Special Issue "Design of Enzyme Inhibitors as Potential Drugs 2020"

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (31 October 2020).

Special Issue Editor

Prof. Dr. Paweł Kafarski
Website
Guest Editor
Department of Bioorganic Chemistry, Faculty of Chemistry, Wrocław University of Technology, Wrocław, Poland
Interests: medicinal chemistry; organic synthesis; biotransformations; enzyme inhibitors; organophosphonates; peptide mimetics; natural products in food
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Special Issue Information

Dear Colleagues,

The combination of an understanding of disease mechanisms, which is the base for the development of new drugs for their treatment, is a major challenge of medicinal chemistry. The strategy of chemotherapy relies on exploitation of the biochemical differences between the host and parasite cells. Drug discovery and development is a lengthy and costly inventive process of finding new medications based on the knowledge of these differences. The most effective means of this process is focused on identifying and optimizing drug candidates that act through inhibition of specific enzyme targets. These enzymes are blocking specific activity at the metabolic level. Thus, the impact of enzyme inhibitors in drug discovery has become a fundamental approach to pharmacology at any pharmaceutical industry.

The discovery of new and potent enzyme inhibitors and their further optimization constitutes a dynamic branch of biochemical and pharmacological research. They remain prime targets for drug design because drugs that function as enzyme inhibitors constitute a significant portion of the orally bioavailable therapeutic agents that are in use today.

The utility of an enzyme inhibitor as a medication depends on the potency of the inhibitor and its specificity toward its target enzyme. These properties, in turn, depend on the number and type of interactions between the inhibitor and the enzyme. Thus, the screening of low molecular weight compounds against new and old protein targets is a good starting point for the design of new drugs. Such a drug design process performed for a single enzyme target is usually facilitated by their three-dimensional structures, searches in huge chemical databases, and a wide variety of computer-aided techniques.

Prof. Dr. Paweł Kafarski
Guest Editor

Manuscript Submission Information

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Keywords

  • Structure-guided drug design
  • Computer-aided inhibitor design
  • Docking-based inhibitor design
  • QSAR driven inhibitor design
  • Machine-learning inhibitor design
  • Fragment-based lead generation
  • Inhibitors of enzyme different conformational states
  • Application of computational methods in synergy with experimental approach
  • Search for bi-substrate inhibitors
  • Design of covalent inhibitors
  • Protein–protein interaction inhibitors
  • Epigenetic drug discovery
  • Rational drug repurposing.

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Published Papers (11 papers)

