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

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 21426

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Dr. Elena Cichero

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Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genova, Viale Benedetto XV 3, 16132 Genova, Italy
Interests: drug design; homology modeling; molecular docking calculations; virtual screening; 3D-QSAR analyses
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Special Issue Information

Dear Colleagues,

Drug discovery is a time-consuming and expensive process, usually carried out through rational design methods or HTS (high-throughput screening) of large libraries of compounds. This requires appropriate experimental models to evaluate and validate the therapeutic potential of the new putative hit compounds and then specific biological assays and clinical trials to evaluate the safety and efficacy profiles of the discovered molecules. Much effort has been made to rationalize, speed up, and lower the costs of the drug discovery process. In this context, virtual screening (VS) is becoming an increasingly fast and inexpensive approach for identifying and selecting biologically active molecules targeting pharmaceutically relevant proteins. The rapid development of new tools to better understand the structure and function of proteins and their pathophysiological correlations has uncovered new promising targets to be exploited for the design and optimization of novel therapeutic approaches. Virtual screening relying on structure-based strategies opens up opportunities to speed up efforts in the search for novel drugs, addressing new challenges in the modern medicinal chemistry scenario. In addition, virtual screening represents a useful tool for performing effective drug repositioning for existing drugs in market, with a remarkable reduction in developmental costs of the whole drug discovery process. This Special Issue will cover all different aspects of virtual screening methodology and applications, leading to hit compounds or to optimized leads based on the structural knowledge of the target, including X-ray crystallography or homology modeling-based structures, or integrated bioinformatics pipelines for fast drug identification.

Dr. Elena Cichero
Guest Editor

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Keywords

virtual screening
orphan target
GPCR
bioinformatics
drug repositioning

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Published Papers (6 papers)

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Research

15 pages, 1379 KiB

Open AccessArticle

Virtual Screening and ADMET Prediction to Uncover the Potency of Flavonoids from Genus Erythrina as Antibacterial Agent through Inhibition of Bacterial ATPase DNA Gyrase B

by Abd. Wahid Rizaldi Akili, Ari Hardianto, Jalifah Latip, Afri Permana and Tati Herlina

Molecules 2023, 28(24), 8010; https://doi.org/10.3390/molecules28248010 - 8 Dec 2023

Cited by 2 | Viewed by 1260

Abstract

The emergence of antimicrobial resistance due to the widespread and inappropriate use of antibiotics has now become the global health challenge. Flavonoids have long been reported to be a potent antimicrobial agent against a wide range of pathogenic microorganisms in vitro. Therefore, new antibiotics development based on flavonoid structures could be a potential strategy to fight against antibiotic-resistant infections. This research aims to screen the potency of flavonoids of the genus Erythrina as an inhibitor of bacterial ATPase DNA gyrase B. From the 378 flavonoids being screened, 49 flavonoids show potential as an inhibitor of ATPase DNA gyrase B due to their lower binding affinity compared to the inhibitor and ATP. Further screening for their toxicity, we identified 6 flavonoids from these 49 flavonoids, which are predicted to have low toxicity. Among these flavonoids, erystagallin B (334) is predicted to have the best pharmacokinetic properties, and therefore, could be further developed as new antibacterial agent. Full article

(This article belongs to the Special Issue Virtual Screening)

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20 pages, 8325 KiB

Open AccessArticle

Pentafuhalol-B, a Phlorotannin from Brown Algae, Strongly Inhibits the PLK-1 Overexpression in Cancer Cells as Revealed by Computational Analysis

by Waseem Ahmad Ansari, Safia Obaidur Rab, Mohammad Saquib, Aqib Sarfraz, Mohd Kamil Hussain, Mohd Sayeed Akhtar, Irfan Ahmad and Mohammad Faheem Khan

Molecules 2023, 28(15), 5853; https://doi.org/10.3390/molecules28155853 - 3 Aug 2023

