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From a Molecule to a Drug: Chemical Features Enhancing Pharmacological Potential II

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A special issue of Molecules (ISSN 1420-3049).

Deadline for manuscript submissions: 31 August 2024 | Viewed by 12781

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Special Issue Editors

Dr. Giovanni Ribaudo

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Guest Editor

Department of Molecular and Translational Medicine, University of Brescia, Viale Europa 11, 25123 Brescia, Italy
Interests: medicinal chemistry; organic synthesis; analytical chemistry; mass spectrometry; NMR; natural products; molecular modeling
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Laura Orian

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Guest Editor

Department of Chemical Sciences, University of Padova, Via Marzolo, 1, 35131 Padova, Italy
Interests: computational chemistry; physical chemistry; catalysis; molecular design
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

An intriguing aspect of chemical reactivity is undoubtedly its connection to molecular structure. In drug design, an even tougher challenge must be faced because molecular features must not only warrantee the chemical reactivity (drug action) but must also efficiently allow targeting the correct receptors in the complex biological environment (drug-likeness and selectivity). For these purposes, computer-aided modelling is nowadays considered a strong and reliable support to drive scientists’ intuition to design functional molecules. This field is intrinsically multidisciplinary, involving chemical and medicinal chemistry effort as well as biochemical, biological, and biomedical research.

This Special Issue is proposed as a continuing contribution in the field, following the successful first edition, due to the submission requests we are still receiving.

The leitmotiv of the manuscripts we are collecting remains a better understanding of the chemistry principles that rule the diseases at the molecular level, as well as the possible mechanisms for restoring the physiological equilibrium.

In this Special Issue, we intend to collect contributions (reviews and original research articles) dealing with successful stories of drug improvement or design by classic protocols, by quantum mechanical mechanistic investigation, or by hybrid approaches such as QM/MM or QM/ML (machine learning). Lastly, we also aim to receive works in which the drug design has been performed without computer help but in the lab with the help of chemical intuition and... serendipity! The common aspect that we stress is the recognition of chemical molecular motifs which are the key aspects for the drug potential. Topics of interest include, but are not limited to, the following:

Antioxidants;
Natural and semi-synthetic compounds;
Natural supplements containing bioactive molecules;
Improved bioactivity of known drugs;
Drugs and drug-like compounds acting through multiple mechanisms of action.

Dr. Giovanni Ribaudo
Prof. Dr. Laura Orian
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 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. 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

antioxidants
organic molecules
analytical chemistry
computer-aided drug design
drug discovery
molecular dynamics (MD)
quantum mechanics (QM) calculations
reaction mechanisms

Published Papers (5 papers)

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Research

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23 pages, 5853 KiB

Open AccessArticle

Synthesis of 2-Amino-N′-aroyl(het)arylhydrazides, DNA Photocleavage, Molecular Docking and Cytotoxicity Studies against Melanoma CarB Cell Lines

by Achilleas Mitrakas, Maria-Eleni K. Stathopoulou, Chrysoula Mikra, Chrystalla Konstantinou, Stergios Rizos, Stella Malichetoudi, Alexandros E. Koumbis, Maria Koffa and Konstantina C. Fylaktakidou

Molecules 2024, 29(3), 647; https://doi.org/10.3390/molecules29030647 - 30 Jan 2024

Viewed by 651

Abstract

Diacylhydrazine bridged anthranilic acids with aryl and heteroaryl domains have been synthesized as the open flexible scaffold of arylamide quinazolinones in order to investigate flexibility versus rigidity towards DNA photocleavage and sensitivity. Most of the compounds have been synthesized via the in situ formation of their anthraniloyl chloride and subsequent reaction with the desired hydrazide and were obtained as precipitates, in moderate yields. All compounds showed high UV-A light absorption and are eligible for DNA photocleavage studies under this “harmless” irradiation. Despite their reduced UV-B light absorption, a first screening indicated the necessity of a halogen at the p-position in relation to the amine group and the lack of an electron-withdrawing group on the aryl group. These characteristics, in general, remained under UV-A light, rendering these compounds as a novel class of UV-A-triggered DNA photocleavers. The best photocleaver, the compound 9, was active at concentrations as low as 2 μΜ. The 5-Nitro-anthranilic derivatives were inactive, giving the opposite results to their related rigid quinazolinones. Molecular docking studies with DNA showed possible interaction sites, whereas cytotoxicity experiments indicated the iodo derivative 17 as a potent cytotoxic agent and the compound 9 as a slight phototoxic compound. Full article