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Research

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Open AccessArticle
Monosubstituted Acetophenone Thiosemicarbazones as Potent Inhibitors of Tyrosinase: Synthesis, Inhibitory Studies, and Molecular Docking
Pharmaceuticals 2021, 14(1), 74; https://doi.org/10.3390/ph14010074 (registering DOI) - 18 Jan 2021
Abstract
A set of 12 monosubstituted acetophenone thiosemicarbazone derivatives (TSCs) were synthesized and their inhibitory properties toward tyrosinase activity were tested. Moreover, their ability to inhibit melanogenesis in the B16F10 murine melanoma cell line was studied. In order to investigate the nature of interactions [...] Read more.
A set of 12 monosubstituted acetophenone thiosemicarbazone derivatives (TSCs) were synthesized and their inhibitory properties toward tyrosinase activity were tested. Moreover, their ability to inhibit melanogenesis in the B16F10 murine melanoma cell line was studied. In order to investigate the nature of interactions between the enzyme and the inhibitors, molecular docking to the active site was performed. TSCs 5, 6, 8, and 9 revealed a half maximal inhibitory concentration (IC50) below 1 µM. Compound 6 turned out to be the most potent tyrosinase inhibitor. All investigated compounds showed reversible inhibition of competitive or mixed type. The para-substituted TSCs had higher affinity for the enzyme as compared to their ortho- and meta-analogues. All investigated compounds inhibited melanin production in B16F10 cells at the micromolar level. Molecular docking showed that the sulfur atom of the thiourea moiety penetrates the active site and interacts with copper ions. The above outcomes might be helpful in the design of new tyrosinase inhibitors in the food and cosmetic industries. Full article
(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2020)
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Open AccessArticle
Repurposing the McoTI-II Rigid Molecular Scaffold in to Inhibitor of ‘Papain Superfamily’ Cysteine Proteases
Pharmaceuticals 2021, 14(1), 7; https://doi.org/10.3390/ph14010007 - 23 Dec 2020
Abstract
Clan C1A or ‘papain superfamily’ cysteine proteases are key players in many important physiological processes and diseases in most living systems. Novel approaches towards the development of their inhibitors can open new avenues in translational medicine. Here, we report a novel design of [...] Read more.
Clan C1A or ‘papain superfamily’ cysteine proteases are key players in many important physiological processes and diseases in most living systems. Novel approaches towards the development of their inhibitors can open new avenues in translational medicine. Here, we report a novel design of a re-engineered chimera inhibitor Mco-cysteine protease inhibitor (CPI) to inhibit the activity of C1A cysteine proteases. This was accomplished by grafting the cystatin first hairpin loop conserved motif (QVVAG) onto loop 1 of the ultrastable cyclic peptide scaffold McoTI-II. The recombinantly expressed Mco-CPI protein was able to bind with micromolar affinity to papain and showed remarkable thermostability owing to the formation of multi-disulphide bonds. Using an in silico approach based on homology modelling, protein–protein docking, the calculation of the free-energy of binding, the mechanism of inhibition of Mco-CPI against representative C1A cysteine proteases (papain and cathepsin L) was validated. Furthermore, molecular dynamics simulation of the Mco-CPI–papain complex validated the interaction as stable. To conclude, in this McoTI-II analogue, the specificity had been successfully redirected towards C1A cysteine proteases while retaining the moderate affinity. The outcomes of this study pave the way for further modifications of the Mco-CPI design for realizing its full potential in therapeutics. This study also demonstrates the relevance of ultrastable peptide-based scaffolds for the development of novel inhibitors via grafting. Full article
(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2020)
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Open AccessArticle
Novel Isoniazid-Carborane Hybrids Active In Vitro against Mycobacterium tuberculosis
Pharmaceuticals 2020, 13(12), 465; https://doi.org/10.3390/ph13120465 - 15 Dec 2020
Abstract
Tuberculosis (TB) is a severe infectious disease with high mortality and morbidity. The emergence of drug-resistant TB has increased the challenge to eliminate this disease. Isoniazid (INH) remains the key and effective component in the therapeutic regimen recommended by World Health Organization (WHO). [...] Read more.
Tuberculosis (TB) is a severe infectious disease with high mortality and morbidity. The emergence of drug-resistant TB has increased the challenge to eliminate this disease. Isoniazid (INH) remains the key and effective component in the therapeutic regimen recommended by World Health Organization (WHO). A series of isoniazid-carborane derivatives containing 1,2-dicarba-closo-dodecaborane, 1,7-dicarba-closo-dodecaborane, 1,12-dicarba-closo-dodecaborane, or 7,8-dicarba-nido-undecaborate anion were synthesized for the first time. The compounds were tested in vitro against the Mycobacterium tuberculosis (Mtb) H37Rv strain and its mutant (ΔkatG) defective in the synthesis of catalase-peroxidase (KatG). N′-((7,8-dicarba-nido-undecaboranyl)methylidene)isonicotinohydrazide (16) showed the highest activity against the wild-type Mtb strain. All hybrids could inhibit the growth of the ΔkatG mutant in lower concentrations than INH. N′-([(1,12-dicarba-closo-dodecaboran-1yl)ethyl)isonicotinohydrazide (25) exhibited more than 60-fold increase in activity against Mtb ΔkatG as compared to INH. This compound was also found to be noncytotoxic up to a concentration four times higher than the minimum inhibitory concentration 99% (MIC99) value. Full article
