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Recent Advances on Multi-Target Directed Ligands
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Recent Advances on Multi-Target Directed Ligands

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: 20 December 2024 | Viewed by 3629

Special Issue Editor

Dr. Alessio Nocentini

E-Mail Website
Guest Editor
Pharmaceutical and Nutraceutical Section, Laboratory of Molecular Modeling Cheminformatics & QSA, Neurofarba Department, University of Florence, Via U. Schiff 6, Sesto Fiorentino, 50019 Florence, Italy
Interests: drug design; organic chemistry; molecular modelling; enzymology; metalloenzymes; carbonic anhydrases; GPCR; enzyme modulators; anticancer; antiinfectives; anti-inflammatory; anti-Alzheimer; multi-target directed ligands; spectroscopic studies; structure-based design; molecular dynamics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Single-target drugs generally fail to achieve an adequate therapeutic outcome when used to treat multifactorial diseases. Drug combination therapies simultaneously modulating multiple targets demonstrated an enhanced therapeutic efficacy for the treatment of complex disorders, including tumors and neurodegenerative diseases. As a natural evolution of combined therapies, the interest in multi-target-directed ligands (MTDLs) has recently spread in the medicinal chemistry field. An MTDL acts as a unique molecular entity capable of concomitantly modulating the activity of more biological targets implicated in a disease. As such, MTLDs show improved pharmacokinetics, reaching the target tissue/organ as a single molecular entity, avoiding drug–drug interactions, and producing an overall greater synergistic effect compared to the simultaneous administration of multiple drugs. MTDLs may thus require lower doses, potentially reducing side effects and overcoming tolerance to single drugs. In this Special Issue, the Editors would like to encourage researchers investigating different research fields to submit their original or review articles with a focus on MTDLs and related design approaches, which have been studied to date in the treatment of diseases such as cancer, hyperlipidemia, HIV, hypertension, cardiovascular disease, pain, inflammation depression, infectious and neurodegenerative diseases, among others.

Dr. Alessio Nocentini
Guest Editor

Manuscript Submission Information

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Keywords

  • multi-target-directed ligands
  • drug discovery
  • drug design
  • synthesis
  • biological activity
  • polypharmacology
  • molecular modelling
  • cancer
  • neurodegenerative diseases
  • inflammation

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Published Papers (3 papers)