Cited by 6 | Viewed by 2169

Abstract

Polo-like kinase-1 (PLK-1) is an essential mitotic serine/threonine (Ser/Thr) kinase that belongs to the Polo-like kinase (PLK) family and is overexpressed in non-small cell lung cancer (NSCLC) via promotion of cell division. Therefore, PLK-1 may act as a promising target for the therapeutic cure of various cancers. Although a variety of anti-cancer drugs, both synthetic and naturally occurring, such as volasertib, onvansertib, thymoquinone, and quercetin, are available either alone or in combination with other therapies, they have limited efficacy, especially in the advanced stages of cancer. To the best of our knowledge, no anticancer agent has been reported from marine algae or microorganisms to date. Thus, the aim of the present study is a high-throughput virtual screening of phlorotannins, obtained from edible brown algae, using molecular docking and molecular dynamic simulation analysis. Among these, Pentafuhalol-B (PtB) showed the lowest binding energy (best of triplicate runs) against the target protein PLK-1 as compared to the reference drug volasertib. Further, in MD simulation (best of triplicate runs), the PtB-PLK-1 complex displayed stability in an implicit water system through the formation of strong molecular interactions. Additionally, MMGBSA calculation (best of triplicate runs) was also performed to validate the PtB-PLK-1 complex binding affinities and stability. Moreover, the chemical reactivity of PtB towards the PLK-1 target was also optimised using density functional theory (DFT) calculations, which exhibited a lower HOMO-LUMO energy gap. Overall, these studies suggest that PtB binds strongly within the pocket sites of PLK-1 through the formation of a stable complex, and also shows higher chemical reactivity than the reference drug volasertib. The present study demonstrated the inhibitory nature of PtB against the PLK-1 protein, establishing its potential usefulness as a small molecule inhibitor for the treatment of different types of cancer. Full article

(This article belongs to the Special Issue Virtual Screening)

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17 pages, 6471 KiB

Open AccessArticle

In Silico Study on the Interactions, Molecular Docking, Dynamics and Simulation of Potential Compounds from Withania somnifera (L.) Dunal Root against Cancer by Targeting KAT6A

by Sanjay H. Deshpande, Abdullatif Bin Muhsinah, Zabin K. Bagewadi, Gireesh M. Ankad, Mater H. Mahnashi, Deepak A. Yaraguppi, Ibrahim Ahmed Shaikh, Aejaz Abdullatif Khan, Harsha V. Hegde and Subarna Roy

Molecules 2023, 28(3), 1117; https://doi.org/10.3390/molecules28031117 - 22 Jan 2023

Cited by 10 | Viewed by 4164

Abstract

Cancer is characterized by the abnormal development of cells that divide in an uncontrolled manner and further take over the body and destroy the normal cells of the body. Although several therapies are practiced, the demand and need for new therapeutic agents are ever-increasing because of issues with the safety, efficacy and efficiency of old drugs. Several plant-based therapeutics are being used for treatment, either as conjugates with existing drugs or as standalone formulations. Withania somnifera (L.) Dunal is a highly studied medicinal plant which is known to possess immunomodulatory activity as well as anticancer properties. The pivotal role of KAT6A in major cellular pathways and its oncogenic nature make it an important target in cancer treatment. Based on the literature and curated datasets, twenty-six compounds from the root of W. somnifera and a standard inhibitor were docked with the target KAT6A using Autodock vina. The compounds and the inhibitor complexes were subjected to molecular dynamics simulation (50 ns) using Desmond to understand the stability and interactions. The top compounds (based on the docking score of less than −8.5 kcal/mol) were evaluated in comparison to the inhibitor. Based on interactions at ARG655, LEU686, GLN760, ARG660, LEU689 and LYS763 amino acids with the inhibitor WM-8014, the compounds from W. somnifera were evaluated. Withanolide D, Withasomniferol C, Withanolide E, 27-Hydroxywithanone, Withanolide G, Withasomniferol B and Sitoindoside IX showed high stability with the residues of interest. The cell viability of human breast cancer MCF-7 cells was evaluated by treating them with W. Somnifera root extract using an MTT assay, which showed inhibitory activity with an IC50 value of 45 µg/mL. The data from the study support the traditional practice of W. somnifera as an anticancer herb. Full article

(This article belongs to the Special Issue Virtual Screening)

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20 pages, 5665 KiB

Open AccessArticle

Pharmacophore-Based Virtual Screening of Novel Competitive Inhibitors of the Neurodegenerative Disease Target Kynurenine-3-Monooxygenase

by Lizaveta Gotina, Seon Hee Seo, Chae Won Kim, Sang Min Lim and Ae Nim Pae

Molecules 2021, 26(11), 3314; https://doi.org/10.3390/molecules26113314 - 31 May 2021

