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Multitarget Ligands in Drug Discovery
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Multitarget Ligands 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 2023) | Viewed by 17014

Special Issue Editor

Prof. Dr. Xingshu Li

E-Mail Website
Guest Editor
School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, China
Interests: multi target drugs; Alzheimer’s disease; cancers; tumor microenvironment; drug synthesis

Special Issue Information

Dear Colleagues,

Although single target drugs have shown significant clinical efficacy, most human diseases are not caused by a single gene or target. Some diseases that is harmful to human health, such as cardiovascular and cerebrovascular diseases, diabetes, malignant tumors, Alzheimer's disease, etc., have complex pathogenesis, and most of which are related to multiple genes, and cannot be effectively controlled or cured by using single target drugs. In clinical practice, the combination of single molecular target drugs has been widely used. Multi target drugs have the advantages of combination of single molecular target drugs. They can act on multiple disease-related targets, produce multiple pharmacological activities, and obtain the required diverse biological regulatory functions. At the same time, they can reduce the possible side effects of combination of single target drugs, and achieve the goal of improving the efficacy and safety.

For multi-target ligands in drug discovery, it is important to balance the activity, selectivity and the pharmacokinetic properties, and is still a challenge for pharmaceutical chemists. In order to provide a platform for readers and scientists interested in this research, we planned this special issue. It is my pleasure to invite our colleagues to submit original research manuscripts within the scope of this Special Issue. Short communication and reviews will also be greatly appreciated.

Prof. Dr. Xingshu Li
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.

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Keywords

  • multitarget ligands
  • drug discovery and evaluation
  • cancers
  • Alzheimer’s disease
  • cardiovascular and cerebrovascular diseases
  • diabetes

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Published Papers (7 papers)

