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Advances in Rational Drug Design: From Target Identification to Drug...
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Advances in Rational Drug Design: From Target Identification to Drug Lead Compounds

A special issue of Chemistry (ISSN 2624-8549). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: 31 October 2026 | Viewed by 22804

Special Issue Editors

Dr. Carmen Di Giovanni

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Guest Editor
Department of Pharmacy, University of Naples Federico II, Via Domenico Montesano 49, 80131 Naples, Italy
Interests: drug discovery; molecular modeling; nutraceutical modeling; bioinformatics; medicinal chemistry
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Antonio Lavecchia

E-Mail Website
Guest Editor
Department of Pharmacy, “Drug Discovery Lab”, University of Naples “Federico II”, Via D. Montesano 49, 80131 Naples, Italy
Interests: drug discovery; medicinal chemistry; molecular modeling; polypharmacology; artificial intelligence; machine learning
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The landscape of drug discovery is rapidly evolving through the integration of innovative computational and experimental approaches. Rational drug design, encompassing both structure-based and ligand-based strategies, has accelerated the identification of novel drug leads by leveraging insights into molecular targets, bioinformatics, and cheminformatics. Advances in artificial intelligence, machine learning, molecular dynamics, and virtual screening are reshaping how researchers predict drug–target interactions, optimize lead compounds, and evaluate pharmacokinetic properties. This Special Issue invites original research articles, reviews, and perspectives on recent developments in target identification, hit-to-lead optimization, computer-aided drug design (CADD), deep learning applications in medicinal chemistry, and the modeling of small molecules and biologics. Contributions exploring multidisciplinary approaches, including the use of big data, multi-omics integration, and innovative experimental validation techniques, are particularly encouraged. We aim to gather a diverse collection of studies to reflect the dynamic cross-disciplinary nature of modern drug discovery and foster knowledge exchange across computational and experimental domains.

Topics of interest include but are not limited to:

  • computer-aided drug discovery (CADD);
  • rational drug design;
  • target identification;
  • lead optimization;
  • molecular modeling;
  • virtual screening;
  • deep learning in drug discovery;
  • ADMET prediction;
  • bioinformatics;
  • artificial intelligence in medicinal chemistry.

We invite you to submit your work to this Special Issue. Full papers, communications, and reviews are all welcome.

Dr. Carmen Di Giovanni
Prof. Dr. Antonio Lavecchia
Guest Editors

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. Chemistry is an international peer-reviewed open access monthly 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 1800 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

  • computer aided-drug discovery
  • drug development
  • lead compounds
  • drug candidates
  • molecular modeling
  • structure-based drug design
  • ligand-based drug design
  • artificial intelligence (AI)

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Published Papers (6 papers)

