International Journal of Molecular Sciences

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12 pages, 2383 KiB

Open AccessCommunication

Entrectinib—A SARS-CoV-2 Inhibitor in Human Lung Tissue (HLT) Cells

by Alejandro Peralta-Garcia, Mariona Torrens-Fontanals, Tomasz Maciej Stepniewski, Judith Grau-Expósito, David Perea, Vikram Ayinampudi, Maria Waldhoer, Mirjam Zimmermann, María J. Buzón, Meritxell Genescà and Jana Selent

Int. J. Mol. Sci. 2021, 22(24), 13592; https://doi.org/10.3390/ijms222413592 - 18 Dec 2021

Cited by 12 | Viewed by 3385

Abstract

Since the start of the COVID-19 outbreak, pharmaceutical companies and research groups have focused on the development of vaccines and antiviral drugs against SARS-CoV-2. Here, we apply a drug repurposing strategy to identify drug candidates that are able to block the entrance of [...] Read more.

Since the start of the COVID-19 outbreak, pharmaceutical companies and research groups have focused on the development of vaccines and antiviral drugs against SARS-CoV-2. Here, we apply a drug repurposing strategy to identify drug candidates that are able to block the entrance of the virus into human cells. By combining virtual screening with in vitro pseudovirus assays and antiviral assays in Human Lung Tissue (HLT) cells, we identify entrectinib as a potential antiviral drug. Full article

(This article belongs to the Special Issue New Avenues in Molecular Docking for Drug Design 2021)

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15 pages, 11891 KiB

Open AccessArticle

Evaluating Molecular Docking Software for Small Molecule Binding to G-Quadruplex DNA

by Jonathan Dickerhoff, Kassandra R. Warnecke, Kaibo Wang, Nanjie Deng and Danzhou Yang

Int. J. Mol. Sci. 2021, 22(19), 10801; https://doi.org/10.3390/ijms221910801 - 6 Oct 2021

Cited by 17 | Viewed by 4804

Abstract

G-quadruplexes are four-stranded nucleic acid secondary structures of biological significance and have emerged as an attractive drug target. The G4 formed in the MYC promoter (MycG4) is one of the most studied small-molecule targets, and a model system for parallel structures that are [...] Read more.

G-quadruplexes are four-stranded nucleic acid secondary structures of biological significance and have emerged as an attractive drug target. The G4 formed in the MYC promoter (MycG4) is one of the most studied small-molecule targets, and a model system for parallel structures that are prevalent in promoter DNA G4s and RNA G4s. Molecular docking has become an essential tool in structure-based drug discovery for protein targets, and is also increasingly applied to G4 DNA. However, DNA, and in particular G4, binding sites differ significantly from protein targets. Here we perform the first systematic evaluation of four commonly used docking programs (AutoDock Vina, DOCK 6, Glide, and RxDock) for G4 DNA-ligand binding pose prediction using four small molecules whose complex structures with the MycG4 have been experimentally determined in solution. The results indicate that there are considerable differences in the performance of the docking programs and that DOCK 6 with GB/SA rescoring performs better than the other programs. We found that docking accuracy is mainly limited by the scoring functions. The study shows that current docking programs should be used with caution to predict G4 DNA-small molecule binding modes. Full article

(This article belongs to the Special Issue New Avenues in Molecular Docking for Drug Design 2021)

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22 pages, 3859 KiB

Open AccessArticle

Halting Tumor Progression via Novel Non-Hydroxamate Triazole-Based Mannich Bases MMP-2/9 Inhibitors; Design, Microwave-Assisted Synthesis, and Biological Evaluation

by Fawzia Faleh Albelwi, Mohamed Teleb, Marwa M. Abu-Serie, Mohamed Nabil Abd Al Moaty, Mai S. Alsubaie, Mohamed A. Zakaria, Yeldez El Kilany, Mohamed Reda Aouad, Mohamed Hagar and Nadjet Rezki

Int. J. Mol. Sci. 2021, 22(19), 10324; https://doi.org/10.3390/ijms221910324 - 25 Sep 2021

Cited by 21 | Viewed by 2596

Abstract

Matrix metalloproteinases (MMPs) are key signaling modulators in the tumor microenvironment. Among MMPs, MMP-2 and MMP-9 are receiving renewed interest as validated druggable targets for halting different tumor progression events. Over the last decades, a diverse range of MMP-2/9 inhibitors has been identified [...] Read more.