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Research

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18 pages, 4891 KiB  
Article
Screening of Multitarget Compounds against Acetaminophen Hepatic Toxicity Using In Silico, In Vitro, and In Vivo Approaches
by Muhammad Ali, Esha Asghar, Waqas Ali, Ghulam Mustafa, Irfan Aamer Ansari, Saadiya Zia, Siddique Akber Ansari and Sumaiya Khan
Molecules 2024, 29(2), 428; https://doi.org/10.3390/molecules29020428 - 16 Jan 2024
Viewed by 1833
Abstract
Combination therapy and multitarget drugs have recently attracted much attention as promising tools to fight against many challenging diseases and, thus, represent a new research focus area. The aim of the current project was to screen multitarget compounds and to study their individual [...] Read more.
Combination therapy and multitarget drugs have recently attracted much attention as promising tools to fight against many challenging diseases and, thus, represent a new research focus area. The aim of the current project was to screen multitarget compounds and to study their individual and combined effects on acetaminophen-induced liver injury. In this study, 2 of the best hepatoprotective multitargeting compounds were selected from a pool of 40 major compounds present in Curcuma longa and Cinnamomum zeylanicum by using molecular docking, ADMET profiling, and Pfizer’s rule of five. The two selected compounds, quercetin and curcumin, showed a high binding affinity for the CYP2E1 enzyme, MAPK, and TLR4 receptors that contribute to liver injury. The candidates caused the decreased viability of cancer cell lines (HepG2 and Huh7) but showed no effect on a normal cell line (Vero). Examination of biochemical parameters (ALT, AST, ALP, and bilirubin) showed the hepatoprotective effect of the candidate drugs in comparison with the control group, which was confirmed by histological findings. Taken together, quercetin and curcumin not only satisfied the drug-like assessment criterion and proved to be multitargeting by preventing liver damage but also showed anticancer activities. Full article
(This article belongs to the Special Issue Multitarget Ligands in Drug Discovery)
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14 pages, 8503 KiB  
Article
In Vitro Evaluation and Bioinformatics Analysis of Schiff Bases Bearing Pyrazole Scaffold as Bioactive Agents: Antioxidant, Anti-Diabetic, Anti-Alzheimer, and Anti-Arthritic
by Hamad M. Alkahtani, Abdulrahman A. Almehizia, Mohamed A. Al-Omar, Ahmad J. Obaidullah, Amer A. Zen, Ashraf S. Hassan and Wael M. Aboulthana
Molecules 2023, 28(20), 7125; https://doi.org/10.3390/molecules28207125 - 17 Oct 2023
Cited by 17 | Viewed by 1965
Abstract
In continuation of our research programs for the discovery, production, and development of the pharmacological activities of molecules for various disease treatments, Schiff bases and pyrazole scaffold have a broad spectrum of activities in biological applications. In this context, this manuscript aims to [...] Read more.
In continuation of our research programs for the discovery, production, and development of the pharmacological activities of molecules for various disease treatments, Schiff bases and pyrazole scaffold have a broad spectrum of activities in biological applications. In this context, this manuscript aims to evaluate and study Schiff base–pyrazole molecules as a new class of antioxidant (total antioxidant capacity, iron-reducing power, scavenging activity against DPPH, and ABTS radicals), anti-diabetic (α-amylase% inhibition), anti-Alzheimer’s (acetylcholinesterase% inhibition), and anti-arthritic (protein denaturation% and proteinase enzyme% inhibitions) therapeutics. Therefore, the Schiff bases bearing pyrazole scaffold (22a, b and 23a, b) were designed and synthesized for evaluation of their antioxidant, anti-diabetic, anti-Alzheimer’s, and anti-arthritic properties. The results for compound 22b demonstrated significant antioxidant, anti-diabetic (α-amylase% inhibition), and anti-Alzheimer’s (ACE%) activities, while compound 23a demonstrated significant anti-arthritic activity. Prediction of in silico bioinformatics analysis (physicochemical properties, bioavailability radar, drug-likeness, and medicinal chemistry) of the target derivatives (22a, b and 23a, b) was performed. The molecular lipophilicity potential (MLP) of the derivatives 22a, b and 23a, b was measured to determine which parts of the surface are hydrophobic and which are hydrophilic. In addition, the molecular polar surface area (PSA) was measured to determine the polar surface area and the non-polar surface area of the derivatives 22a, b and 23a, b. This study could be useful to help pharmaceutical researchers discover a new series of potent agents that may act as an antioxidant, anti-diabetic, anti-Alzheimer, and anti-arthritic. Full article
(This article belongs to the Special Issue Multitarget Ligands in Drug Discovery)
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16 pages, 2741 KiB  
Article
Novel Dual-Target Kinase Inhibitors of EGFR and ALK Were Designed, Synthesized, and Induced Cell Apoptosis in Non-Small Cell Lung Cancer
by Yangyang Fan, Wei Li, Wenyan Nie, Han Yao, Yuanyuan Ren, Mengxuan Wang, Haoran Nie, Chenxi Gu, Jiadai Liu and Baijiao An
Molecules 2023, 28(5), 2006; https://doi.org/10.3390/molecules28052006 - 21 Feb 2023
Cited by 2 | Viewed by 2203
Abstract
ALK-positive NSCLC coexisting with EGFR mutations is a frequently occurring clinical phenomenon. Targeting ALK and EGFR simultaneously may be an effective way to treat these cancer patients. In this study, we designed and synthesized ten new dual-target EGFR/ALK inhibitors. Among them, the optimal [...] Read more.
ALK-positive NSCLC coexisting with EGFR mutations is a frequently occurring clinical phenomenon. Targeting ALK and EGFR simultaneously may be an effective way to treat these cancer patients. In this study, we designed and synthesized ten new dual-target EGFR/ALK inhibitors. Among them, the optimal compound 9j exhibited good activity with IC50 values of 0.07829 ± 0.03 μM and 0.08183 ± 0.02 μM against H1975 (EGFR T790M/L858R) and H2228 (EML4-ALK) cells, respectively. Immunofluorescence assays indicated that the compound could simultaneously inhibit the expression of phosphorylated EGFR and ALK proteins. A kinase assay demonstrated that compound 9j could inhibit both EGFR and ALK kinases; thus, exerting an antitumor effect. Additionally, compound 9j induced apoptosis in a dose-dependent manner and inhibited the invasion and migration of tumor cells. All of these results indicate that 9j is worthy of further study. Full article