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Research

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15 pages, 615 KB  
Article
Novel 1,4-Naphthoquinone-Zidovudine Hybrid: Design, Synthesis, and In Vitro Evaluation of Its Anti-Trypanosomatid and Cytotoxic Activities
by Thiago de Souza Dias Silva, Afonso Santine M. M. Velez, Tiago Ribeiro Rodriguez, João Vitor da Costa Silva, Henrique Previtalli-Silva, Flávia de Oliveira Cardoso, Célio Geraldo Freire-de-Lima, Otávio Augusto Chaves, Debora Decote-Ricardo and Marco Edilson Freire de Lima
Chemistry 2026, 8(2), 15; https://doi.org/10.3390/chemistry8020015 - 29 Jan 2026
Viewed by 664
Abstract
This work reports the synthesis and characterization of a new molecular hybrid 4, created by combining 1,4-naphthoquinone with the drug zidovudine (AZT) through an azide-alkyne cycloaddition reaction catalyzed by Cu1+. In vitro studies assessed the anti-trypanosomatid activity of hybrid 4 [...] Read more.
This work reports the synthesis and characterization of a new molecular hybrid 4, created by combining 1,4-naphthoquinone with the drug zidovudine (AZT) through an azide-alkyne cycloaddition reaction catalyzed by Cu1+. In vitro studies assessed the anti-trypanosomatid activity of hybrid 4, along with its precursors and synthetic intermediates (1, 2, and 3), against Trypanosoma cruzi (T. cruzi Tulahuen C2C4 LacZ), Trypanosoma brucei (T. b. brucei 427), and Leishmania infantum, as well as cytotoxicity in RAW 264.7 macrophages and LLC-MK2 cells. The biological results confirm the molecular design, showing that the new hybrid is effective against both epimastigotes and amastigotes of T. cruzi (IC50 = 22.26 ± 5.78 μM and 143.10 ± 5.79 μM, respectively), with approximately 4.5-fold better capacity than AZT to inhibit the epimastigote form. Additionally, the hybrid was also active against bloodstream T. b. brucei (IC50 = 54.47 ± 6.70 μM), with approximately 2.2-fold better capacity than AZT to inhibit this parasite. It also shows low toxicity in RAW 264.7 macrophages (CC50 > 200 μM) and LLC-MK2 cells (CC50 > 200 μM). For example, hybrid 4 exhibited approximately a 6.6-fold higher SI than 1,4-naphthoquinone 1 against T. cruzi amastigotes. In this context, the work contributes to the broader knowledge base guiding the design of hybrid molecules for antiparasitic chemotherapy. It provides a rational foundation for preparing subsequent, more potent analogues. Full article
(This article belongs to the Special Issue Advances in Rational Drug Design: From Target Identification to Drug Lead Compounds)
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21 pages, 1459 KB  
Article
Salicylic Acid Derivatives as Antifungal Agents: Synthesis, In Vitro Evaluation, and Molecular Modeling
by Ana Júlia de Morais Santos Oliveira, Danielle da N. Alves, Marcelo Cavalcante Duarte, Ricardo Dias de Castro, Yunierkis Perez-Castillo and Damião Pergentino de Sousa
Chemistry 2025, 7(5), 151; https://doi.org/10.3390/chemistry7050151 - 17 Sep 2025
Cited by 1 | Viewed by 2705
Abstract
A series of twenty-five salicylic acid derivatives was synthesized and structurally characterized by 1H and 13C-APT NMR and IR spectroscopic techniques, and HRMS analysis. The derivatives were subjected to biological evaluation against species of the genus Candida (C. albicans ATCC [...] Read more.
A series of twenty-five salicylic acid derivatives was synthesized and structurally characterized by 1H and 13C-APT NMR and IR spectroscopic techniques, and HRMS analysis. The derivatives were subjected to biological evaluation against species of the genus Candida (C. albicans ATCC 90028, C. albicans CBS 5602, C. tropicalis CBS 94, and C. krusei CBS 573). In assays were used the broth microdilution method to determine the minimum inhibitory concentration (MIC) and verify the probable mechanism of action for antifungal activity. In the antifungal evaluation, compounds N-isobutyl-2-hidroxybenzamide (14), N-cyclohexyl-2-hydroxybenzamide (15), N-benzyl-2-hydroxybenzamide (16), N-4-methylbenzyl-2-hydroxybenzamide (17), N-4-methoxybenzyl-2-hydroxybenzamide (18), N-2,4-dimethoxybenzyl-2-hydroxybenzamide (19), N-4-fluorbenzyl-2-hiydroxybenzamide (22), and N-4-chlorobenzyl-2-hydroxybenzamide (23) were bioactive against at least one fungal strain. The compound with the best antifungal profile was N-cyclohexyl-2-hydroxybenzamide (15), which presented a MIC of 570.05 μM against most of the strains tested. The tests using ergosterol and sorbitol demonstrated that the compound does not act by altering cell wall functions or the plasmatic membrane in Candida species. The in silico analysis of 15 for antifungal activity in various biological targets suggested a probable multitarget mechanism. Therefore, the synthesis of salicylic acid derivatives resulted in compounds with a good antifungal profile. Full article
(This article belongs to the Special Issue Advances in Rational Drug Design: From Target Identification to Drug Lead Compounds)
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24 pages, 2450 KB  
Article
Synthesis and Characterization of a New Hydrogen-Bond-Stabilized 1,10-Phenanthroline–Phenol Schiff Base: Integrated Spectroscopic, Electrochemical, Theoretical Studies, and Antimicrobial Evaluation
