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Cutting-Edge Studies of Computational Approaches in Drug Discovery
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Cutting-Edge Studies of Computational Approaches in Drug Discovery

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

Deadline for manuscript submissions: closed (30 November 2024) | Viewed by 4002

Special Issue Editor

Prof. Dr. Tiziano Tuccinardi

E-Mail Website
Guest Editor
Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy
Interests: medicinal chemistry; drug design; ligand–protein binding; molecular interactions; molecular modeling; hit identification; lead optimization
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This Special Issue is entitled “Cutting-Edge Studies of Computational Approaches in Drug Discovery”. The contribution of computational methodologies to drug discovery is no longer a matter of dispute, and most of the world’s pharmaceutical and biotechnology companies use molecular modeling tools. Computer-aided drug design comprises computational methods and resources that are used to facilitate the design and discovery of new therapeutic solutions. Docking, pharmacophore modeling, artificial intelligence, and molecular dynamics simulations are examples of computational techniques that are widely used in hit identification, hit-to-lead, and lead optimization campaigns. Beyond these fundamental steps in the drug discovery process, today, computational chemistry also plays a key role in the ADMET prediction of potential drugs.

This Special Issue welcomes submissions from researchers in the field of computational drug discovery and design, including original research and review articles related to this field.

You may choose our Joint Special Issue in Molecules.

Prof. Dr. Tiziano Tuccinardi
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.

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 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 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

  • docking
  • pharmacophore modeling
  • free energy calculation
  • artificial intelligence
  • molecular dynamics
  • ADMET prediction
  • computer-aided drug design
  • lead optimization
  • QSAR and 3D-QSAR
  • virtual screening

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Published Papers (3 papers)