Matrix metalloproteinases (MMPs) are key signaling modulators in the tumor microenvironment. Among MMPs, MMP-2 and MMP-9 are receiving renewed interest as validated druggable targets for halting different tumor progression events. Over the last decades, a diverse range of MMP-2/9 inhibitors has been identified starting from the early hydroxamic acid-based peptidomimetics to the next generation non-hydroxamates. Herein, focused 1,2,4-triazole-1,2,3-triazole molecular hybrids with varying lengths and decorations, mimicking the thematic features of non-hydroxamate inhibitors, were designed and synthesized using efficient protocols and were alkylated with pharmacophoric amines to develop new Mannich bases. After full spectroscopic characterization the newly synthesized triazoles tethering Mannich bases were subjected to safety assessment via MTT assay against normal human fibroblasts, then evaluated for their potential anticancer activities against colon (Caco-2) and breast (MDA-MB 231) cancers. The relatively lengthy bis-Mannich bases 15 and 16 were safer and more potent than 5-fluorouracil with sub-micromolar IC₅₀ and promising selectivity to the screened cancer cell lines rather than normal cells. Both compounds upregulated p53 (2–5.6-fold) and suppressed cyclin D expression (0.8–0.2-fold) in the studied cancers, and thus, induced apoptosis. 15 was superior to 16 in terms of cytotoxic activities, p53 induction, and cyclin D suppression. Mechanistically, both were efficient MMP-2/9 inhibitors with comparable potencies to the reference prototype hydroxamate-based MMP inhibitor NNGH at their anticancer IC₅₀ concentrations. 15 (IC₅₀ = 0.143 µM) was 4-fold more potent than NNGH against MMP-9 with promising selectivity (3.27-fold) over MMP-2, whereas 16 was comparable to NNGH. Concerning MMP-2, 16 (IC₅₀ = 0.376 µM) was 1.2-fold more active than 15. Docking simulations predicted their possible binding modes and highlighted the possible structural determinants of MMP-2/9 inhibitory activities. Computational prediction of their physicochemical properties, ADMET, and drug-likeness metrics revealed acceptable drug-like criteria. Full article

(This article belongs to the Special Issue New Avenues in Molecular Docking for Drug Design 2021)

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14 pages, 4331 KiB

Open AccessArticle

AMIDE v2: High-Throughput Screening Based on AutoDock-GPU and Improved Workflow Leading to Better Performance and Reliability

by Pierre Darme, Manuel Dauchez, Arnaud Renard, Laurence Voutquenne-Nazabadioko, Dominique Aubert, Sandie Escotte-Binet, Jean-Hugues Renault, Isabelle Villena, Luiz-Angelo Steffenel and Stéphanie Baud

Int. J. Mol. Sci. 2021, 22(14), 7489; https://doi.org/10.3390/ijms22147489 - 13 Jul 2021

Cited by 8 | Viewed by 3818

Abstract

Molecular docking is widely used in computed drug discovery and biological target identification, but getting fast results can be tedious and often requires supercomputing solutions. AMIDE stands for AutoMated Inverse Docking Engine. It was initially developed in 2014 to perform inverse docking on [...] Read more.