by Alexander Carreño, Evys Ancede-Gallardo, Ana G. Suárez, Marjorie Cepeda-Plaza, Mario Duque-Noreña, Roxana Arce, Manuel Gacitúa, Roberto Lavín, Osvaldo Inostroza, Fernando Gil, Ignacio Fuentes and Juan A. Fuentes
Chemistry 2025, 7(4), 135; https://doi.org/10.3390/chemistry7040135 - 21 Aug 2025
Cited by 2 | Viewed by 3172
Abstract
A new Schiff base, (E)-2-(((1,10-phenanthrolin-5-yl)imino)methyl)-4,6-di-tert-butylphenol (Fen-IHB), was designed to incorporate an intramolecular hydrogen bond (IHB) between the phenolic OH and the azomethine nitrogen with the goal of modulating its physicochemical and biological properties. Fen-IHB was synthesized by condensation of [...] Read more.
A new Schiff base, (E)-2-(((1,10-phenanthrolin-5-yl)imino)methyl)-4,6-di-tert-butylphenol (Fen-IHB), was designed to incorporate an intramolecular hydrogen bond (IHB) between the phenolic OH and the azomethine nitrogen with the goal of modulating its physicochemical and biological properties. Fen-IHB was synthesized by condensation of 5-amino-1,10-phenanthroline with 3,5-di-tert-butyl-2-hydroxybenzaldehyde and exhaustively characterized by HR-ESI-MS, FTIR, 1D/2D NMR (1H, 13C, DEPT-45, HH-COSY, CH-COSY, D2O exchange), and UV–Vis spectroscopy. Cyclic voltammetry in anhydrous CH3CN revealed a single irreversible cathodic peak at −1.43 V (vs. Ag/Ag+), which is consistent with the intramolecular reductive coupling of the azomethine moiety. Density functional theory (DFT) calculations, including MEP mapping, Fukui functions, dual descriptor analysis, and Fukui potentials with dual descriptor potential, identified the exocyclic azomethine carbon as the principal nucleophilic site and the phenolic ring (hydroxyl oxygen and adjacent carbons) as the main electrophilic region. Noncovalent interaction (NCI) analysis further confirmed the strength and geometry of the intramolecular hydrogen bond (IHB). In vitro antimicrobial assays indicated that Fen-IHB was inactive against Gram-negative facultative anaerobes (Salmonella enterica serovar Typhimurium and Typhi, Escherichia coli) and strictly anaerobic Gram-positive species (Clostridioides difficile, Roseburia inulinivorans, Blautia coccoides), as any growth inhibition was indistinguishable from the DMSO control. Conversely, Fen-IHB displayed measurable activity against Gram-positive aerobes and aerotolerant anaerobes, including Bacillus subtilis, Streptococcus pyogenes, Enterococcus faecalis, Staphylococcus aureus, and Staphylococcus haemolyticus. Overall, these comprehensive characterization results confirm the distinctive chemical and electronic properties of Fen-IHB, underlining the crucial role of the intramolecular hydrogen bond and electronic descriptors in defining its reactivity profile and selective biological activity. Full article
(This article belongs to the Special Issue Advances in Rational Drug Design: From Target Identification to Drug Lead Compounds)
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21 pages, 3617 KB  
Article
Characterization and Computational Insights into the Potential Biological Activity of 4-Hydroxyphenyl 8-Chlorooctanoate Purified from Endophytic Fusarium solani
by Muhammad Salim, Sajjad Ahmad and Saeed Ullah Khattak
Chemistry 2025, 7(4), 130; https://doi.org/10.3390/chemistry7040130 - 14 Aug 2025
Viewed by 2352
Abstract
Endophytes are important sources of bioactive secondary metabolites with therapeutic and agricultural relevance. This study reports the isolation and characterization of bioactive compounds from endophytic Fusarium solani associated with Solanum surattense. The fungal strain, selected after preliminary screening for its antimicrobial potential, [...] Read more.
Endophytes are important sources of bioactive secondary metabolites with therapeutic and agricultural relevance. This study reports the isolation and characterization of bioactive compounds from endophytic Fusarium solani associated with Solanum surattense. The fungal strain, selected after preliminary screening for its antimicrobial potential, was identified through morphological and molecular methods. A pure compound, 4-hydroxyphenyl 8-chlorooctanoate with a molecular mass of 270, was obtained and structurally characterized using GC–MS, FTIR, and NMR spectroscopy. Its anti-microbial potential was evaluated through molecular docking against key bacterial (Staphylococcus aureus) and fungal (Aspergillus fumigatus) targets, showing notable binding affinities with ClpP protease (−7.1 kcal/mol) and 14α-demethylase (−7.4 kcal/mol), respectively. Molecular dynamics simulations further confirmed the stability of the 5FRB-compound complex, with lower RMSD and RMSF values indicating strong structural integrity. Supporting analyses (B-factor and radius of gyration) confirmed the compactness and rigidity of the complex. These findings highlight the potential of 4-hydroxyphenyl 8-chlorooctanoate as a promising antimicrobial agent and provide a strong basis for further in vitro and in vivo validation of the purified compound as an antimicrobial candidate. Full article
(This article belongs to the Special Issue Advances in Rational Drug Design: From Target Identification to Drug Lead Compounds)
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Review