Cited by 8 | Viewed by 3409

Abstract

The pathogenesis of several neurodegenerative diseases such as Alzheimer’s or Huntington’s disease has been associated with metabolic dysfunctions caused by imbalances in the brain and cerebral spinal fluid levels of neuroactive metabolites. Kynurenine monooxygenase (KMO) is considered an ideal therapeutic target for the regulation of neuroactive tryptophan metabolites. Despite significant efforts, the known KMO inhibitors lack blood–brain barrier (BBB) permeability and upon the mimicking of the substrate binding mode, are subject to produce reactive oxygen species as a side reaction. The computational drug design is further complicated by the absence of complete crystal structure information for human KMO (hKMO). In the current work, we performed virtual screening of readily available compounds using several protein–ligand complex pharmacophores. Each of the pharmacophores accounts for one of three distinct reported KMO protein-inhibitor binding conformations. As a result, six novel KMO inhibitors were discovered based on an in vitro fluorescence assay. Compounds VS1 and VS6 were predicted to be BBB permeable and avoid the hydrogen peroxide production dilemma, making them valuable, novel hit compounds for further drug property optimization and advancement in the drug design pipeline. Full article

(This article belongs to the Special Issue Virtual Screening)

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14 pages, 6713 KiB

Open AccessArticle

Prioritisation of Compounds for 3CL^pro Inhibitor Development on SARS-CoV-2 Variants

by Marko Jukič, Blaž Škrlj, Gašper Tomšič, Sebastian Pleško, Črtomir Podlipnik and Urban Bren

Molecules 2021, 26(10), 3003; https://doi.org/10.3390/molecules26103003 - 18 May 2021

Cited by 21 | Viewed by 4860

Abstract

COVID-19 represents a new potentially life-threatening illness caused by severe acute respiratory syndrome coronavirus 2 or SARS-CoV-2 pathogen. In 2021, new variants of the virus with multiple key mutations have emerged, such as B.1.1.7, B.1.351, P.1 and B.1.617, and are threatening to render available vaccines or potential drugs ineffective. In this regard, we highlight 3CL^pro, the main viral protease, as a valuable therapeutic target that possesses no mutations in the described pandemically relevant variants. 3CL^pro could therefore provide trans-variant effectiveness that is supported by structural studies and possesses readily available biological evaluation experiments. With this in mind, we performed a high throughput virtual screening experiment using CmDock and the “In-Stock” chemical library to prepare prioritisation lists of compounds for further studies. We coupled the virtual screening experiment to a machine learning-supported classification and activity regression study to bring maximal enrichment and available structural data on known 3CL^pro inhibitors to the prepared focused libraries. All virtual screening hits are classified according to 3CL^pro inhibitor, viral cysteine protease or remaining chemical space based on the calculated set of 208 chemical descriptors. Last but not least, we analysed if the current set of 3CL^pro inhibitors could be used in activity prediction and observed that the field of 3CL^pro inhibitors is drastically under-represented compared to the chemical space of viral cysteine protease inhibitors. We postulate that this methodology of 3CL^pro inhibitor library preparation and compound prioritisation far surpass the selection of compounds from available commercial “corona focused libraries”. Full article

(This article belongs to the Special Issue Virtual Screening)

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13 pages, 2821 KiB

Open AccessArticle

Discovery of Monoacylglycerol Lipase (MAGL) Inhibitors Based on a Pharmacophore-Guided Virtual Screening Study

by Vibhu Jha, Marzia Biagi, Valeria Spinelli, Miriana Di Stefano, Marco Macchia, Filippo Minutolo, Carlotta Granchi, Giulio Poli and Tiziano Tuccinardi

Molecules 2021, 26(1), 78; https://doi.org/10.3390/molecules26010078 - 26 Dec 2020

Cited by 9 | Viewed by 4066

Abstract

Monoacylglycerol lipase (MAGL) is an important enzyme of the endocannabinoid system that catalyzes the degradation of the major endocannabinoid 2-arachidonoylglycerol (2-AG). MAGL is associated with pathological conditions such as pain, inflammation and neurodegenerative diseases like Parkinson’s and Alzheimer’s disease. Furthermore, elevated levels of MAGL have been found in aggressive breast, ovarian and melanoma cancer cells. Due to its different potential therapeutic implications, MAGL is considered as a promising target for drug design and the discovery of novel small-molecule MAGL inhibitors is of great interest in the medicinal chemistry field. In this context, we developed a pharmacophore-based virtual screening protocol combined with molecular docking and molecular dynamics simulations, which showed a final hit rate of 50% validating the reliability of the in silico workflow and led to the identification of two promising and structurally different reversible MAGL inhibitors, VS1 and VS2. These ligands represent a valuable starting point for structure-based hit-optimization studies aimed at identifying new potent MAGL inhibitors. Full article

(This article belongs to the Special Issue Virtual Screening)

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