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

Deadline for manuscript submissions: closed (30 September 2019) | Viewed by 68223

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Prof. Dr. Rainer Riedl

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

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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 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

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Published Papers (10 papers)

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Research

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9 pages, 486 KiB

Open AccessArticle

Matrix Metalloproteinase Triple-Helical Peptide Inhibitors: Potential Cross-Reactivity with Caspase-11

by Anna M. Knapinska, Melissa Hart, Gary Drotleff and Gregg B. Fields

Molecules 2019, 24(23), 4355; https://doi.org/10.3390/molecules24234355 - 28 Nov 2019

Cited by 3 | Viewed by 4019

Abstract

Triple-helical peptide inhibitors (THPIs) of matrix metalloproteinases (MMPs) have recently been demonstrated to be effective in a variety of animal models of disease, coincidental with knockout studies. However, passenger mutations have been described in MMP knockout mice that impact the activity of other proteins, including caspase-11. Thus, it is possible that the results observed with THPIs may be based on inhibition of caspase-11, not MMPs. The present study evaluated whether THPIs were cross-reactive with caspase-11. Two different THPIs were tested, one that is known to inhibit MMP-1 and MMP-8 (GlyΨ{PO₂H-CH₂}Ile-His-Lys-Gln THPI) and one that is selective for MMP-2 and MMP-9 (α1(V)GlyΨ{PO₂H-CH₂}Val [mep_14,32,Flp_15,33] THPI). No inhibition of caspase-11 was observed with GlyΨ{PO₂H–CH₂}Ile–His–Lys–Gln THPI, even at an inhibitor concentration of 5 μM, while 5 μM α1(V)GlyΨ{PO₂H-CH₂}Val [mep_14,32,Flp_15,33] THPI exhibited 40% inhibition of caspase-11. Further testing of GlyΨ{PO₂H-CH₂}Ile-His-Lys-Gln THPI revealed nM inhibition of MMP-2, MMP-9, and MMP-13. Thus, the effectiveness of GlyΨ{PO₂H-CH₂}Ile-His-Lys-Gln THPI observed in a sepsis animal model may not be due to caspase-11 inhibition, but may be due to broader MMP inhibition than previously thought. Full article

(This article belongs to the Special Issue Drug Design)

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20 pages, 2670 KiB

Open AccessArticle

Multimerization through Pegylation Improves Pharmacokinetic Properties of scFv Fragments of GD2-Specific Antibodies

by Irina V. Kholodenko, Daniel V. Kalinovsky, Elena V. Svirshchevskaya, Igor I. Doronin, Maria V. Konovalova, Alexey V. Kibardin, Tatyana V. Shamanskaya, Sergey S. Larin, Sergey M. Deyev and Roman V. Kholodenko

Molecules 2019, 24(21), 3835; https://doi.org/10.3390/molecules24213835 - 24 Oct 2019

Cited by 23 | Viewed by 5220

Abstract

Antigen-binding fragments of antibodies specific to the tumor-associated ganglioside GD2 are well poised to play a substantial role in modern GD2-targeted cancer therapies, however, rapid elimination from the body and reduced affinity compared to full-length antibodies limit their therapeutic potential. In this study, scFv fragments of GD2-specific antibodies 14.18 were produced in a mammalian expression system that specifically bind to ganglioside GD2, followed by site-directed pegylation to generate mono-, di-, and tetra-scFv fragments. Fractionated pegylated dimers and tetramers of scFv fragments showed significant increase of the binding to GD2 which was not accompanied by cross-reactivity with other gangliosides. Pegylated multimeric di-scFvs and tetra-scFvs exhibited cytotoxic effects in GD2-positive tumor cells, while their circulation time in blood significantly increased compared with monomeric antibody fragments. We also demonstrated a more efficient tumor uptake of the multimers in a syngeneic GD2-positive mouse cancer model. The findings of this study provide the rationale for improving therapeutic characteristics of GD2-specific antibody fragments by multimerization and propose a strategy to generate such molecules. On the basis of multimeric antibody fragments, bispecific antibodies and conjugates with cytotoxic drugs or radioactive isotopes may be developed that will possess improved pharmacokinetic and pharmacodynamic properties. Full article

(This article belongs to the Special Issue Drug Design)

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23 pages, 7205 KiB

Open AccessFeature PaperArticle

Novel Benzothiazole-Based Ureas as 17β-HSD10 Inhibitors, A Potential Alzheimer’s Disease Treatment

by Laura Aitken, Ondrej Benek, Brogan E. McKelvie, Rebecca E. Hughes, Lukas Hroch, Monika Schmidt, Louise L. Major, Lucie Vinklarova, Kamil Kuca, Terry K. Smith, Kamil Musilek and Frank J. Gunn-Moore