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23 pages, 3772 KB  
Review
Benzimidazole Derivatives: A Review of Advances in Synthesis, Biological Potential, Computational Modelling, and Specialized Material Functions
by Nuaman F. Alheety, Sameer A. Awad, Mustafa A. Alheety, Mohanned Y. Darwesh, Jalal A. Abbas and Rafaâ Besbes
Chemistry 2026, 8(1), 1; https://doi.org/10.3390/chemistry8010001 - 19 Dec 2025
Cited by 8 | Viewed by 2621
Abstract
Benzimidazole derivatives are a privileged family of heterocyclic compounds that have remarkable structural diversity and find various pharmacological and industrial applications. In this article, we report on their synthetic procedures, ranging from classic condensation methodologies to modern green chemistry methodologies (microwave-assisted methods and [...] Read more.
Benzimidazole derivatives are a privileged family of heterocyclic compounds that have remarkable structural diversity and find various pharmacological and industrial applications. In this article, we report on their synthetic procedures, ranging from classic condensation methodologies to modern green chemistry methodologies (microwave-assisted methods and catalyst-free methods). The biological significance of these derivatives is discussed, and their anticancer, antimicrobial, anti-inflammatory, antioxidant, antiparasitic, antiviral, antihypertensive, antidiabetic, and neuroprotective activities are reported. This article also reviews recent industrial applications, with special reference to hydrogen storage and environmental sustainability. The latest computational techniques, such as density functional theory (DFT), molecular docking, and molecular dynamics simulation, are particularly emphasized because they can be instrumental in understanding structure–activity relationships and rational drug design. In summary, the present review describes the importance of new benzimidazole derivatives, which are considered a different class of multitarget agents in medicinal chemistry and computational drug design. Full article
(This article belongs to the Special Issue Advances in Rational Drug Design: From Target Identification to Drug Lead Compounds)
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38 pages, 2987 KB  
Review
Benzothiazole-Based Therapeutics: FDA Insights and Clinical Advances
by Subba Rao Cheekatla
Chemistry 2025, 7(4), 118; https://doi.org/10.3390/chemistry7040118 - 25 Jul 2025
Cited by 7 | Viewed by 9793
Abstract
Benzothiazole derivatives have emerged as being highly significant in drug discovery due to their versatile biological activities and structural adaptability. Incorporating nitrogen and sulfur, this fused heterocyclic scaffold exhibits wide-ranging pharmacological properties, including anticancer, antimicrobial, anti-inflammatory, antidiabetic, neuroprotective, and diagnostic applications. A diverse [...] Read more.
Benzothiazole derivatives have emerged as being highly significant in drug discovery due to their versatile biological activities and structural adaptability. Incorporating nitrogen and sulfur, this fused heterocyclic scaffold exhibits wide-ranging pharmacological properties, including anticancer, antimicrobial, anti-inflammatory, antidiabetic, neuroprotective, and diagnostic applications. A diverse set of clinically approved and investigational compounds, such as flutemetamol for Alzheimer’s diagnosis, riluzole for ALS, and quizartinib for AML, illustrates the scaffold’s therapeutic potential in varied applications. These agents act via mechanisms such as enzyme inhibition, receptor modulation, and amyloid imaging, demonstrating the scaffold’s high binding affinity and target specificity. Advances in synthetic strategies and our understanding of structure–activity relationships (SARs) continue to drive the development of novel benzothiazole-based therapeutics with improved potency, selectivity, and safety profiles. We also emphasize recent in vitro and in vivo studies, including drug candidates in clinical trials, to provide a comprehensive perspective on the therapeutic potential of benzothiazole-based compounds in modern drug discovery. This review brings together recent progress to help guide the development of new benzothiazole-based compounds for future therapeutic applications. Full article
(This article belongs to the Special Issue Advances in Rational Drug Design: From Target Identification to Drug Lead Compounds)
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