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Small-Molecule Drug Design and Discovery
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Small-Molecule Drug Design and Discovery

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

Deadline for manuscript submissions: 31 July 2026 | Viewed by 7511

Special Issue Editor

Dr. Qiuqin He

E-Mail Website
Guest Editor
Department of Chemistry, Fudan University, Shanghai, China
Interests: drug design; small-molecule drugs; methodologies for synthetic drugs
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Small-molecule drug design involves creating novel chemical drugs that may achieve therapeutic effects based on the chemical structures of biological targets, utilizing the chemical structures, electrical charges, shapes, and other characteristics of organic small molecules. This process typically encompasses multiple steps, including target selection, molecular design, synthesis, and biological evaluation. The methods for small-molecule drug design are numerous, encompassing structure-based drug design, fragment-based drug discovery, and more contemporary advancements like PROTAC technology, molecular glue methodologies, and artificial intelligence technology. Through persistent exploration and groundbreaking innovations, we anticipate the emergence of numerous small-molecule drugs, thereby significantly enhancing our contributions to the advancement of human health.

Dr. Qiuqin He
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 250 words) can be sent to the Editorial Office for assessment.

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

  • small-molecule drug design
  • structure-based drug design
  • fragment-based drug discovery
  • PROTAC technology
  • artificial intelligence technology
  • biological evaluation

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Published Papers (5 papers)

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Research

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18 pages, 2846 KB  
Article
Design, Synthesis and Anticancer Activity of 6-Substituted-1-(3,4,5-trimethoxyphenyl)-1H-indole Against Tubulin Polymerisation
by Yuanna Gu, Conghao Gai, Sijie Zou, Yan Song, Juan Zhang, Qingjie Zhao, Xiaoyun Chai and Peipei Wang
Molecules 2025, 30(23), 4538; https://doi.org/10.3390/molecules30234538 - 24 Nov 2025
Viewed by 605
Abstract
Using virtual FragLites screening and a fragment-based drug discovery (FBDD) strategy, we designed and synthesized a series of 6-substituted-1-(3,4,5-trimethoxyphe-nyl)-1H-indole derivatives as potential tubulin polymerization inhibitors. Among them, compound 3g exhibited the best antiproliferative activity within this series and affected microtubule dynamics [...] Read more.
Using virtual FragLites screening and a fragment-based drug discovery (FBDD) strategy, we designed and synthesized a series of 6-substituted-1-(3,4,5-trimethoxyphe-nyl)-1H-indole derivatives as potential tubulin polymerization inhibitors. Among them, compound 3g exhibited the best antiproliferative activity within this series and affected microtubule dynamics in a concentration-dependent manner. Further studies indicated that 3g induced G2/M cell-cycle arrest and triggered apoptosis in MCF-7 cells. In vivo, 3g achieved tumor growth inhibition rates of 23.3% and 44.2% at 20 mg/kg and 50 mg/kg, respectively, without evident systemic toxicity. These results suggest that 3g shows preliminary antitumor efficacy and may serve as a starting point for further mechanistic and structural studies. Further optimization and detailed pharmacokinetic and toxicity studies are merited to advance these inhibitors in preclinical development. Full article
(This article belongs to the Special Issue Small-Molecule Drug Design and Discovery)
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21 pages, 4111 KB  
Article
Structural and Computational Insights into Transketolase-like 1 (TKTL-1): Distinction from TKT and Implications for Cancer Metabolism and Therapeutic Targeting
by Ahmad Junaid, Caleb J. Nwaogwugwu and Sameh H. Abdelwahed
Molecules 2025, 30(19), 3905; https://doi.org/10.3390/molecules30193905 - 27 Sep 2025
Viewed by 1135
Abstract
Transketolase-like protein 1 (TKTL-1) has been implicated in altered cancer metabolism, yet its structure and molecular function remain poorly understood. In this study, we established a homology model of TKTL-1 using multiple templates and validated it through sequence alignment and structural comparison with [...] Read more.
Transketolase-like protein 1 (TKTL-1) has been implicated in altered cancer metabolism, yet its structure and molecular function remain poorly understood. In this study, we established a homology model of TKTL-1 using multiple templates and validated it through sequence alignment and structural comparison with the canonical transketolase (TKT). Binding-site identification was performed using CASTp, receptor cavity mapping, and blind docking, all of which consistently pointed to a conserved region involving interactive residues shared between TKT and TKTL-1. Comparative docking revealed the reduced affinity of TKTL-1 for TDP, supporting functional divergence between TKTL-1 and TKT. We further analyzed conserved residues and receptor surfaces, which enabled us to propose predictive scaffolds as potential modulators of TKTL-1. While these scaffolds remain theoretical, they provide a computational framework to guide future pharmacophore modeling, molecular dynamics simulations, and experimental validation. Together, our study highlights the structural features of TKTL-1, establishes its key differences from TKT, and lays the groundwork for future drug discovery efforts targeting cancer metabolism. Full article
(This article belongs to the Special Issue Small-Molecule Drug Design and Discovery)
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Review