(This article belongs to the Special Issue Multitarget Ligands in Drug Discovery)
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15 pages, 3804 KiB  
Article
Design, Synthesis and Antitumor Activity of Novel Selenium-Containing Tepotinib Derivatives as Dual Inhibitors of c-Met and TrxR
by Jinhui Hu, Li Chen, Zhonghui Lu, Han Yao, Yunfei Hu, Luanqi Feng, Yanqing Pang, Jia-Qiang Wu, Zhiling Yu and Wen-Hua Chen
Molecules 2023, 28(3), 1304; https://doi.org/10.3390/molecules28031304 - 30 Jan 2023
Cited by 7 | Viewed by 2499
Abstract
Cellular mesenchymal–epithelial transition factor (c-Met), an oncogenic transmembrane receptor tyrosine kinase (RTK), plays an essential role in cell proliferation during embryo development and liver regeneration. Thioredoxin reductase (TrxR) is overexpressed and constitutively active in most tumors closely related to cancer recurrence. Multi-target-directed ligands [...] Read more.
Cellular mesenchymal–epithelial transition factor (c-Met), an oncogenic transmembrane receptor tyrosine kinase (RTK), plays an essential role in cell proliferation during embryo development and liver regeneration. Thioredoxin reductase (TrxR) is overexpressed and constitutively active in most tumors closely related to cancer recurrence. Multi-target-directed ligands (MTDLs) strategy provides a logical approach to drug combinations and would adequately address the pathological complexity of cancer. In this work, we designed and synthesized a series of selenium-containing tepotinib derivatives by means of selenium-based bioisosteric modifications and evaluated their antiproliferative activity. Most of these selenium-containing hybrids exhibited potent dual inhibitory activity toward c-Met and TrxR. Among them, compound 8b was the most active, with an IC50 value of 10 nM against MHCC97H cells. Studies on the mechanism of action revealed that compound 8b triggered cell cycle arrest at the G1 phase and caused ROS accumulations by targeting TrxR, and these effects eventually led to cell apoptosis. These findings strongly suggest that compound 8b serves as a dual inhibitor of c-Met and TrxR, warranting further exploitation for cancer therapy. Full article
(This article belongs to the Special Issue Multitarget Ligands in Drug Discovery)
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12 pages, 2398 KiB  
Article
Explaining Accurate Predictions of Multitarget Compounds with Machine Learning Models Derived for Individual Targets
by Alec Lamens and Jürgen Bajorath
Molecules 2023, 28(2), 825; https://doi.org/10.3390/molecules28020825 - 13 Jan 2023
Cited by 5 | Viewed by 1723
Abstract
In drug discovery, compounds with well-defined activity against multiple targets (multitarget compounds, MT-CPDs) provide the basis for polypharmacology and are thus of high interest. Typically, MT-CPDs for polypharmacology have been discovered serendipitously. Therefore, over the past decade, computational approaches have also been adapted [...] Read more.
In drug discovery, compounds with well-defined activity against multiple targets (multitarget compounds, MT-CPDs) provide the basis for polypharmacology and are thus of high interest. Typically, MT-CPDs for polypharmacology have been discovered serendipitously. Therefore, over the past decade, computational approaches have also been adapted for the design of MT-CPDs or their identification via computational screening. Such approaches continue to be under development and are far from being routine. Recently, different machine learning (ML) models have been derived to distinguish between MT-CPDs and corresponding compounds with activity against the individual targets (single-target compounds, ST-CPDs). When evaluating alternative models for predicting MT-CPDs, we discovered that MT-CPDs could also be accurately predicted with models derived for corresponding ST-CPDs; this was an unexpected finding that we further investigated using explainable ML. The analysis revealed that accurate predictions of ST-CPDs were determined by subsets of structural features of MT-CPDs required for their prediction. These findings provided a chemically intuitive rationale for the successful prediction of MT-CPDs using different ML models and uncovered general-feature subset relationships between MT- and ST-CPDs with activities against different targets. Full article
(This article belongs to the Special Issue Multitarget Ligands in Drug Discovery)
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15 pages, 1342 KiB  
Article
Biginelli Reaction Synthesis of Novel Multitarget-Directed Ligands with Ca2+ Channel Blocking Ability, Cholinesterase Inhibition, Antioxidant Capacity, and Nrf2 Activation
by Rim Malek, Alexey Simakov, Audrey Davis, Maciej Maj, Paul J. Bernard, Artur Wnorowski, Helene Martin, José Marco-Contelles, Fakher Chabchoub, Patrick Dallemagne, Christophe Rochais, Krzysztof Jozwiak and Lhassane Ismaili
Molecules 2023, 28(1), 71; https://doi.org/10.3390/molecules28010071 - 22 Dec 2022
Cited by 6 | Viewed by 2254
Abstract
Novel multitarget-directed ligands BIGI 4a-d and BIGI 5a-d were designed and synthesized with a simple and cost-efficient procedure via a one-pot three-component Biginelli reaction targeting acetyl-/butyrylcholinesterases inhibition, calcium channel antagonism, and antioxidant ability. Among these multitarget-directed ligands, BIGI 4b, BIGI 4d, and BIGI [...] Read more.
Novel multitarget-directed ligands BIGI 4a-d and BIGI 5a-d were designed and synthesized with a simple and cost-efficient procedure via a one-pot three-component Biginelli reaction targeting acetyl-/butyrylcholinesterases inhibition, calcium channel antagonism, and antioxidant ability. Among these multitarget-directed ligands, BIGI 4b, BIGI 4d, and BIGI 5b were identified as promising new hit compounds showing in vitro balanced activities toward the recognized AD targets. In addition, these compounds showed suitable physicochemical properties and a good druglikeness score predicted by Data Warrior software. Full article
(This article belongs to the Special Issue Multitarget Ligands in Drug Discovery)
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Review