(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2020)
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Open AccessArticle
Potent Quinoline-Containing Combretastatin A-4 Analogues: Design, Synthesis, Antiproliferative, and Anti-Tubulin Activity
Pharmaceuticals 2020, 13(11), 393; https://doi.org/10.3390/ph13110393 - 15 Nov 2020
Abstract
A novel series of quinoline derivatives of combretastatin A-4 incorporating rigid hydrazone and a cyclic oxadiazole linkers were synthesized and have demonstrated potent tubulin polymerization inhibitory properties. Many of these novel derivatives have shown significant antiproliferative activities in the submicromolar range. The most [...] Read more.
A novel series of quinoline derivatives of combretastatin A-4 incorporating rigid hydrazone and a cyclic oxadiazole linkers were synthesized and have demonstrated potent tubulin polymerization inhibitory properties. Many of these novel derivatives have shown significant antiproliferative activities in the submicromolar range. The most potent compound, 19h, demonstrated superior IC50 values ranging from 0.02 to 0.04 µM against four cancer cell lines while maintaining low cytotoxicity in MCF-10A non-cancer cells, thereby suggesting 19h’s selectivity towards proliferating cancer cells. In addition to tubulin polymerization inhibition, 19h caused cell cycle arrest in MCF-7 cells at the G2/M phase and induced apoptosis. Collectively, these findings indicate that 19h holds potential for further investigation as a potent chemotherapeutic agent targeting tubulin. Full article
(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2020)
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Open AccessArticle
Synthesis, 3D-QSAR, and Molecular Modeling Studies of Triazole Bearing Compounds as a Promising Scaffold for Cyclooxygenase-2 Inhibition
Pharmaceuticals 2020, 13(11), 370; https://doi.org/10.3390/ph13110370 - 06 Nov 2020
Cited by 1
Abstract
Targeting of cyclooxygenase-2 (COX-2) has emerged as a powerful tool for therapeutic intervention because the overexpression of this enzyme is synonymous with inflammation, cancer, and neurodegenerative diseases. Herein, a new series of 1,2,4-triazole Schiff bases scaffold with aryl and heteroaryl systems 9a–12d were [...] Read more.
Targeting of cyclooxygenase-2 (COX-2) has emerged as a powerful tool for therapeutic intervention because the overexpression of this enzyme is synonymous with inflammation, cancer, and neurodegenerative diseases. Herein, a new series of 1,2,4-triazole Schiff bases scaffold with aryl and heteroaryl systems 9a–12d were designed, synthesized, structurally elucidated, and biologically evaluated as a potent COX-2 blocker. The rationale beyond the current study is to increase the molecule bulkiness allowing a selective binding to the unique hydrophobic pocket of COX-2. Among the triazole–thiazole hybrids, the one with the para-methoxy moiety linked to a phenyl ring 12d showed the highest In vitro selectivity by COX-2 inhibition assay (IC50 of 0.04 μM) and in situ anti-inflammatory activity when evaluated using the protein denaturation assay (IC50 of 0.88 μM) in comparison with commercially available selective COX-2 inhibitor, Celecoxib (IC50 of 0.05 μM). Towards the COX-2 selectivity, ligand-based three dimensional quantitative structures activity relationship (3D-QSAR) employing atomic-based and field-based approaches were performed and resulted in the necessity of triazole and thiazole/oxazole scaffolds for COX-2 blocking. Furthermore, the molecular modeling study indicated a high selectivity and promising affinity of our prepared compounds to COX-2, especially the hydrophobic pocket and the mouth of the active site holding hydrogen-bonding, hydrophobic, and electrostatic interactions. In Silico absorption, delivery, metabolism, and excretion (ADME) predictions showed that all the pharmacokinetic and physicochemical features are within the appropriate range for human use. Full article
(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2020)
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Open AccessArticle
A Proline-Based Tectons and Supramolecular Synthons for Drug Design 2.0: A Case Study of ACEI
Pharmaceuticals 2020, 13(11), 338; https://doi.org/10.3390/ph13110338 - 24 Oct 2020
Abstract
Proline is a unique, endogenous amino acid, prevalent in proteins and essential for living organisms. It is appreciated as a tecton for the rational design of new bio-active substances. Herein, we present a short overview of the subject. We analyzed 2366 proline-derived structures [...] Read more.
