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Drug Design: Science and Practice

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

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 18231

Special Issue Editor

Department of Chemistry, Faculty of Pharmacy, Medical University of Sofia, 2 Dunav st., 1000 Sofia, Bulgaria
Interests: drug design; molecular docking; molecular dynamics; immunoinformatics

Special Issue Information

Dear Colleagues,

Drug design is a rational approach for drug discovery and development. Since its emergence in the early 1960s, drug design has been constantly evolving by the inclusion of novel in silico and in vitro techniques and methods. Currently, it is the most widely used approach for the discovery of new molecules and for iterative optimization of their structures, aiming to achieve optimal affinity, selectivity, non-toxicity, solubility, permeability and bioavailability properties, which are needed for a molecule to become a drug.

Drug design is a complex science using the achievements and methods of all natural sciences, starting with classical sciences such as chemistry and biology, including all their interdisciplinary derivatives (biochemistry, medical chemistry, molecular biology, biotechnology), and ending with newer sciences like genomics, proteomics, molecular modeling, computational chemistry, bioinformatics, etc.

Most of the drugs approved during the last 50–60 years have been developed by the methods of drug design. Advanced in silico modeling technologies accelerate the iterative process of design–synthesis tests by reducing the experimental work, time, resources and animal lives. Nowadays, the utilization of artificial intelligence makes the design process almost autonomic. The pressure caused by the COVID-19 pandemic has forced the discovery of new vaccines and drugs to be drastically shortened from the usual 10–15 years to several months.

This Special Issue aims to focus on the science and practice of current drug design. We welcome articles applying any of the wide variety of ligand-based or structure-based drug design methods for developing promising drug candidates as well as theoretical studies on novel methods and techniques in the field. 

Prof. Dr. Irini Doytchinova
Guest Editor

Manuscript Submission Information

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Keywords

  • understanding drug–receptor recognition and interactions
  • illuminating the druggable genome and proteome
  • virtual screening, molecular docking and pharmacophore search
  • molecular dynamics simulations and energy calculations
  • SAR and QSAR analysis by statistical and machine learning methods
  • in silico ADMET modeling and profiling
  • chemoinformatics, bioinformatics and data mining
  • artificial intelligence and data visualization

Published Papers (9 papers)

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Editorial

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9 pages, 799 KiB  
Editorial
Drug Design—Past, Present, Future
Molecules 2022, 27(5), 1496; https://doi.org/10.3390/molecules27051496 - 23 Feb 2022
Cited by 18 | Viewed by 4807
Abstract
Drug design is a complex pharmaceutical science with a long history. Many achievements have been made in the field of drug design since the end of 19th century, when Emil Fisher suggested that the drug–receptor interaction resembles the key and lock interplay. Gradually, [...] Read more.
Drug design is a complex pharmaceutical science with a long history. Many achievements have been made in the field of drug design since the end of 19th century, when Emil Fisher suggested that the drug–receptor interaction resembles the key and lock interplay. Gradually, drug design has been transformed into a coherent and well-organized science with a solid theoretical background and practical applications. Now, drug design is the most advanced approach for drug discovery. It utilizes the innovations in science and technology and includes them in its wide-ranging arsenal of methods and tools in order to achieve the main goal: discovery of effective, specific, non-toxic, safe and well-tolerated drugs. Drug design is one of the most intensively developing modern sciences and its progress is accelerated by the implication of artificial intelligence. The present review aims to capture some of the most important milestones in the development of drug design, to outline some of the most used current methods and to sketch the future perspective according to the author’s point of view. Without pretending to cover fully the wide range of drug design topics, the review introduces the reader to the content of Molecules’ Special Issue “Drug Design—Science and Practice”. Full article
(This article belongs to the Special Issue Drug Design: Science and Practice)
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Research

