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Special Issue "Drug Design"

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

Deadline for manuscript submissions: 30 September 2019

Special Issue Editor

Guest Editor
Prof. Dr. Rainer Riedl

Center for Organic and Medicinal Chemistry, Institute of Chemistry and Biotechnology, Zurich University of Applied Sciences ZHAW, Einsiedlerstrasse 31, 8820 Wädenswil, Switzerland
Website | E-Mail
Interests: medicinal chemistry; drug discovery and development; organic synthesis; drug design; drug resistance; antimicrobials; natural products; peptides

Special Issue Information

Dear Colleagues,

The treatment of diseases requires the design of drug molecules with defined properties in order to modulate the associated therapeutic targets. Drug design is therefore a key component of the drug discovery and development process to provide pharmacologically active substances with a particular function. Here, the affinity and selectivity profiles of drug molecules in their biological context are important factors in the complex effort to optimize molecules for clinical use, but ADMET properties have to be considered during the design process as well. Different approaches have been developed for the rational design of drug molecules with targeted properties: Structure-based, ligand-based, fragment-based, computer-aided, and de novo approaches, to name a few, have emerged over time and demonstrated their value.

These strategies delivered excellent results on a multitude of therapeutically relevant drug targets such as proteases, kinases, and G protein-coupled receptors, with broad implications on diverse indications like oncology or infectious diseases.

The design of drug molecules with tailored biological activity is a very creative process, which includes traditional small molecules as well as antibodies and biologics but also conjugates of these molecular entities.

As this multidisciplinary field is rapidly progressing, the intention of this Special Issue is to cover current developments on all aspects related to drug design by original research and review articles.

This includes medicinal chemistry with all its intriguing aspects, including synthetic chemistry for realizing the designed agents, and the biological disciplines that benefit from tailor-made drug molecules.

Articles addressing the topics listed below are particularly welcome.

Prof. Dr. Rainer Riedl
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 papers will be 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 1800 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 discovery
  • Lead optimization
  • Clinical candidate development
  • Molecular modelling
  • De novo drug design
  • Structure-based drug design
  • Ligand-based drug design
  • Computer-aided drug design
  • ADMET
  • Pharmacophores
  • Polypharmacology
  • Chemical biology
  • Protein–protein interactions
  • Small molecule drugs
  • Antibodies
  • Protein–drug conjugates (ADCs/PDCs)
  • Fragment-based drug discovery
  • Structure–activity relationships

Published Papers (2 papers)

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Research

Open AccessArticle
Design, Synthesis, and Evaluation of Monoamine Oxidase A Inhibitors–Indocyanine Dyes Conjugates as Targeted Antitumor Agents
Molecules 2019, 24(7), 1400; https://doi.org/10.3390/molecules24071400
Received: 18 March 2019 / Revised: 5 April 2019 / Accepted: 6 April 2019 / Published: 10 April 2019
PDF Full-text (2692 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Monoamine oxidase A (MAOA) is an important mitochondria-bound enzyme that catalyzes the oxidative deamination of monoamine neurotransmitters. Accumulating evidence suggests a significant association of increased MAOA expression and advanced high-grade prostate cancer (PCa) progression and metastasis. Herein, a series of novel conjugates combining [...] Read more.
Monoamine oxidase A (MAOA) is an important mitochondria-bound enzyme that catalyzes the oxidative deamination of monoamine neurotransmitters. Accumulating evidence suggests a significant association of increased MAOA expression and advanced high-grade prostate cancer (PCa) progression and metastasis. Herein, a series of novel conjugates combining the MAOA inhibitor isoniazid (INH) and tumor-targeting near-infrared (NIR) heptamethine cyanine dyes were designed and synthesized. The synthesized compounds G1G13 were evaluated in vitro for their cytotoxicity against PC-3 cells using the MTT assay, and molecular docking studies were performed. Results showed that most tested compounds exhibited improved antitumor efficacy compared with INH. Moreover, conjugates G10 and G11 showed potent anticancer activity with IC50 values (0.85 and 0.4 μM respectively) comparable to that of doxorubicin (DOX). This may be attributable to the preferential accumulation of these conjugates in tumor cells. G10, G11, and G12 also demonstrated moderate MAOA inhibitory activities. This result and the results of molecular docking studies were consistent with their cytotoxicity activities. Taken together, these data suggest that a combination of the MAOA inhibitor INH with tumor-targeting heptamethine cyanine dyes may prove to be a highly promising tool for the treatment of advanced prostate cancer. Full article
(This article belongs to the Special Issue Drug Design)
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Graphical abstract

