzyme. This study identified two potential inhibitors of HK-II and can be helpful for developing potential drugs targeting HK-II in tumor therapy. Full article
(This article belongs to the Special Issue Small-Molecule Inhibitors: Insights into Drug Design from Structure)
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15 pages, 5057 KiB  
Article
Uncovering the Molecular Basis for the Better Gefitinib Sensitivity of EGFR with Complex Mutations over Single Rare Mutation: Insights from Molecular Simulations
by Miaomiao Li, Mengrong Li, Yanjie Xie and Jingjing Guo
Molecules 2022, 27(12), 3844; https://doi.org/10.3390/molecules27123844 - 15 Jun 2022
Cited by 4 | Viewed by 1658
Abstract
Epidermal growth factor receptor (EGFR) is an intensively focused target for anti-tumor compounds used in non-small cell lung cancer (NSCLC) therapy. Compared to the classical activating mutations, there are still many uncommon EGFR mutations associated with poorer responses to EGFR inhibitors. A detailed [...] Read more.
Epidermal growth factor receptor (EGFR) is an intensively focused target for anti-tumor compounds used in non-small cell lung cancer (NSCLC) therapy. Compared to the classical activating mutations, there are still many uncommon EGFR mutations associated with poorer responses to EGFR inhibitors. A detailed understanding of the molecular basis for multiple EGFR mutants exhibiting diverse responses to inhibitors is of critical importance for related drug development. Herein, we explored the molecular determinants contributing to the distinct responses of EGFR with a single rare mutation (G719S) or combined mutations (G719S/L858R and G719S/l861Q) to Gefitinib (IRE). Our results indicated that interactions, formed within the tetrad of residues S768 (in the αC-helix), D770 (in the αC-β4 loop), Y827 (in the αE-helix), and R831 (in the catalytic loop), play an important role in the stability of αC-helix and the maintenance of K745–E762 salt bridge in the absence of IRE, which are weakened in the EGFRG719S system and enhanced in the EGFRG719S/L858R system upon IRE binding. Besides, the introduced hydrogen bonds by the co-occurring mutation partner also contribute to the stability of αC-helix. The work done for inhibitor dissociation suggests that IRE exhibits a stronger binding affinity to EGFRG719S/L858R mutant. Together, these findings provide a deeper understanding of minor mutations, which is essential for drug development targeting EGFR with less common mutations. Full article
(This article belongs to the Special Issue Small-Molecule Inhibitors: Insights into Drug Design from Structure)
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20 pages, 24017 KiB  
Article
Virtual Screening of Natural Chemical Databases to Search for Potential ACE2 Inhibitors
by Huiping Yao
Molecules 2022, 27(5), 1740; https://doi.org/10.3390/molecules27051740 - 07 Mar 2022
Cited by 1 | Viewed by 3156
Abstract
The angiotensin-converting enzyme II (ACE2) is a multifunctional protein in both health and disease conditions, which serves as a counterregulatory component of RAS function in a cardioprotective role. ACE2 modulation may also have relevance to ovarian cancer, diabetes, acute lung injury, fibrotic diseases, [...] Read more.
The angiotensin-converting enzyme II (ACE2) is a multifunctional protein in both health and disease conditions, which serves as a counterregulatory component of RAS function in a cardioprotective role. ACE2 modulation may also have relevance to ovarian cancer, diabetes, acute lung injury, fibrotic diseases, etc. Furthermore, since the outbreak of the coronavirus disease in 2019 (COVID-19), ACE2 has been recognized as the host receptor of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The receptor binding domain of the SARS-CoV-2 S-protein has a strong interaction with ACE2, so ACE2 may be a potent drug target to prevent the virus from invading host cells for anti-COVID-19 drug discovery. In this study, structure- and property-based virtual screening methods were combined to filter natural product databases from ChemDiv, TargetMol, and InterBioScreen to find potential ACE2 inhibitors. The binding affinity between protein and ligands was predicted using both Glide SP and XP scoring functions and the MM-GBSA method. ADME properties were also calculated to evaluate chemical drug-likeness. Then, molecular dynamics (MD) simulations were performed to further explore the binding modes between the highest-potential compounds and ACE2. Results showed that the compounds 154-23-4 and STOCK1N-07141 possess potential ACE2 inhibition activities and deserve further study. Full article
(This article belongs to the Special Issue Small-Molecule Inhibitors: Insights into Drug Design from Structure)
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