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15 pages, 15661 KiB  
Article
A KNIME Workflow to Assist the Analogue Identification for Read-Across, Applied to Aromatase Activity
Molecules 2023, 28(4), 1832; https://doi.org/10.3390/molecules28041832 - 15 Feb 2023
Cited by 3 | Viewed by 1492
Abstract
The reduction and replacement of in vivo tests have become crucial in terms of resources and animal benefits. The read-across approach reduces the number of substances to be tested, exploiting existing experimental data to predict the properties of untested substances. Currently, several tools [...] Read more.
The reduction and replacement of in vivo tests have become crucial in terms of resources and animal benefits. The read-across approach reduces the number of substances to be tested, exploiting existing experimental data to predict the properties of untested substances. Currently, several tools have been developed to perform read-across, but other approaches, such as computational workflows, can offer a more flexible and less prescriptive approach. In this paper, we are introducing a workflow to support analogue identification for read-across. The implementation of the workflow was performed using a database of azole chemicals with in vitro toxicity data for human aromatase enzymes. The workflow identified analogues based on three similarities: structural similarity (StrS), metabolic similarity (MtS), and mechanistic similarity (McS). Our results showed how multiple similarity metrics can be combined within a read-across assessment. The use of the similarity based on metabolism and toxicological mechanism improved the predictions in particular for sensitivity. Beyond the results predicting a large population of substances, practical examples illustrate the advantages of the proposed approach. Full article
(This article belongs to the Special Issue Drug Design: Science and Practice)
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14 pages, 3213 KiB  
Article
Synthesis and DNase I Inhibitory Properties of New Squaramides
Molecules 2023, 28(2), 538; https://doi.org/10.3390/molecules28020538 - 05 Jan 2023
Cited by 1 | Viewed by 1677
Abstract
Three new monosquaramides (3ac) were synthesized, characterized by IR, NMR and X-ray, and evaluated for inhibitory activity against deoxyribonuclease I (DNase I) and xanthine oxidase (XO) in vitro. The target compounds inhibited DNase I with IC50 values below [...] Read more.
Three new monosquaramides (3ac) were synthesized, characterized by IR, NMR and X-ray, and evaluated for inhibitory activity against deoxyribonuclease I (DNase I) and xanthine oxidase (XO) in vitro. The target compounds inhibited DNase I with IC50 values below 100 μM, being at the same time more potent DNase I inhibitors than crystal violet, used as a positive control. 3-Ethoxy-4-((1-(pyridin-3-yl)propan-2-yl)amino)cyclobut-3-ene-1,2-dione (3c) stood out as the most potent compound, exhibiting a slightly better IC50 value (48.04 ± 7.98 μM) compared to the other two compounds. In order to analyze potential binding sites for the studied compounds with DNase I, a molecular docking study was performed. Compounds 3ac are among the most potent small organic DNase I inhibitors tested to date. Full article
(This article belongs to the Special Issue Drug Design: Science and Practice)
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23 pages, 5454 KiB  
Article
Pyridyl Methylsulfinyl Benzimidazole Derivatives as Promising Agents against Giardia lamblia and Trichomonas vaginalis
Molecules 2022, 27(24), 8902; https://doi.org/10.3390/molecules27248902 - 14 Dec 2022
Cited by 4 | Viewed by 1320
Abstract
Protozoan parasites, such as Giardia lamblia and Trichomonas vaginalis, cause the most prevalent infections in humans in developing countries and provoke significant morbidity and mortality in endemic countries. Despite its side-effects, metronidazole is still the drug of choice as a giardiacidal and [...] Read more.
Protozoan parasites, such as Giardia lamblia and Trichomonas vaginalis, cause the most prevalent infections in humans in developing countries and provoke significant morbidity and mortality in endemic countries. Despite its side-effects, metronidazole is still the drug of choice as a giardiacidal and trichomonacidal tissue-active agent. However, the emergence of metronidazole resistance and its evolved strategies of parasites to evade innate host defenses have hindered the identification and development of new therapeutic strategies against these parasites. Here, we tested five synthesized benzimidazole derivatives as possible drugs for treating giardiasis and trichomoniasis, probing the bifunctional enzyme glucose 6-phosphate dehydrogenase::6-phosphogluconolactone from G. lamblia (GlG6PD::6PGL) and T. vaginalis (TvG6PD::6PGL) as a drug target. The investigated benzimidazole derivatives were H-B2M1, H-B2M2, H2N-BZM6, O2N-BZM7, and O2N-BZM9. The recombinant enzymes were used in inhibition assays, and in silico computational predictions and spectroscopic studies were applied to follow the structural alteration of the enzymes and identify the possible mechanism of inhibition. We identified two potent benzimidazole compounds (O2N-BZM7 and O2N-BZM9), which are capable of inhibiting both protozoan G6PD::6PGL enzymes and in vitro assays with these parasites, showing that these compounds also affect their viability. These results demonstrate that other therapeutic targets of the compounds are the enzymes GlG6PD::6PGL and TvG6PD::6PGL, which contribute to their antiparasitic effect and their possible use in antigiardial and trichomonacidal therapies. Full article
(This article belongs to the Special Issue Drug Design: Science and Practice)
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18 pages, 8747 KiB  
Article
Virtual Screening of FDA-Approved Drugs for Enhanced Binding with Mitochondrial Aldehyde Dehydrogenase
Molecules 2022, 27(24), 8773; https://doi.org/10.3390/molecules27248773 - 10 Dec 2022
Cited by 3 | Viewed by 1187
Abstract
Mitochondrial aldehyde dehydrogenase (ALDH2) is a potential target for the treatment of substance use disorders such as alcohol addiction. Here, we adopted computational methods of molecular dynamics (MD) simulation, docking, and molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) analysis to perform a virtual screening [...] Read more.