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19 pages, 1003 KB  
Review
Suzetrigine, a NaV1.8 Inhibitor as a Novel Approach for Pain Therapy—A Medicinal and Chemical Drug Profile
by Rawan M. Medhat, Omnia A. Kotb and Daniel Baecker
Molecules 2026, 31(2), 358; https://doi.org/10.3390/molecules31020358 - 20 Jan 2026
Viewed by 306
Abstract
Suzetrigine was approved by the US American Food and Drug Administration in 2025 as the first oral, non-opioid, selective inhibitor of NaV1.8 sodium channel for the treatment of acute pain. Therefore, it represents a groundbreaking advancement in pain management. This review [...] Read more.
Suzetrigine was approved by the US American Food and Drug Administration in 2025 as the first oral, non-opioid, selective inhibitor of NaV1.8 sodium channel for the treatment of acute pain. Therefore, it represents a groundbreaking advancement in pain management. This review aims to provide an overview of the milestones in the medicinal-chemical development of NaV1.8 inhibitors, eventually leading to suzetrigine. The multi-step synthesis route of suzetrigine is presented. Taking structural features into account, insights are provided into what plays a role for the inhibition of the NaV1.8 channel. In addition, pharmacodynamic and pharmacokinetic aspects of the new drug, such as bioavailability, metabolism, and interaction with CYP450 enzymes, are discussed. A summary based on a large number of clinical trials demonstrating remarkable efficacy completes this comprehensive drug profile of suzetrigine, while also addressing limitations of the clinical trials and suggesting future perspectives. Full article
(This article belongs to the Special Issue Small-Molecule Drug Design and Discovery)
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25 pages, 1400 KB  
Review
Designing a Small Molecule for PET Radiotracing: [18F]MC225 in Human Trials for Early Diagnosis in CNS Pathologies
by Francesco Mastropasqua, Gert Luurtsema, Cristina Filosa and Nicola Antonio Colabufo
Molecules 2025, 30(18), 3696; https://doi.org/10.3390/molecules30183696 - 11 Sep 2025
Cited by 2 | Viewed by 1981
Abstract
P-Glycoprotein (P-gp, also known as MDR1 or ABCB1) is an ATP-binding cassette (ABC) transporter that actively effluxes a wide range of structurally and functionally diverse molecules, playing a crucial role in drug absorption, distribution, and excretion. P-gp is highly expressed at key biological [...] Read more.
P-Glycoprotein (P-gp, also known as MDR1 or ABCB1) is an ATP-binding cassette (ABC) transporter that actively effluxes a wide range of structurally and functionally diverse molecules, playing a crucial role in drug absorption, distribution, and excretion. P-gp is highly expressed at key biological barriers, such as the blood–brain barrier (BBB), intestine, liver, and kidneys, and it serves as a gatekeeper against xenobiotics and therapeutics. Its dysregulation is involved in multidrug resistance (MDR), epilepsy, cancer, infectious diseases, and neurodegenerative disorders. Several small molecules were synthesized using SAfIR and SAR, and, among them, [18F]MC225 showed the most promising results for in vivo human studies, with appropriate pharmacodynamics and pharmacokinetics profiles for in vivo use. [18F]MC225 is currently being employed in PHASE II human trials at the UMC Groningen, the Netherlands, in patients diagnosed with AD, PD and MCI, as well as PHASE II human trials at the Policlinico Gemelli in Rome Italy to diagnose P-gp resistant depression. Preliminary studies show that [18F]MC225 radiotracer is behaving according to the initial predictions, that is, it accurately diagnoses the aforementioned pathologies, more so than previously developed small molecules for the same goal. Full article
(This article belongs to the Special Issue Small-Molecule Drug Design and Discovery)
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39 pages, 5729 KB  
Review
Metabolism, a Blossoming Target for Small-Molecule Anticancer Drugs
by Michela Puxeddu, Romano Silvestri and Giuseppe La Regina
Molecules 2025, 30(17), 3457; https://doi.org/10.3390/molecules30173457 - 22 Aug 2025
Cited by 1 | Viewed by 2850
Abstract
Reprogramming is recognized as a promising target in cancer therapy. It is well known that the altered metabolism in cancer cells, in particular malignancies, are characterized by increased aerobic glycolysis (Warburg effect) which promotes rapid proliferation. The effort to design compounds able to [...] Read more.
Reprogramming is recognized as a promising target in cancer therapy. It is well known that the altered metabolism in cancer cells, in particular malignancies, are characterized by increased aerobic glycolysis (Warburg effect) which promotes rapid proliferation. The effort to design compounds able to modulate these hallmarks of cancer are gaining increasing attention in drug discovery. In this context, the present review explores recent progress in the development of small molecule inhibitors of key metabolic pathways, such as glycolysis, glutamine metabolism and fatty acid synthesis. In particular, different mechanisms of action of these compounds are analyzed, which can target distinct enzymes, including LDH, HK2, PKM2, GLS and FASN. The findings underscore the relevance of metabolism-based strategies in developing next-generation anticancer agents with potential for improved efficacy and reduced systemic toxicity. Full article
(This article belongs to the Special Issue Small-Molecule Drug Design and Discovery)
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