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Research

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17 pages, 2960 KiB  
Article
Hydrogen Sulfide-Releasing Carbonic Anhydrase Inhibitors Effectively Suppress Cancer Cell Growth
by Alessandro Bonardi, Alessio Nocentini, Viviana de Luca, Clemente Capasso, Eslam B. Elkaeed, Wagdy M. Eldehna and Claudiu T. Supuran
Int. J. Mol. Sci. 2024, 25(18), 10006; https://doi.org/10.3390/ijms251810006 - 17 Sep 2024
Viewed by 589
Abstract
This study proposes a novel therapeutic strategy for cancer management by combining the antitumor effects of hydrogen sulfide (H2S) and inhibition of carbonic anhydrases (CAs; EC 4.2.1.1), specifically isoforms IV, IX, and XII. H2S has demonstrated cytotoxicity against various [...] Read more.
This study proposes a novel therapeutic strategy for cancer management by combining the antitumor effects of hydrogen sulfide (H2S) and inhibition of carbonic anhydrases (CAs; EC 4.2.1.1), specifically isoforms IV, IX, and XII. H2S has demonstrated cytotoxicity against various cancers at high concentrations. The inhibition of tumor-associated CAs leads to lethal intracellular alkalinization and acidification of the extracellular tumor microenvironment and restores tumor responsiveness to the immune system, chemotherapy, and radiotherapy. The study proposes H2S donor–CA inhibitor (CAI) hybrids for tumor management. These compounds effectively inhibit the target CAs, release H2S consistently, and exhibit potent antitumor effects against MDA-MB-231, HCT-116, and A549 cancer cell lines. Notably, some compounds display high cytotoxicity across all investigated cell lines. Derivative 30 shows a 2-fold increase in cytotoxicity (0.93 ± 0.02 µM) under chemically induced hypoxia in HCT-116 cells. These compounds also disturb the cell cycle, leading to a reduction in cell populations in G0/G1 and S phases, with a notable increase in G2/M and Sub-G1. This disruption is correlated with induced apoptosis, with fold increases of 37.2, 24.5, and 32.9 against HCT-116 cells and 14.2, 13.1, and 19.9 against A549 cells compared to untreated cells. These findings suggest the potential of H2S releaser–CAI hybrids as effective and versatile tools in cancer treatment. Full article
(This article belongs to the Special Issue Recent Advances on Multi-Target Directed Ligands)
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13 pages, 2304 KiB  
Article
The Interactive Complex between Cytomegalovirus Kinase vCDK/pUL97 and Host Factors CDK7–Cyclin H Determines Individual Patterns of Transcription in Infected Cells
by Martin Schütz, Arne Cordsmeier, Christina Wangen, Anselm H. C. Horn, Emanuel Wyler, Armin Ensser, Heinrich Sticht and Manfred Marschall
Int. J. Mol. Sci. 2023, 24(24), 17421; https://doi.org/10.3390/ijms242417421 - 13 Dec 2023
Cited by 2 | Viewed by 1126
Abstract
The infection of human cytomegalovirus (HCMV) is strongly determined by the host–cell interaction in a way that the efficiency of HCMV lytic replication is dependent on the regulatory interplay between viral and cellular proteins. In particular, the activities of protein kinases, such as [...] Read more.
The infection of human cytomegalovirus (HCMV) is strongly determined by the host–cell interaction in a way that the efficiency of HCMV lytic replication is dependent on the regulatory interplay between viral and cellular proteins. In particular, the activities of protein kinases, such as cyclin-dependent kinases (CDKs) and the viral CDK ortholog (vCDK/pUL97), play an important role in both viral reproduction and virus–host interaction. Very recently, we reported on the complexes formed between vCDK/pUL97, human cyclin H, and CDK7. Major hallmarks of this interplay are the interaction between cyclin H and vCDK/pUL97, which is consistently detectable across various conditions and host cell types of infection, the decrease or increase in pUL97 kinase activity resulting from cyclin H knock-down or elevated levels, respectively, and significant trans-stimulation of human CDK7 activity by pUL97 in vitro. Due to the fact that even a ternary complex of vCDK/pUL97–cyclin H–CDK7 can be detected by coimmunoprecipitation and visualized by bioinformatic structural modeling, we postulated a putative impact of the respective kinase activities on the patterns of transcription in HCMV-infected cells. Here, we undertook a first vCDK/pUL97-specific transcriptomic analysis, which combined conditions of fully lytic HCMV replication with those under specific vCDK/pUL97 or CDK7 drug-mediated inhibition or transient cyclin H knockout. The novel results were further strengthened using bioinformatic modeling of the involved multi-protein complexes. Our data underline the importance of these kinase activities for the C-terminal domain (CTD) phosphorylation-driven activation of host RNA polymerase in HCMV-infected cells. The impact of the individual experimental conditions on differentially expressed gene profiles is described in detail and discussed. Full article
(This article belongs to the Special Issue Recent Advances on Multi-Target Directed Ligands)
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Review

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24 pages, 6492 KiB  
Review
‘Getting Better’—Is It a Feasible Strategy of Broad Pan-Antiherpesviral Drug Targeting by Using the Nuclear Egress-Directed Mechanism?
by Julia Tillmanns, Jintawee Kicuntod, Josephine Lösing and Manfred Marschall
Int. J. Mol. Sci. 2024, 25(5), 2823; https://doi.org/10.3390/ijms25052823 - 29 Feb 2024
Viewed by 1113
Abstract
The herpesviral nuclear egress represents an essential step of viral replication efficiency in host cells, as it defines the nucleocytoplasmic release of viral capsids. Due to the size limitation of the nuclear pores, viral nuclear capsids are unable to traverse the nuclear envelope [...] Read more.
The herpesviral nuclear egress represents an essential step of viral replication efficiency in host cells, as it defines the nucleocytoplasmic release of viral capsids. Due to the size limitation of the nuclear pores, viral nuclear capsids are unable to traverse the nuclear envelope without a destabilization of this natural host-specific barrier. To this end, herpesviruses evolved the regulatory nuclear egress complex (NEC), composed of a heterodimer unit of two conserved viral NEC proteins (core NEC) and a large-size extension of this complex including various viral and cellular NEC-associated proteins (multicomponent NEC). Notably, the NEC harbors the pronounced ability to oligomerize (core NEC hexamers and lattices), to multimerize into higher-order complexes, and, ultimately, to closely interact with the migrating nuclear capsids. Moreover, most, if not all, of these NEC proteins comprise regulatory modifications by phosphorylation, so that the responsible kinases, and additional enzymatic activities, are part of the multicomponent NEC. This sophisticated basis of NEC-specific structural and functional interactions offers a variety of different modes of antiviral interference by pharmacological or nonconventional inhibitors. Since the multifaceted combination of NEC activities represents a highly conserved key regulatory stage of herpesviral replication, it may provide a unique opportunity towards a broad, pan-antiherpesviral mechanism of drug targeting. This review presents an update on chances, challenges, and current achievements in the development of NEC-directed antiherpesviral strategies. Full article
(This article belongs to the Special Issue Recent Advances on Multi-Target Directed Ligands)
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