Molecules 2019, 24(15), 2757; https://doi.org/10.3390/molecules24152757 - 29 Jul 2019

Cited by 23 | Viewed by 4774

Abstract

It has long been established that mitochondrial dysfunction in Alzheimer’s disease (AD) patients can trigger pathological changes in cell metabolism by altering metabolic enzymes such as the mitochondrial 17β-hydroxysteroid dehydrogenase type 10 (17β-HSD10), also known as amyloid-binding alcohol dehydrogenase (ABAD). We and others have shown that frentizole and riluzole derivatives can inhibit 17β-HSD10 and that this inhibition is beneficial and holds therapeutic merit for the treatment of AD. Here we evaluate several novel series based on benzothiazolylurea scaffold evaluating key structural and activity relationships required for the inhibition of 17β-HSD10. Results show that the most promising of these compounds have markedly increased potency on our previously published inhibitors, with the most promising exhibiting advantageous features like low cytotoxicity and target engagement in living cells. Full article

(This article belongs to the Special Issue Drug Design)

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13 pages, 2692 KiB

Open AccessArticle

Design, Synthesis, and Evaluation of Monoamine Oxidase A Inhibitors–Indocyanine Dyes Conjugates as Targeted Antitumor Agents

by Xiao-Guang Yang, Yan-Hua Mou, Yong-Jun Wang, Jian Wang, Yan-Yu Li, Rui-Heng Kong, Meng Ding, Dun Wang and Chun Guo

Molecules 2019, 24(7), 1400; https://doi.org/10.3390/molecules24071400 - 10 Apr 2019

Cited by 21 | Viewed by 4494

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 the MAOA inhibitor isoniazid (INH) and tumor-targeting near-infrared (NIR) heptamethine cyanine dyes were designed and synthesized. The synthesized compounds G1–G13 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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13 pages, 5168 KiB

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

by Thomas Fischer, Symeon M. Koulas, Anastasia S. Tsagkarakou, Efthimios Kyriakis, George A. Stravodimos, Vassiliki T. Skamnaki, Panagiota G.V. Liggri, Spyros E. Zographos, Rainer Riedl and Demetres D. Leonidas

Molecules 2019, 24(7), 1322; https://doi.org/10.3390/molecules24071322 - 3 Apr 2019

Cited by 12 | Viewed by 3991

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 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)

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Review

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32 pages, 3555 KiB

Open AccessReview

In Silico Strategies in Tuberculosis Drug Discovery

by Stephani Joy Y. Macalino, Junie B. Billones, Voltaire G. Organo and Maria Constancia O. Carrillo

Molecules 2020, 25(3), 665; https://doi.org/10.3390/molecules25030665 - 4 Feb 2020

Cited by 48 | Viewed by 10873

Abstract

Tuberculosis (TB) remains a serious threat to global public health, responsible for an estimated 1.5 million mortalities in 2018. While there are available therapeutics for this infection, slow-acting drugs, poor patient compliance, drug toxicity, and drug resistance require the discovery of novel TB drugs. Discovering new and more potent antibiotics that target novel TB protein targets is an attractive strategy towards controlling the global TB epidemic. In silico strategies can be applied at multiple stages of the drug discovery paradigm to expedite the identification of novel anti-TB therapeutics. In this paper, we discuss the current TB treatment, emergence of drug resistance, and the effective application of computational tools to the different stages of TB drug discovery when combined with traditional biochemical methods. We will also highlight the strengths and points of improvement in in silico TB drug discovery research, as well as possible future perspectives in this field. Full article

(This article belongs to the Special Issue Drug Design)

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23 pages, 8072 KiB

Open AccessReview

Rational Drug Design of Peptide-Based Therapies for Sickle Cell Disease

by Olujide O. Olubiyi, Maryam O. Olagunju and Birgit Strodel

Molecules 2019, 24(24), 4551; https://doi.org/10.3390/molecules24244551 - 12 Dec 2019