Mitochondrial aldehyde dehydrogenase (ALDH2) is a potential target for the treatment of substance use disorders such as alcohol addiction. Here, we adopted computational methods of molecular dynamics (MD) simulation, docking, and molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) analysis to perform a virtual screening of FDA-approved drugs, hitting potent inhibitors against ALDH2. Using MD-derived conformations as receptors, butenafine (net charge q = +1 e) and olaparib (q = 0) were selected as promising compounds with a low toxicity and a binding strength equal to or stronger than previously reported potent inhibitors of daidzin and CVT-10216. A few negatively charged compounds were also hit from the docking with the Autodock Vina software, while the MM-PBSA analysis yielded positive binding energies (unfavorable binding) for these compounds, mainly owing to electrostatic repulsion in association with a negatively charged receptor (q = −6 e for ALDH2 plus the cofactor NAD+). This revealed a deficiency of the Vina scoring in dealing with strong charge–charge interactions between binding partners, due to its built-in protocol of not using atomic charges for electrostatic interactions. These observations indicated a requirement of further verification using MD and/or MM-PBSA after docking prediction. The identification of key residues for the binding implied that the receptor residues at the bottom and entrance of the substrate-binding hydrophobic tunnel were able to offer additional interactions with different inhibitors such as π-π, π-alkyl, van der Waals contacts, and polar interactions, and that the rational use of these interactions is beneficial to the design of potent inhibitors against ALDH2. Full article
(This article belongs to the Special Issue Drug Design: Science and Practice)
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12 pages, 1411 KiB  
Article
Gallium (III) Complexes with 5-Bromosalicylaldehyde Benzoylhydrazones: In Silico Studies and In Vitro Cytotoxic Activity
Molecules 2022, 27(17), 5493; https://doi.org/10.3390/molecules27175493 - 26 Aug 2022
Cited by 4 | Viewed by 1081
Abstract
Gallium (III) complexes with the ligands 5-bromosalicylaldehyde-4-hydroxybenzoylhydrazone and 5-bromosalicylaldehyde isonicotinoylhydrazone were synthesized to receive compounds with improved antiproliferative action. Compounds were characterized by elemental analysis, IR, and NMR spectroscopy. Density functional theory calculations with Becke’s 3-parameter hybrid functional and 6-31+G(d,p) basis set were [...] Read more.
Gallium (III) complexes with the ligands 5-bromosalicylaldehyde-4-hydroxybenzoylhydrazone and 5-bromosalicylaldehyde isonicotinoylhydrazone were synthesized to receive compounds with improved antiproliferative action. Compounds were characterized by elemental analysis, IR, and NMR spectroscopy. Density functional theory calculations with Becke’s 3-parameter hybrid functional and 6-31+G(d,p) basis set were carried out to investigate the structural features of the ligands and Ga(III) complexes. Cytotoxic screening by MTT-dye reduction assay was carried out using cisplatin and melphalan as reference cytotoxic agents. A general formula [Ga(HL)2]NO3 for the complexes obtained was suggested. The complexes are mononuclear with the Ga(III) ions being surrounded by two ligands. The ligands acted as monoanionic tridentate (ONO) donor molecules. The analysis revealed coordination binding through deprotonated phenolic-oxygen, azomethine-nitrogen, and amide-oxygen atoms. The bioassay demonstrated that all compounds exhibited concentration-dependent antiproliferative activity at low micromolar concentrations against the acute myeloid leukemia HL-60 and T-cell leukemia SKW-3 cell lines. IC50 values of 5-bromo-derivative ligands and gallium (III) complexes are lower than those of cisplatin and much lower than these of melphalan. The coordination to gallium (III) additionally increased the cytotoxicity compared to the metal-free hydrazones. Full article
(This article belongs to the Special Issue Drug Design: Science and Practice)
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19 pages, 5641 KiB  
Article
Novel Hits for N-Myristoyltransferase Inhibition Discovered by Docking-Based Screening
Molecules 2022, 27(17), 5478; https://doi.org/10.3390/molecules27175478 - 26 Aug 2022
Cited by 2 | Viewed by 2010
Abstract
N-myristoyltransferase (NMT) inhibitors that were initially developed for treatment of parasitic protozoan infections, including sleeping sickness, malaria, and leismaniasis, have also shown great promise as treatment for oncological diseases. The successful transition of NMT inhibitors, which are currently at preclinical to early clinical [...] Read more.
N-myristoyltransferase (NMT) inhibitors that were initially developed for treatment of parasitic protozoan infections, including sleeping sickness, malaria, and leismaniasis, have also shown great promise as treatment for oncological diseases. The successful transition of NMT inhibitors, which are currently at preclinical to early clinical stages, toward clinical approval and utilization may depend on the development and design of a diverse set of drug molecules with particular selectivity or pharmacological properties. In our study, we report that a common feature in the inhibitory mechanism of NMT is the formation of a salt bridge between a positively charged chemical group of the small molecule and the negatively charged C-terminus of an enzyme. Based on this observation, we designed a virtual screening protocol to identify novel ligands that mimic this mode of interaction. By screening over 1.1 million structures downloaded from the ZINC database, several hits were identified that displayed NMT inhibitory activity. The stability of the inhibitor-NMT complexes was evaluated by molecular dynamics simulations. The ligands from the stable complexes were tested in vitro and some of them appear to be promising leads for further optimization. Full article
(This article belongs to the Special Issue Drug Design: Science and Practice)
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19 pages, 4407 KiB  
Article
Virtual Screening and Hit Selection of Natural Compounds as Acetylcholinesterase Inhibitors
Molecules 2022, 27(10), 3139; https://doi.org/10.3390/molecules27103139 - 13 May 2022
Cited by 10 | Viewed by 2236
Abstract
Acetylcholinesterase (AChE) is one of the classical targets in the treatment of Alzheimer’s disease (AD). Inhibition of AChE slows down the hydrolysis of acetycholine and increases choline levels, improving the cognitive function. The achieved success of plant-based natural drugs acting as AChE inhibitors, [...] Read more.
Acetylcholinesterase (AChE) is one of the classical targets in the treatment of Alzheimer’s disease (AD). Inhibition of AChE slows down the hydrolysis of acetycholine and increases choline levels, improving the cognitive function. The achieved success of plant-based natural drugs acting as AChE inhibitors, such as galantamine (GAL) from Galanthus genus and huperzine A from Huperzia serrate (approved drug in China), in the treatment of AD, and the fact that natural compounds (NCs) are considered as safer and less toxic compared to synthetic drugs, led us to screen the available NCs (almost 150,000) in the ZINC12 database for AChE inhibitory activity. The compounds were screened virtually by molecular docking, filtered for suitable ADME properties, and 32 ligands from 23 structural groups were selected. The stability of the complexes was estimated via 1 μs molecular dynamics simulation. Ten compounds formed stable complexes with the enzyme and had a vendor and a reasonable price per mg. They were tested for AChE inhibitory and antioxidant activity. Five compounds showed weak AChE inhibition and three of them exhibited high antioxidant activity. Full article
(This article belongs to the Special Issue Drug Design: Science and Practice)
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Review