Open AccessArticle
High Consistency of Structure-Based Design and X-Ray Crystallography: Design, Synthesis, Kinetic Evaluation and Crystallographic Binding Mode Determination of Biphenyl-N-acyl-β-d-Glucopyranosylamines as Glycogen Phosphorylase Inhibitors
Molecules 2019, 24(7), 1322; https://doi.org/10.3390/molecules24071322
Received: 15 March 2019 / Revised: 30 March 2019 / Accepted: 1 April 2019 / Published: 3 April 2019
PDF Full-text (5168 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Structure-based design and synthesis of two biphenyl-N-acyl-β-d-glucopyranosylamine derivatives as well as their assessment as inhibitors of human liver glycogen phosphorylase (hlGPa, a pharmaceutical target for type 2 diabetes) is presented. X-ray crystallography revealed the importance of structural water molecules [...] Read more.
Structure-based design and synthesis of two biphenyl-N-acyl-β-d-glucopyranosylamine derivatives as well as their assessment as inhibitors of human liver glycogen phosphorylase (hlGPa, a pharmaceutical target for type 2 diabetes) is presented. X-ray crystallography revealed the importance of structural water molecules and that the inhibitory efficacy correlates with the degree of disturbance caused by the inhibitor binding to a loop crucial for the catalytic mechanism. The in silico-derived models of the binding mode generated during the design process corresponded very well with the crystallographic data. Full article
(This article belongs to the Special Issue Drug Design)
Figures

Graphical abstract

Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Siderophore-Antibiotic Conjugate Design: New Drugs for Bad Bugs?

James T. Hodgkinson

Abstract: Antibiotic resistance is a global health concern and a current threat to modern medicine and society. New strategies for antibiotic drug design and delivery offer a glimmer of hope in a currently limited pipeline of new antibiotics. One strategy involves conjugating high-affinity iron chelating microbial siderophores to an antibiotic or antimicrobial agent to enhance bacterial uptake and killing potency. Cefiderocol (S-649266) is a promising siderophore-cephalosporin conjugate currently in phase III clinical trials that demonstrates enhanced killing potency against multi-drug resistant (MDR) Gram-negative pathogens. Such molecules offer optimism that siderophore-antibiotic conjugates could be important future medicines to add to our antibiotic arsenal and drive new siderophore-antibiotic design and drug development. This review focuses on the latest siderophore-antibiotic conjugates in the literature and their molecular design. A particular emphasis is placed on modifying Gram-positive antibiotics for Gram-negative uptake, new linker methodologies, and new antimicrobial agents for conjugation. The review should offer a comprehensive guide in siderophore-antibiotic conjugate design. 

 

Title: Designing Novel Biologicals Based on Matrix Metalloproteinase Proteolytic Mechanisms

Gregg B. Fields

 

Title: Tetraazamacrocyclic derivatives and their metal complexes as antileishmanial leads

Tim Hubin

Abstract: Leishmaniasis, a vector-born parasitic disease caused by Leishmania donovani, affects 350 million people worldwide, yet currently available treatments are severely toxic and not effective.  To discover a tetraazamacrocyclic based new drug lead, a significant number of bis- and monocyclic polyamines and their transition metal complexes were synthesized and screened in vitro against the L. donovani promastigotes, axenic amastigotes and intracellular amastigotes in THP1 cells. The IC50 and/or IC90 values showed that multiple compounds were similarly potent as pentamidine against promastigotes.

 

Title: A review of indispensable role of HIV-1 Gag in Protease-associated mutation resistance: a co-dependent resistance model for drug design

Chinh Tran To Su

Abstract: HIV strategies for either cure or controlling the virus to improve quality of lives have been developed over the past decades. However, viral resistance to these therapies has been increasingly documented. Studies have significantly shown that the viral substrate Gag is a factor that is involved in HIV-1 Protease inhibitor resistance, consequently making those inhibitors ineffective. A study of Gag-Protease co-evolution therefore provides a deeper understanding into viral fitness compensation due to mutations. Given various mutations discovered by previous studies, we will highlight Gag and Protease co-evolved mutations that have conferred resistance against most Protease inhibitors, and will further discuss the possibility of a potential Gag inhibitor that likely bridges both Gag and Protease, subsequently causing cell death.

 

Title: Tuberculosis target fishing via reverse docking of pyridine macrocycles

Junie B. Billones, Maria Constancia O. Carrillo, Voltaire G. Organo, Raul V. Destura, Stephani Joy Y. Macalino, Inno A. Emnacen, Jamie Bernadette A. Sy, Nina Abigail B. Clavio, Beatrice Marie L. Pique, Princess Alyssa S. Abid, and Nadia B. Morales

Abstract: Tuberculosis (TB) continues to be a threat to world public health, involving nearly 1.5 million deaths last 2014. While therapeutics have long been available for this infection, slow-acting drugs, poor patient compliance, and drug resistance necessitate the discovery of new TB drugs. Macrocycles are large compounds derived from natural sources and despite its structural complexity leading to violations of the Lipinski’s rule of 5, they have been established as suitable starting points for drug discovery against various disease targets due to their remarkable therapeutic potential. In this study, we explored pyridine macrocycles (PyMACs) as potential TB inhibitors via reverse molecular docking and in vitro resazurin assay. From the docking studies, the designed PyMacs were found to target ddlA, LdtMt2, and BioA, showing lower binding energies relative to the known inhibitors of the respective proteins. In combination with in silico ADMET results, LH and LMe were selected for synthesis and further testing. Resazurin microtiter assay revealed that LH moderately inhibited TB activity at 25 uM. Hence, LH can be used as an effective scaffold for further optimization to design novel and potent anti-TB compounds.

 

Navigation in Chemical Space

Karl-Heinz Baringhaus, Gerhard Hessler

This short review will include virtual screening, de novo design and artificial intelligence aspects with respect to navigation and analysis of chemical space.

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