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Structural Biology Approach in Drug Discovery
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Structural Biology Approach in Drug Discovery

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

Deadline for manuscript submissions: closed (31 October 2022) | Viewed by 10300

Special Issue Editor

Prof. Dr. Jung-Hsin Lin

E-Mail Website
Guest Editor
Biomedical Translation Research Center & Research Center for Applied Sciences, Academia Sinica, No. 128 Academia Rd. Sec. 2, Nankang, Taipei 11529, Taiwan
Interests: structural bioinformatics; molecular simulations; computational drug design; biophysics; artificial intelligence; neural network; machine learning

Special Issue Information

Dear Colleagues,

To date, there are approximately 180,000 biomolecular structures available in the Protein Data Bank, which has substantially enriched our understanding of the physical-chemical interactions among biomolecules in a wide variety of assemblies and oligomeric configurations. Many of these biomolecular structures have facilitated important drug design tasks. It is arguably true that computational approaches are the only promising direction of efficiently navigating the immense drug-like chemical space to find new candidate structures for further investigation. Currently, there are about 1 billion commercially available compounds curated by the UCSF ZINC database, which is impossible to be physically maintained by any single academic laboratory or pharmaceutical company. On the other hand, it cannot be overemphasized that most current computational methods are of an approximate nature, and thus a majority of computationally identified hits are false positives. This Special Issue focuses on recent endeavors to construct novel computational schemes to improve agreement with biophysical assays and evidence from structural biology investigations. Applications involving the design of small chemical molecules, peptides, proteins, and vaccines are all within the scope of this Special Issue.

Prof. Dr. Jung-Hsin Lin
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. 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

  • drug design
  • structural biology
  • virtual screening
  • target identification
  • de novo design
  • fragment-based
  • protein-ligand interaction
  • peptide design
  • protein design

Published Papers (4 papers)