(This article belongs to the Special Issue From a Molecule to a Drug: Chemical Features Enhancing Pharmacological Potential II)

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21 pages, 15429 KiB

Open AccessArticle

A Workflow Combining Machine Learning with Molecular Simulations Uncovers Potential Dual-Target Inhibitors against BTK and JAK3

by Lu Liu, Risong Na, Lianjuan Yang, Jixiang Liu, Yingjia Tan, Xi Zhao, Xuri Huang and Xuecheng Chen

Molecules 2023, 28(20), 7140; https://doi.org/10.3390/molecules28207140 - 17 Oct 2023

Viewed by 1032

Abstract

The drug development process suffers from low success rates and requires expensive and time-consuming procedures. The traditional one drug–one target paradigm is often inadequate to treat multifactorial diseases. Multitarget drugs may potentially address problems such as adverse reactions to drugs. With the aim to discover a multitarget potential inhibitor for B-cell lymphoma treatment, herein, we developed a general pipeline combining machine learning, the interpretable model SHapley Additive exPlanation (SHAP), and molecular dynamics simulations to predict active compounds and fragments. Bruton’s tyrosine kinase (BTK) and Janus kinase 3 (JAK3) are popular synergistic targets for B-cell lymphoma. We used this pipeline approach to identify prospective potential dual inhibitors from a natural product database and screened three candidate inhibitors with acceptable drug absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. Ultimately, the compound CNP0266747 with specialized binding conformations that exhibited potential binding free energy against BTK and JAK3 was selected as the optimum choice. Furthermore, we also identified key residues and fingerprint features of this dual-target inhibitor of BTK and JAK3. Full article

(This article belongs to the Special Issue From a Molecule to a Drug: Chemical Features Enhancing Pharmacological Potential II)

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19 pages, 3185 KiB

Open AccessArticle

Microwave-Assisted Synthesis of Aminophosphonic Derivatives and Their Antifungal Evaluation against Lomentospora prolificans

by Zuleyma Martínez-Campos, Mariana Elizondo-Zertuche, Emanuel Hernández-Núñez, Eugenio Hernández-Fernández, Efrén Robledo-Leal and Susana T. López-Cortina

Molecules 2023, 28(10), 3995; https://doi.org/10.3390/molecules28103995 - 10 May 2023

Cited by 1 | Viewed by 1563

Abstract

Lomentospora prolificans is a pathogenic and multidrug-resistant fungus that can infect both immunocompetent and immunocompromised patients, with mortality rates up to 87%. The World Health Organization (WHO) included this fungal species in its first list of 19 priority fungal pathogens, which focused on fungal pathogens that can cause invasive acute and subacute systemic fungal infections. Therefore, there is a growing interest in finding new therapeutic alternatives. In this work, the synthesis of twelve α-aminophosphonates by the microwave-assisted Kabachnik–Fields reaction and twelve α-aminophosphonic acids by a monohydrolysis reaction is reported. All compounds were evaluated by the agar diffusion method as a preliminary screening in comparison with voriconazole, showing inhibition halos for compounds 7, 11, 13, 22 and 27. The five active compounds in the preliminary tests were evaluated against five strains of L. prolificans following protocol M38-A2 from CLSI. The results showed that these compounds exhibit antifungal activity in the concentration range of 900->900 μg/mL. Cytotoxicity against healthy COS-7 cells was also evaluated by the MTT assay, and it was shown that compound 22 was the least cytotoxic, with a viability of 67.91%, comparable to the viability exhibited by voriconazole (68.55%). Docking studies showed that the possible mechanism of action of the active compounds could be through the inhibition of the enzyme lanosterol-14-alpha-demethylase in an allosteric hydrophobic cavity. Full article