Cited by 9 | Viewed by 9298

Abstract

Sickle cell disease (SCD) is a group of inherited disorders affecting red blood cells, which is caused by a single mutation that results in substitution of the amino acid valine for glutamic acid in the sixth position of the β-globin chain of hemoglobin. These mutant hemoglobin molecules, called hemoglobin S, can polymerize upon deoxygenation, causing erythrocytes to adopt a sickled form and to suffer hemolysis and vaso-occlusion. Until recently, only two drug therapies for SCD, which do not even fully address the manifestations of SCD, were approved by the United States (US) Food and Drug Administration. A third treatment was newly approved, while a monoclonal antibody preventing vaso-occlusive crises is also now available. The complex nature of SCD manifestations provides multiple critical points where drug discovery efforts can be and have been directed. These notwithstanding, the need for new therapeutic approaches remains high and one of the recent efforts includes developments aimed at inhibiting the polymerization of hemoglobin S. This review focuses on anti-sickling approaches using peptide-based inhibitors, ranging from individual amino acid dipeptides investigated 30–40 years ago up to more promising 12- and 15-mers under consideration in recent years. Full article

(This article belongs to the Special Issue Drug Design)

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16 pages, 4528 KiB

Open AccessFeature PaperReview

Siderophore–Antibiotic Conjugate Design: New Drugs for Bad Bugs?

by Kokob H. Negash, James K.S. Norris and James T. Hodgkinson

Molecules 2019, 24(18), 3314; https://doi.org/10.3390/molecules24183314 - 11 Sep 2019

Cited by 103 | Viewed by 12236

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 iron-chelating microbial siderophores to an antibiotic or antimicrobial agent to enhance uptake and antibacterial potency. Cefiderocol (S-649266) is a promising cephalosporin–catechol conjugate currently in phase III clinical trials that utilizes iron-mediated active transport and demonstrates enhanced potency against multi-drug resistant (MDR) Gram-negative pathogens. Such molecules demonstrate that siderophore–antibiotic conjugates could be important future medicines to add to our antibiotic arsenal. This review is written in the context of the chemical design of siderophore–antibiotic conjugates focusing on the differing siderophore, linker, and antibiotic components that make up conjugates. We selected chemically distinct siderophore–antibiotic conjugates as exemplary conjugates, rather than multiple analogues, to highlight findings to date. The review should offer a general guide to the uninitiated in the molecular design of siderophore–antibiotic conjugates. Full article

(This article belongs to the Special Issue Drug Design)

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13 pages, 2376 KiB

Open AccessReview

Reviewing HIV-1 Gag Mutations in Protease Inhibitors Resistance: Insights for Possible Novel Gag Inhibitor Designs

by Chinh Tran-To Su, Darius Wen-Shuo Koh and Samuel Ken-En Gan

Molecules 2019, 24(18), 3243; https://doi.org/10.3390/molecules24183243 - 6 Sep 2019

Cited by 15 | Viewed by 6780

Abstract

HIV protease inhibitors against the viral protease are often hampered by drug resistance mutations in protease and in the viral substrate Gag. To overcome this drug resistance and inhibit viral maturation, targeting Gag alongside protease rather than targeting protease alone may be more efficient. In order to successfully inhibit Gag, understanding of its drug resistance mutations and the elicited structural changes on protease binding needs to be investigated. While mutations on Gag have already been mapped to protease inhibitor resistance, there remain many mutations, particularly the non-cleavage mutations, that are not characterized. Through structural studies to unravel how Gag mutations contributes to protease drug resistance synergistically, it is thus possible to glean insights to design novel Gag inhibitors. In this review, we discuss the structural role of both novel and previously reported Gag mutations in PI resistance, and how new Gag inhibitors can be designed. Full article

(This article belongs to the Special Issue Drug Design)

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17 pages, 3195 KiB

Open AccessReview

Inhibitory Antibodies Designed for Matrix Metalloproteinase Modulation

by Thomas Fischer and Rainer Riedl

Molecules 2019, 24(12), 2265; https://doi.org/10.3390/molecules24122265 - 18 Jun 2019

Cited by 36 | Viewed by 5172

Abstract

The family of matrix metalloproteinases (MMPs) consists of a set of biological targets that are involved in a multitude of severe pathogenic events such as different forms of cancers or arthritis. Modulation of the target class with small molecule drugs has not led to the anticipated success until present, as all clinical trials failed due to unacceptable side effects or a lack of therapeutic outcome. Monoclonal antibodies offer a tremendous therapeutic potential given their high target selectivity and good pharmacokinetic profiles. For the treatment of a variety of diseases there are already antibody therapies available and the number is increasing. Recently, several antibodies were developed for the selective inhibition of single MMPs that showed high potency and were therefore investigated in in vivo studies with promising results. In this review, we highlight the progress that has been achieved toward the design of inhibitory antibodies that successfully modulate MMP-9 and MMP-14. Full article

(This article belongs to the Special Issue Drug Design)

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