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12 pages, 968 KiB  
Review
To Affinity and Beyond: A Personal Reflection on the Design and Discovery of Drugs
Molecules 2022, 27(21), 7624; https://doi.org/10.3390/molecules27217624 - 07 Nov 2022
Cited by 1 | Viewed by 1383
Abstract
Faced with new and as yet unmet medical need, the stark underperformance of the pharmaceutical discovery process is well described if not perfectly understood. Driven primarily by profit rather than societal need, the search for new pharmaceutical products—small molecule drugs, biologicals, and vaccines—is [...] Read more.
Faced with new and as yet unmet medical need, the stark underperformance of the pharmaceutical discovery process is well described if not perfectly understood. Driven primarily by profit rather than societal need, the search for new pharmaceutical products—small molecule drugs, biologicals, and vaccines—is neither properly funded nor sufficiently systematic. Many innovative approaches remain significantly underused and severely underappreciated, while dominant methodologies are replete with problems and limitations. Design is a component of drug discovery that is much discussed but seldom realised. In and of itself, technical innovation alone is unlikely to fulfil all the possibilities of drug discovery if the necessary underlying infrastructure remains unaltered. A fundamental revision in attitudes, with greater reliance on design powered by computational approaches, as well as a move away from the commercial imperative, is thus essential to capitalise fully on the potential of pharmaceutical intervention in healthcare. Full article
(This article belongs to the Special Issue Drug Design: Science and Practice)
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