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Research

14 pages, 3806 KiB  
Article
The First Snake Venom KTS/Disintegrins-Integrin Interactions Using Bioinformatics Approaches
by Oussema Khamessi, Hazem Ben Mabrouk, Selim Kamoun, Chaima Hkimi, Kais Ghedira and Riadh Kharrat
Molecules 2023, 28(1), 325; https://doi.org/10.3390/molecules28010325 - 31 Dec 2022
Cited by 1 | Viewed by 2334
Abstract
Snake venom contains a number of active molecules that have been shown to possess high anti-tumor activities; disintegrins are an excellent example among these. Their ability to interact and bind with integrins suggests that they could be very valuable molecules for the development [...] Read more.
Snake venom contains a number of active molecules that have been shown to possess high anti-tumor activities; disintegrins are an excellent example among these. Their ability to interact and bind with integrins suggests that they could be very valuable molecules for the development of new cancer therapeutic approaches. However, in the absence of a clear Lysine-Threonine-Serine (KTS) Disintegrins Integrin interaction model, the exact compound features behind it are still unknown. In this study, we investigated the structural characteristics of three KTS-disintegrins and the interaction mechanisms with the α1β1 integrin receptor using in silico bioinformatics approaches. Normal mode analysis showed that the flexibility of the KTSR motif and the C-terminal region play a key role and influence the KTS-Disintegrin-integrin interaction. Protein-protein docking also suggested that the interaction involving the KTSR motif is highly dependent on the residue following K21, S23 and R24. These findings contribute to a better understanding of the KTS-Disintegrin-Integrin structural differences and their interactions with α1β1 receptors, which could improve the selection process of the best active molecules for antitumor therapies. Full article
(This article belongs to the Special Issue Structural Biology Approach in Drug Discovery)
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20 pages, 31536 KiB  
Article
Computer-Aided Screening for Potential Coronavirus 3-Chymotrypsin-like Protease (3CLpro) Inhibitory Peptides from Putative Hemp Seed Trypsinized Peptidome
by Kansate Prasertsuk, Kasidit Prongfa, Piyapach Suttiwanich, Nathaphat Harnkit, Mattanun Sangkhawasi, Pongsakorn Promta and Pramote Chumnanpuen
Molecules 2023, 28(1), 50; https://doi.org/10.3390/molecules28010050 - 21 Dec 2022
Cited by 6 | Viewed by 2225
Abstract
To control the COVID-19 pandemic, antivirals that specifically target the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are urgently required. The 3-chymotrypsin-like protease (3CLpro) is a promising drug target since it functions as a catalytic dyad in hydrolyzing polyprotein during the viral life [...] Read more.
To control the COVID-19 pandemic, antivirals that specifically target the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are urgently required. The 3-chymotrypsin-like protease (3CLpro) is a promising drug target since it functions as a catalytic dyad in hydrolyzing polyprotein during the viral life cycle. Bioactive peptides, especially food-derived peptides, have a variety of functional activities, including antiviral activity, and also have a potential therapeutic effect against COVID-19. In this study, the hemp seed trypsinized peptidome was subjected to computer-aided screening against the 3CLpro of SARS-CoV-2. Using predictive trypsinized products of the five major proteins in hemp seed (i.e., edestin 1, edestin 2, edestin 3, albumin, and vicilin), the putative hydrolyzed peptidome was established and used as the input dataset. To select the Cannabis sativa antiviral peptides (csAVPs), a predictive bioinformatic analysis was performed by three webserver screening programs: iAMPpred, AVPpred, and Meta-iAVP. The amino acid composition profile comparison was performed by COPid to screen for the non-toxic and non-allergenic candidates, ToxinPred and AllerTOP and AllergenFP, respectively. GalaxyPepDock and HPEPDOCK were employed to perform the molecular docking of all selected csAVPs to the 3CLpro of SARS-CoV-2. Only the top docking-scored candidate (csAVP4) was further analyzed by molecular dynamics simulation for 150 nanoseconds. Molecular docking and molecular dynamics revealed the potential ability and stability of csAVP4 to inhibit the 3CLpro catalytic domain with hydrogen bond formation in domain 2 with short bonding distances. In addition, these top ten candidate bioactive peptides contained hydrophilic amino acid residues and exhibited a positive net charge. We hope that our results may guide the future development of alternative therapeutics against COVID-19. Full article
(This article belongs to the Special Issue Structural Biology Approach in Drug Discovery)
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15 pages, 2376 KiB  
Article
Potential Immunogenic Activity of Computationally Designed mRNA- and Peptide-Based Prophylactic Vaccines against MERS, SARS-CoV, and SARS-CoV-2: A Reverse Vaccinology Approach
by Taimoor Khan, Abbas Khan, Jawad Khaliq Ansari, Muzammil Hasan Najmi, Dong-Qing Wei, Khalid Muhammad and Yasir Waheed
Molecules 2022, 27(7), 2375; https://doi.org/10.3390/molecules27072375 - 6 Apr 2022
Cited by 11 | Viewed by 2625
Abstract
The continued emergence of human coronaviruses (hCoVs) in the last few decades has posed an alarming situation and requires advanced cross-protective strategies against these pandemic viruses. Among these, Middle East Respiratory Syndrome coronavirus (MERS-CoV), Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), and Severe Acute [...] Read more.
The continued emergence of human coronaviruses (hCoVs) in the last few decades has posed an alarming situation and requires advanced cross-protective strategies against these pandemic viruses. Among these, Middle East Respiratory Syndrome coronavirus (MERS-CoV), Severe Acute Respiratory Syndrome coronavirus (SARS-CoV), and Severe Acute Respiratory Syndrome coronavirus-2 (SARS-CoV-2) have been highly associated with lethality in humans. Despite the challenges posed by these viruses, it is imperative to develop effective antiviral therapeutics and vaccines for these human-infecting viruses. The proteomic similarity between the receptor-binding domains (RBDs) among the three viral species offers a potential target for advanced cross-protective vaccine designs. In this study, putative immunogenic epitopes including Cytotoxic T Lymphocytes (CTLs), Helper T Lymphocytes (HTLs), and Beta-cells (B-cells) were predicted for each RBD-containing region of the three highly pathogenic hCoVs. This was followed by the structural organization of peptide- and mRNA-based prophylactic vaccine designs. The validated 3D structures of these epitope-based vaccine designs were subjected to molecular docking with human TLR4. Furthermore, the CTL and HTL epitopes were processed for binding with respective human Lymphocytes Antigens (HLAs). In silico cloning designs were obtained for the prophylactic vaccine designs and may be useful in further experimental designs. Additionally, the epitope-based vaccine designs were evaluated for immunogenic activity through immune simulation. Further studies may clarify the safety and efficacy of these prophylactic vaccine designs through experimental testing against these human-pathogenic coronaviruses. Full article
(This article belongs to the Special Issue Structural Biology Approach in Drug Discovery)
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24 pages, 2063 KiB  
Article
A Comprehensive Computational Investigation into the Conserved Virulent Proteins of Shigella species Unveils Potential Small-Interfering RNA Candidates as a New Therapeutic Strategy against Shigellosis
by Parag Palit, Farhana Tasnim Chowdhury, Namrata Baruah, Bonoshree Sarkar, Sadia Noor Mou, Mehnaz Kamal, Towfida Jahan Siddiqua, Zannatun Noor and Tahmeed Ahmed
Molecules 2022, 27(6), 1936; https://doi.org/10.3390/molecules27061936 - 17 Mar 2022
Viewed by 2507
Abstract
Shigella species account for the second-leading cause of deaths due to diarrheal diseases among children of less than 5 years of age. The emergence of multi-drug-resistant Shigella isolates and the lack of availability of Shigella vaccines have led to the pertinence in the [...] Read more.
Shigella species account for the second-leading cause of deaths due to diarrheal diseases among children of less than 5 years of age. The emergence of multi-drug-resistant Shigella isolates and the lack of availability of Shigella vaccines have led to the pertinence in the efforts made for the development of new therapeutic strategies against shigellosis. Consequently, designing small-interfering RNA (siRNA) candidates against such infectious agents represents a novel approach to propose new therapeutic candidates to curb the rampant rise of anti-microbial resistance in such pathogens. In this study, we analyzed 264 conserved sequences from 15 different conserved virulence genes of Shigella sp., through extensive rational validation using a plethora of first-generation and second-generation computational algorithms for siRNA designing. Fifty-eight siRNA candidates were obtained by using the first-generation algorithms, out of which only 38 siRNA candidates complied with the second-generation rules of siRNA designing. Further computational validation showed that 16 siRNA candidates were found to have a substantial functional efficiency, out of which 11 siRNA candidates were found to be non-immunogenic. Finally, three siRNA candidates exhibited a sterically feasible three-dimensional structure as exhibited by parameters of nucleic acid geometry such as: the probability of wrong sugar puckers, bad backbone confirmations, bad bonds, and bad angles being within the accepted threshold for stable tertiary structure. Although the findings of our study require further wet-lab validation and optimization for therapeutic use in the treatment of shigellosis, the computationally validated siRNA candidates are expected to suppress the expression of the virulence genes, namely: IpgD (siRNA 9) and OspB (siRNA 15 and siRNA 17) and thus act as a prospective tool in the RNA interference (RNAi) pathway. However, the findings of our study require further wet-lab validation and optimization for regular therapeutic use for treatment of shigellosis. Full article
(This article belongs to the Special Issue Structural Biology Approach in Drug Discovery)
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