Proline is a unique, endogenous amino acid, prevalent in proteins and essential for living organisms. It is appreciated as a tecton for the rational design of new bio-active substances. Herein, we present a short overview of the subject. We analyzed 2366 proline-derived structures deposited in the Cambridge Structure Database, with emphasis on the angiotensin-converting enzyme inhibitors. The latter are the first-line antihypertensive and cardiological drugs. Their side effects prompt a search for improved pharmaceuticals. Characterization of tectons (molecular building blocks) and the resulting supramolecular synthons (patterns of intermolecular interactions) involving proline derivatives, as presented in this study, may be useful for in silico molecular docking and macromolecular modeling studies. The DFT, Hirshfeld surface and energy framework methods gave considerable insight into the nature of close inter-contacts and supramolecular topology. Substituents of proline entity are important for the formation and cooperation of synthons. Tectonic subunits contain proline moieties characterized by diverse ionization states: -N and -COOH(-COO), -N+ and -COOH(-COO), -NH and -COOH(-COO), -NH+ and -COOH(-COO), and -NH2+ and -COOH(-COO). Furthermore, pharmacological profiles of ACE inhibitors and their impurities were determined via an in silico approach. The above data were used to develop comprehensive classification, which may be useful in further drug design studies. Full article
(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2020)
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Open AccessArticle
Identification of New Rofecoxib-Based Cyclooxygenase-2 Inhibitors: A Bioinformatics Approach
Pharmaceuticals 2020, 13(9), 209; https://doi.org/10.3390/ph13090209 - 26 Aug 2020
Cited by 3
Abstract
The cyclooxygenase-2 receptor is a therapeutic target for planning potential drugs with anti-inflammatory activity. The selective cyclooxygenase-2 (COX-2) inhibitor rofecoxib was selected as a pivot molecule to perform virtual ligand-based screening from six commercial databases. We performed the search for similarly shaped Rapid [...] Read more.
The cyclooxygenase-2 receptor is a therapeutic target for planning potential drugs with anti-inflammatory activity. The selective cyclooxygenase-2 (COX-2) inhibitor rofecoxib was selected as a pivot molecule to perform virtual ligand-based screening from six commercial databases. We performed the search for similarly shaped Rapid Overlay of Chemical Structures (ROCS) and electrostatic (EON) compounds. After, we used pharmacokinetic and toxicological parameters to determine the best potential compounds, obtained through the softwares QikProp and Derek, respectively. Then, the compounds proceeded to the molecular anchorage study, which showed promising results of binding affinity with the hCOX-2 receptor: LMQC72 (∆G = −11.0 kcal/mol), LMQC36 (∆G = −10.6 kcal/mol), and LMQC50 (∆G = −10.2 kcal/mol). LMQC72 and LMQC36 showed higher binding affinity compared to rofecoxib (∆G = −10.4 kcal/mol). Finally, molecular dynamics (MD) simulations were used to evaluate the interaction of the compounds with the target hCOX-2 during 150 ns. In all MD simulation trajectories, the ligands remained interacting with the protein until the end of the simulation. The compounds were also complexing with hCOX-2 favorably. The compounds obtained the following affinity energy values: rofecoxib: ΔGbind = −45.31 kcal/mol; LMQC72: ΔGbind = −38.58 kcal/mol; LMQC36: ΔGbind = −36.10 kcal/mol; and LMQC50: ΔGbind = −39.40 kcal/mol. The selected LMQC72, LMQC50, and LMQC36 structures showed satisfactory pharmacokinetic results related to absorption and distribution. The toxicological predictions of these compounds did not display alerts for possible toxic groups and lower risk of cardiotoxicity compared to rofecoxib. Therefore, future in vitro and in vivo studies are needed to confirm the anti-inflammatory potential of the compounds selected here with bioinformatics approaches based on rofecoxib ligand. Full article
(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2020)
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Open AccessArticle
Design and Development of Novel Urea, Sulfonyltriurea, and Sulfonamide Derivatives as Potential Inhibitors of Sphingosine Kinase 1
Pharmaceuticals 2020, 13(6), 118; https://doi.org/10.3390/ph13060118 - 09 Jun 2020
Cited by 1
Abstract
Sphingosine kinase 1 (SphK1) is one of the well-studied drug targets for cancer and inflammatory diseases. Recently discovered small-molecule inhibitors of SphK1 have been recommended in cancer therapeutics; however, selectivity and potency of first-generation inhibitors are great challenge. In search of effective SphK1 [...] Read more.
Sphingosine kinase 1 (SphK1) is one of the well-studied drug targets for cancer and inflammatory diseases. Recently discovered small-molecule inhibitors of SphK1 have been recommended in cancer therapeutics; however, selectivity and potency of first-generation inhibitors are great challenge. In search of effective SphK1 inhibitors, a set of small molecules have been designed and synthesized bearing urea, sulfonylurea, sulfonamide, and sulfonyltriurea groups. The binding affinity of these inhibitors was measured by fluorescence-binding assay and isothermal titration calorimetry. Compounds 1, 5, 6, and 7 showed an admirable binding affinity to the SphK1 in the sub-micromolar range and significantly inhibited SphK1 activity with admirable IC50 values. Molecular docking studies revealed that these compounds fit well into the sphingosine binding pocket of SphK1 and formed significant number of hydrogen bonds and van der Waals interactions. These molecules may be exploited as potent and selective inhibitors of SphK1 that could be implicated in cancer therapeutics after the required in vivo validation. Full article
(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2020)
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Review