(This article belongs to the Special Issue From a Molecule to a Drug: Chemical Features Enhancing Pharmacological Potential II)

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16 pages, 2404 KiB

Open AccessArticle

Ultrasound Assisted Synthesis and In Silico Modelling of 1,2,4-Triazole Coupled Acetamide Derivatives of 2-(4-Isobutyl phenyl)propanoic acid as Potential Anticancer Agents

by Sadaf Mahmood, Samreen Gul Khan, Azhar Rasul, Jørn Bolstad Christensen and Mohammed A. S. Abourehab

Molecules 2022, 27(22), 7984; https://doi.org/10.3390/molecules27227984 - 17 Nov 2022

Cited by 5 | Viewed by 1417

Abstract

The development of an economical method for the synthesis of biologically active compounds was the major goal of this research. In the present study, we have reported the ultrasound-radiation-assisted synthesis of a series of novel N-substituted 1,2,4-triazole-2-thiol derivatives. The target compounds 6a–f were efficiently synthesized in significant yields (75–89%) by coupling 1,2,4-triazole of 2-(4-isobutylphenyl) propanoic acid 1 with different electrophiles using ultrasound radiation under different temperatures. The sonication process accelerated the rate of the reaction as well as yielded all derivatives compared to conventional methods. All derivatives were confirmed by spectroscopic (FTIR, ¹HNMR, ¹³CNMR, HRMS) and physiochemical methods. All derivatives were further screened for their anticancer effects against the HepG2 cell line. Compound 6d containing two electron-donating methyl moieties demonstrated the most significant anti-proliferative activity with an IC₅₀ value of 13.004 µg/mL, while compound 6e showed the lowest potency with an IC₅₀ value of 28.399 µg/mL. The order of anticancer activity was found to be: 6d > 6b > 6f > 6a > 6c > 6e, respectively. The in silico modelling of all derivatives was performed against five different protein targets and the results were consistent with the biological activities. Ligand 6d showed the best binding affinity with the Protein Kinase B (Akt) pocket with the lowest ∆G value of −176.152 kcal/mol. Compound 6d has been identified as a promising candidate for treatment of liver cancer. Full article

(This article belongs to the Special Issue From a Molecule to a Drug: Chemical Features Enhancing Pharmacological Potential II)

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Review

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64 pages, 12106 KiB

Open AccessReview

Recent Advances in Age-Related Macular Degeneration Therapies

by Marie Fabre, Lou Mateo, Diana Lamaa, Stéphanie Baillif, Gilles Pagès, Luc Demange, Cyril Ronco and Rachid Benhida

Molecules 2022, 27(16), 5089; https://doi.org/10.3390/molecules27165089 - 10 Aug 2022

Cited by 23 | Viewed by 7253

Abstract

Age-related macular degeneration (AMD) was described for the first time in the 1840s and is currently the leading cause of blindness for patients over 65 years in Western Countries. This disease impacts the eye’s posterior segment and damages the macula, a retina section with high levels of photoreceptor cells and responsible for the central vision. Advanced AMD stages are divided into the atrophic (dry) form and the exudative (wet) form. Atrophic AMD consists in the progressive atrophy of the retinal pigment epithelium (RPE) and the outer retinal layers, while the exudative form results in the anarchic invasion by choroidal neo-vessels of RPE and the retina. This invasion is responsible for fluid accumulation in the intra/sub-retinal spaces and for a progressive dysfunction of the photoreceptor cells. To date, the few existing anti-AMD therapies may only delay or suspend its progression, without providing cure to patients. However, in the last decade, an outstanding number of research programs targeting its different aspects have been initiated by academics and industrials. This review aims to bring together the most recent advances and insights into the mechanisms underlying AMD pathogenicity and disease evolution, and to highlight the current hypotheses towards the development of new treatments, i.e., symptomatic vs. curative. The therapeutic options and drugs proposed to tackle these mechanisms are analyzed and critically compared. A particular emphasis has been given to the therapeutic agents currently tested in clinical trials, whose results have been carefully collected and discussed whenever possible. Full article

(This article belongs to the Special Issue From a Molecule to a Drug: Chemical Features Enhancing Pharmacological Potential II)

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