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Research

14 pages, 1995 KiB  
Article
Computational Design and Synthesis of Phthalimide Derivatives as TGF-β Pathway Inhibitors for Cancer Therapeutics
by Héctor M. Heras-Martínez, Blanca Sánchez-Ramírez, Linda-Lucila Landeros-Martínez, Víctor H. Ramos-Sánchez, Alejandro A. Camacho-Dávila, Kostiantyn O. Marichev, Alejandro Bugarin and David Chávez-Flores
Chemistry 2025, 7(2), 31; https://doi.org/10.3390/chemistry7020031 - 26 Feb 2025
Viewed by 631
Abstract
Background: This study investigates the synthesis and pharmacological potential of N-substituted isoindoline-1,3-dione (phthalimide) derivatives. Using the M06 meta-GGA hybrid functional with a polarized 6-311G(d,p) basis set, computational evaluations assessed their impact on apoptosis modulation in colon cancer cells. Molecular docking studies targeted [...] Read more.
Background: This study investigates the synthesis and pharmacological potential of N-substituted isoindoline-1,3-dione (phthalimide) derivatives. Using the M06 meta-GGA hybrid functional with a polarized 6-311G(d,p) basis set, computational evaluations assessed their impact on apoptosis modulation in colon cancer cells. Molecular docking studies targeted the TGF-β protein (PDB: 1RW8) at the ALK5 binding site. On this study fourteen molecules were evaluated (P1–P14) and six (P1, P3, P4, P5, P7, and P13) demonstrated promising binding values. Methods: from the fourteen studied compounds five compounds (P2, P4, P7, P10, and P11) were successfully synthesized and fully characterized. The reactions were monitored via TLC and HPLC confirming high-purity compounds. Functional groups were identified through FTIR and structural characterization was supported by NMR analyses. Results: Density functional theory calculations and docking simulations allowed to classified the compounds as potential ALK5 inhibitors. Synthesized derivatives were developed in yields from 85 to 99% and showed better binding affinities than Capecitabine (−6.95 kcal/mol) used as control compound, with P7 (5-hydroxy-4-oxo-2-phenyl-4H-chromen-7-yl 2-(1,3-dioxoisoindolin-2-yl) acetate) leading the group with a binding energy of −12.28 kcal/mol. Other synthesized compounds also exhibited significant affinities: P4 (−11.42 kcal/mol), P10 (−8.99 kcal/mol), P11 (−7.50 kcal/mol), and P2 (−7.22 kcal/mol). Conclusions: Integrating computational insights with experimental validation highlights the therapeutic potential of phthalimide derivatives, particularly P7. The study underscores a rigorous approach to identifying promising candidates for anticancer therapeutics, warranting further exploration. Full article
(This article belongs to the Special Issue Cutting-Edge Studies of Computational Approaches in Drug Discovery)
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19 pages, 2581 KiB  
Article
Design, Synthesis, and Evaluation of EA-Sulfonamides and Indazole-Sulfonamides as Promising Anticancer Agents: Molecular Docking, ADME Prediction, and Molecular Dynamics Simulations
by Nassima Saghdani, Nabil El Brahmi, Abdelmoula El Abbouchi, Rachid Haloui, Souad Elkhattabi, Gérald Guillaumet and Saïd El Kazzouli
Chemistry 2024, 6(6), 1396-1414; https://doi.org/10.3390/chemistry6060083 - 9 Nov 2024
Cited by 1 | Viewed by 1234
Abstract
New EA-sulfonamides and indazole-sulfonamides were synthesized, characterized, and evaluated for their anticancer activities. The target compound structures were elucidated using various spectroscopic techniques such as NMR-{1H and 13C}, infrared spectroscopy, and high-resolution mass spectrometry. The anticancer activities of the [...] Read more.
New EA-sulfonamides and indazole-sulfonamides were synthesized, characterized, and evaluated for their anticancer activities. The target compound structures were elucidated using various spectroscopic techniques such as NMR-{1H and 13C}, infrared spectroscopy, and high-resolution mass spectrometry. The anticancer activities of the novel compounds were evaluated against four human cancer cell lines, namely A-549, MCF-7, Hs-683, and SK-MEL-28 as well as the normal cell line HaCaT, using 5-fluorouracil and etoposide as reference drugs. Among the tested compounds, 9, 10, and 13 exhibited potent anticancer activities which are better than or similar to the reference compounds 5-fluorouracil and etoposide, against the A-549, MCF-7, and Hs-683 cancer cell lines, with IC50 values ranging from 0.1 to 1 μM. Molecular docking studies of compounds 9, 10, and 13 showed a strong binding with selected protein kinase targets, which are linked to the tested cancer types. Furthermore, the analysis of the molecular dynamics simulation results demonstrated that compound 9 exhibits significant stability when bound to both JAK3 and ROCK1 kinases. This new compound has the potential to be developed as a novel therapeutic agent against various cancers. Full article
(This article belongs to the Special Issue Cutting-Edge Studies of Computational Approaches in Drug Discovery)
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19 pages, 4090 KiB  
Article
An Experimental Dynamic Investigation of the Influence of Melatonin, Serotonin and Tryptophan on the Stability of the DNA Structure
by Cristina Manuela Drăgoi, Anca Zanfirescu, Ion-Bogdan Dumitrescu, Anca Ungurianu, Denisa Marilena Margină and Alina-Crenguţa Nicolae
Chemistry 2024, 6(5), 922-940; https://doi.org/10.3390/chemistry6050054 - 8 Sep 2024
Viewed by 1468
Abstract
Background: Small molecules play a crucial role in the exploration of physiological pathways and in drug development by targeting deoxyribonucleic acid (DNA). DNA is a central focus for both endogenous and exogenous ligands, which interact directly or indirectly to regulate transcription and replication [...] Read more.
Background: Small molecules play a crucial role in the exploration of physiological pathways and in drug development by targeting deoxyribonucleic acid (DNA). DNA is a central focus for both endogenous and exogenous ligands, which interact directly or indirectly to regulate transcription and replication processes, thus controlling genetic expression in specific cells. Among these molecules, indole derivatives like tryptophan, serotonin, and melatonin are notable for their widespread presence in nature and significant biological effects. Tryptophan, an essential amino acid, serves as a vital structural element in proteins and a precursor for bioactive compounds like serotonin and melatonin, which impact various physiological functions. Methods: Experimental studies have been conducted to reveal the interaction mechanisms of these endogenous indole derivatives with calf thymus DNA (ct-DNA). These investigations involve viscosity measurements and analysis of double-stranded DNA behavior in the presence of indole molecules, using spectrophotometric UV absorption techniques to assess their impact on DNA stability. Additionally, the influence of calcium and magnesium ions on the resulting complexes of these indole derivatives with ct-DNA has been evaluated. Molecular docking validated our findings, offering additional insights into potential DNA–ligand interactions. Utilizing a crystallographic oligomer with an intercalation gap improved docking accuracy, distinguishing intercalation from groove recognition and enhancing assessment precision. Results: Our study offers detailed insights into the interaction patterns of the indole derivatives with DNA and is highly supported by molecular docking analyses: the indole derivatives were predominantly localized between C and G, interacting via π-π interactions and hydrogen bonds and aligning with known data on conventional intercalators. These findings underscore the importance of small compounds’ planar structure and appropriate size, facilitating tight insertion between adjacent base pairs and disrupting regular DNA stacking. Conclusions: Indoles’ physiological roles and potential as drug candidates targeting specific pathways are highlighted, emphasizing their significance as ubiquitous molecules with the ability to modulate biological effects on DNA structure. Full article
(This article belongs to the Special Issue Cutting-Edge Studies of Computational Approaches in Drug Discovery)
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