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Role of Molecular Dynamics Simulations and Related Methods in Drug Discovery

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

Deadline for manuscript submissions: 30 June 2024 | Viewed by 3102

Special Issue Editor

Prof. Dr. Huanxiang Liu

E-Mail Website
Guest Editor
Faculty of Applied Science, Macao Polytechnic University, Macao 999078, China
Interests: the methodology development of drug design based on artificial intelligence; molecular simulations of structure and function of biomacromolecules; drug discovery for some important targets
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Molecular dynamics simulations together with some related methods such as binding free energy calculation, Markov state model, etc., have been widely applied in the field of drug discovery due to their special advantages in uncovering the dynamics conformational features of protein and studying the thermodynamics and dissociation kinetics of protein–ligand interactions. By disclosing the molecular mechanism of the conformational transition of protein, molecular dynamics simulations play an irreplaceable role in the study of the pathogenesis of neurodegenerative diseases and provide useful information and strategies for drug discovery for these incurable diseases. Molecular dynamics simulations are also applied to obtain a more trustable and representative structure, which can be further applied for structure-based drug discovery and improve the success rate of drug discovery. By disclosing the protein–ligand interaction mechanism, molecular dynamics simulations can increase our comprehension of how a drug can interfere with the pathophysiology of a biological target and provide valuable information for drug design and optimization of lead compounds.

This Special Issue focuses on the various applications of molecular dynamics simulation and related computing methods in the drug discovery process, including virtual screening, binding free energy calculation, protein–ligand interaction, residence time, dissociation paths, and other related research articles. Studies providing such information are also welcome, which will help to elucidate the rationale for molecular modification and new drug development. As IJMS is a journal of molecular science, pure clinical studies will not be suitable for our journal. However, clinical or pure model submissions with biomolecular experiments are welcomed.

Prof. Dr. Huanxiang Liu
Guest Editor

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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • drug discovery
  • virtual screening
  • molecular dynamics simulations
  • lead compounds
  • binding free energy
  • ligand dissociation
  • residence time

Published Papers (3 papers)