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Open AccessReview
Bowman-Birk Inhibitors: Insights into Family of Multifunctional Proteins and Peptides with Potential Therapeutical Applications
Pharmaceuticals 2020, 13(12), 421; https://doi.org/10.3390/ph13120421 - 25 Nov 2020
Abstract
Bowman-Birk inhibitors (BBIs) are found primarily in seeds of legumes and in cereal grains. These canonical inhibitors share a highly conserved nine-amino acids binding loop motif CTP1SXPPXC (where P1 is the inhibitory active site, while X stands for various amino acids). They are [...] Read more.
Bowman-Birk inhibitors (BBIs) are found primarily in seeds of legumes and in cereal grains. These canonical inhibitors share a highly conserved nine-amino acids binding loop motif CTP1SXPPXC (where P1 is the inhibitory active site, while X stands for various amino acids). They are natural controllers of plants’ endogenous proteases, but they are also inhibitors of exogenous proteases present in microbials and insects. They are considered as plants’ protective agents, as their elevated levels are observed during injury, presence of pathogens, or abiotic stress, i.a. Similar properties are observed for peptides isolated from amphibians’ skin containing 11-amino acids disulfide-bridged loop CWTP1SXPPXPC. They are classified as Bowman-Birk like trypsin inhibitors (BBLTIs). These inhibitors are resistant to proteolysis and not toxic, and they are reported to be beneficial in the treatment of various pathological states. In this review, we summarize up-to-date research results regarding BBIs’ and BBLTIs’ inhibitory activity, immunomodulatory and anti-inflammatory activity, antimicrobial and insecticidal strength, as well as chemopreventive properties. Full article
(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2020)
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Open AccessReview
Papain-Like Proteases as Coronaviral Drug Targets: Current Inhibitors, Opportunities, and Limitations
Pharmaceuticals 2020, 13(10), 277; https://doi.org/10.3390/ph13100277 - 28 Sep 2020
Cited by 2
Abstract
Papain-like proteases (PLpro) of coronaviruses (CoVs) support viral reproduction and suppress the immune response of the host, which makes CoV PLpro perspective pharmaceutical targets. Their inhibition could both prevent viral replication and boost the immune system of the host, leading to the speedy [...] Read more.
Papain-like proteases (PLpro) of coronaviruses (CoVs) support viral reproduction and suppress the immune response of the host, which makes CoV PLpro perspective pharmaceutical targets. Their inhibition could both prevent viral replication and boost the immune system of the host, leading to the speedy recovery of the patient. Coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the third CoV outbreak in the last 20 years. Frequent mutations of the viral genome likely lead to the emergence of more CoVs. Inhibitors for CoV PLpro can be broad-spectrum and can diminish present and prevent future CoV outbreaks as PLpro from different CoVs have conservative structures. Several inhibitors have been developed to withstand SARS-CoV and Middle East respiratory syndrome CoV (MERS-CoV). This review summarizes the structural features of CoV PLpro, the inhibitors that have been identified over the last 20 years, and the compounds that have the potential to become novel effective therapeutics against CoVs in the near future. Full article
(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2020)
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Open AccessReview
Novel 1,2,4-Oxadiazole Derivatives in Drug Discovery
Pharmaceuticals 2020, 13(6), 111; https://doi.org/10.3390/ph13060111 - 29 May 2020
Cited by 4
Abstract
Five-membered 1,2,4-oxadiazole heterocyclic ring has received considerable attention because of its unique bioisosteric properties and an unusually wide spectrum of biological activities. Thus, it is a perfect framework for the novel drug development. After a century since the 1,2,4-oxadiazole have been discovered, the [...] Read more.
Five-membered 1,2,4-oxadiazole heterocyclic ring has received considerable attention because of its unique bioisosteric properties and an unusually wide spectrum of biological activities. Thus, it is a perfect framework for the novel drug development. After a century since the 1,2,4-oxadiazole have been discovered, the uncommon potential attracted medicinal chemists’ attention, leading to the discovery of a few presently accessible drugs containing 1,2,4-oxadiazole unit. It is worth noting that the interest in a 1,2,4-oxadiazoles’ biological application has been doubled in the last fifteen years. Herein, after a concise historical introduction, we present a comprehensive overview of the recent achievements in the synthesis of 1,2,4-oxadiazole-based compounds and the major advances in their biological applications in the period of the last five years as well as brief remarks on prospects for further development. Full article
(This article belongs to the Special Issue Design of Enzyme Inhibitors as Potential Drugs 2020)
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