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22 pages, 5590 KiB  
Review
The Use of Zidovudine Pharmacophore in Multi-Target-Directed Ligands for AIDS Therapy
by Maria da Conceição Avelino Dias Bianco, Debora Inacio Leite, Frederico Silva Castelo Branco, Nubia Boechat, Elisa Uliassi, Maria Laura Bolognesi and Monica Macedo Bastos
Molecules 2022, 27(23), 8502; https://doi.org/10.3390/molecules27238502 - 3 Dec 2022
Cited by 7 | Viewed by 3679
Abstract
The concept of polypharmacology embraces multiple drugs combined in a therapeutic regimen (drug combination or cocktail), fixed dose combinations (FDCs), and a single drug that binds to different targets (multi-target drug). A polypharmacology approach is widely applied in the treatment of acquired immunodeficiency [...] Read more.
The concept of polypharmacology embraces multiple drugs combined in a therapeutic regimen (drug combination or cocktail), fixed dose combinations (FDCs), and a single drug that binds to different targets (multi-target drug). A polypharmacology approach is widely applied in the treatment of acquired immunodeficiency syndrome (AIDS), providing life-saving therapies for millions of people living with HIV. Despite the success in viral load suppression and patient survival of combined antiretroviral therapy (cART), the development of new drugs has become imperative, owing to the emergence of resistant strains and poor adherence to cART. 3′-azido-2′,3′-dideoxythymidine, also known as azidothymidine or zidovudine (AZT), is a widely applied starting scaffold in the search for new compounds, due to its good antiretroviral activity. Through the medicinal chemistry tool of molecular hybridization, AZT has been included in the structure of several compounds allowing for the development of multi-target-directed ligands (MTDLs) as antiretrovirals. This review aims to systematically explore and critically discuss AZT-based compounds as potential MTDLs for the treatment of AIDS. The review findings allowed us to conclude that: (i) AZT hybrids are still worth exploring, as they may provide highly active compounds targeting different steps of the HIV-1 replication cycle; (ii) AZT is a good starting point for the preparation of co-drugs with enhanced cell permeability. Full article
(This article belongs to the Special Issue Multitarget Ligands in Drug Discovery)
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