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Research

17 pages, 4346 KiB  
Article
Revealing the Interaction Mechanism between Mycobacterium tuberculosis GyrB and Novobiocin, SPR719 through Binding Thermodynamics and Dissociation Kinetics Analysis
by Xiaofei Qiu, Qianqian Zhang, Zhaoguo Li, Juan Zhang and Huanxiang Liu
Int. J. Mol. Sci. 2024, 25(7), 3764; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms25073764 - 28 Mar 2024
Viewed by 464
Abstract
With the rapid emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb), various levels of resistance against existing anti-tuberculosis (TB) drugs have developed. Consequently, the identification of new anti-TB targets and drugs is critically urgent. DNA gyrase subunit B (GyrB) has been identified as [...] Read more.
With the rapid emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb), various levels of resistance against existing anti-tuberculosis (TB) drugs have developed. Consequently, the identification of new anti-TB targets and drugs is critically urgent. DNA gyrase subunit B (GyrB) has been identified as a potential anti-TB target, with novobiocin and SPR719 proposed as inhibitors targeting GyrB. Therefore, elucidating the molecular interactions between GyrB and its inhibitors is crucial for the discovery and design of efficient GyrB inhibitors for combating multidrug-resistant TB. In this study, we revealed the detailed binding mechanisms and dissociation processes of the representative inhibitors, novobiocin and SPR719, with GyrB using classical molecular dynamics (MD) simulations, tau-random acceleration molecular dynamics (τ-RAMD) simulations, and steered molecular dynamics (SMD) simulations. Our simulation results demonstrate that both electrostatic and van der Waals interactions contribute favorably to the inhibitors’ binding to GyrB, with Asn52, Asp79, Arg82, Lys108, Tyr114, and Arg141 being key residues for the inhibitors’ attachment to GyrB. The τ-RAMD simulations indicate that the inhibitors primarily dissociate from the ATP channel. The SMD simulation results reveal that both inhibitors follow a similar dissociation mechanism, requiring the overcoming of hydrophobic interactions and hydrogen bonding interactions formed with the ATP active site. The binding and dissociation mechanisms of GyrB with inhibitors novobiocin and SPR719 obtained in our work will provide new insights for the development of promising GyrB inhibitors. Full article
(This article belongs to the Special Issue Role of Molecular Dynamics Simulations and Related Methods in Drug Discovery)
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16 pages, 11886 KiB  
Article
EGCG-Mediated Protection of Transthyretin Amyloidosis by Stabilizing Transthyretin Tetramers and Disrupting Transthyretin Aggregates
by Huizhen Zou and Shuangyan Zhou
Int. J. Mol. Sci. 2023, 24(18), 14146; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241814146 - 15 Sep 2023
Viewed by 896
Abstract
Transthyretin amyloidosis (ATTR) is a progressive and systemic disease caused by the misfolding and amyloid aggregation of transthyretin (TTR). Stabilizing the TTR tetramers and disrupting the formed TTR aggregation are treated as a promising strategy for the treatment of ATTR. Previous studies have [...] Read more.
Transthyretin amyloidosis (ATTR) is a progressive and systemic disease caused by the misfolding and amyloid aggregation of transthyretin (TTR). Stabilizing the TTR tetramers and disrupting the formed TTR aggregation are treated as a promising strategy for the treatment of ATTR. Previous studies have reported that epigallocatechin gallate (EGCG) can participate in the whole process of TTR aggregation to prevent ATTR. However, the interaction mechanism of EGCG in this process is still obscure. In this work, we performed molecular dynamics simulations to investigate the interactions between EGCG and TTR tetramers, and between EGCG and TTR aggregates formed by the V30M mutation. The obtained results suggest that EGCG at the binding site of the V30M TTR tetramer can form stable hydrogen bonds with residues in the flexible AB-loop and EF-helix-loop, which reduces the structural mobility of these regions significantly. Additionally, the polyaromatic property of EGCG contributes to the increasement of hydrophobicity at the binding site and thus makes the tetramer difficult to be solvated and dissociated. For V30M-TTR-generated aggregates, EGCG can promote the dissociation of boundary β-strands by destroying key residue interactions of TTR aggregates. Moreover, EGCG is capable of inserting into the side-chain of residues of neighboring β-strands and disrupting the highly structured aggregates. Taken together, this study elucidates the role of EGCG in preventing TTR amyloidosis, which can provide important theoretical support for the future of drug design for ATTR. Full article
(This article belongs to the Special Issue Role of Molecular Dynamics Simulations and Related Methods in Drug Discovery)
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20 pages, 3747 KiB  
Article
Molecular Dynamics Study of the Effect of Charge and Glycosyl on Superoxide Anion Distribution near Lipid Membrane
by Xuan Meng, Huiyu Liu, Ning Zhao, Yajun Yang, Kai Zhao and Yujie Dai
Int. J. Mol. Sci. 2023, 24(13), 10926; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms241310926 - 30 Jun 2023
Cited by 1 | Viewed by 1171
Abstract
To examine the effects of membrane charge, the electrolyte species and glycosyl on the distribution of negatively charged radical of superoxide anion (·O2−) around the cell membrane, different phospholipid bilayer systems containing ·O2− radicals, different electrolytes and phospholipid [...] Read more.
To examine the effects of membrane charge, the electrolyte species and glycosyl on the distribution of negatively charged radical of superoxide anion (·O2−) around the cell membrane, different phospholipid bilayer systems containing ·O2− radicals, different electrolytes and phospholipid bilayers were constructed through Charmm-GUI and Amber16. These systems were equilibrated with molecular dynamics by using Gromacs 5.0.2 to analyze the statistical behaviors of ·O2− near the lipid membrane under different conditions. It was found that in the presence of potassium rather than sodium, the negative charge of the phospholipid membrane is more likely to rarefy the superoxide anion distribution near the membrane surface. Further, the presence of glycosyl significantly reduced the density of ·O2− near the phospholipid bilayer by 78.3% compared with that of the neutral lipid membrane, which may have a significant contribution to reducing the lipid peroxidation from decreasing the ·O2− density near the membrane. Full article
(This article belongs to the Special Issue Role of Molecular Dynamics Simulations and Related Methods in Drug Discovery)
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