Molecular docking is widely used in computed drug discovery and biological target identification, but getting fast results can be tedious and often requires supercomputing solutions. AMIDE stands for AutoMated Inverse Docking Engine. It was initially developed in 2014 to perform inverse docking on High Performance Computing. AMIDE version 2 brings substantial speed-up improvement by using AutoDock-GPU and by pulling a total revision of programming workflow, leading to better performances, easier use, bug corrections, parallelization improvements and PC/HPC compatibility. In addition to inverse docking, AMIDE is now an optimized tool capable of high throughput inverse screening. For instance, AMIDE version 2 allows acceleration of the docking up to 12.4 times for 100 runs of AutoDock compared to version 1, without significant changes in docking poses. The reverse docking of a ligand on 87 proteins takes only 23 min on 1 GPU (Graphics Processing Unit), while version 1 required 300 cores to reach the same execution time. Moreover, we have shown an exponential acceleration of the computation time as a function of the number of GPUs used, allowing a significant reduction of the duration of the inverse docking process on large datasets. Full article

(This article belongs to the Special Issue New Avenues in Molecular Docking for Drug Design 2021)

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20 pages, 5322 KiB

Open AccessArticle

Spectroscopic and In Silico Studies on the Interaction of Substituted Pyrazolo[1,2-a]benzo[1,2,3,4]tetrazine-3-one Derivatives with c-Myc G4-DNA

by Simone Mulliri, Aatto Laaksonen, Pietro Spanu, Riccardo Farris, Matteo Farci, Francesco Mingoia, Giovanni N. Roviello and Francesca Mocci

Int. J. Mol. Sci. 2021, 22(11), 6028; https://doi.org/10.3390/ijms22116028 - 2 Jun 2021

Cited by 14 | Viewed by 4836

Abstract

Herein we describe a combined experimental and in silico study of the interaction of a series of pyrazolo[1,2-a]benzo[1,2,3,4]tetrazin-3-one derivatives (PBTs) with parallel G-quadruplex (GQ) DNA aimed at correlating their previously reported anticancer activities and the stabilizing effects observed by us on c-myc oncogene [...] Read more.

Herein we describe a combined experimental and in silico study of the interaction of a series of pyrazolo[1,2-a]benzo[1,2,3,4]tetrazin-3-one derivatives (PBTs) with parallel G-quadruplex (GQ) DNA aimed at correlating their previously reported anticancer activities and the stabilizing effects observed by us on c-myc oncogene promoter GQ structure. Circular dichroism (CD) melting experiments were performed to characterize the effect of the studied PBTs on the GQ thermal stability. CD measurements indicate that two out of the eight compounds under investigation induced a slight stabilizing effect (2–4 °C) on GQ depending on the nature and position of the substituents. Molecular docking results allowed us to verify the modes of interaction of the ligands with the GQ and estimate the binding affinities. The highest binding affinity was observed for ligands with the experimental melting temperatures (T_ms). However, both stabilizing and destabilizing ligands showed similar scores, whilst Molecular Dynamics (MD) simulations, performed across a wide range of temperatures on the GQ in water solution, either unliganded or complexed with two model PBT ligands with the opposite effect on the T_ms, consistently confirmed their stabilizing or destabilizing ability ascertained by CD. Clues about a relation between the reported anticancer activity of some PBTs and their ability to stabilize the GQ structure of c-myc emerged from our study. Furthermore, Molecular Dynamics simulations at high temperatures are herein proposed for the first time as a means to verify the stabilizing or destabilizing effect of ligands on the GQ, also disclosing predictive potential in GQ-targeting drug discovery. Full article

(This article belongs to the Special Issue New Avenues in Molecular Docking for Drug Design 2021)

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Graphical abstract

8 pages, 1904 KiB

Open AccessArticle

Virtual Screening of FDA-Approved Drugs against Triose Phosphate Isomerase from Entamoeba histolytica and Giardia lamblia Identifies Inhibitors of Their Trophozoite Growth Phase

by Alfredo Juárez-Saldivar, Elizabeth Barbosa-Cabrera, Edgar E. Lara-Ramírez, Alma D. Paz-González, Ana V. Martínez-Vázquez, Virgilio Bocanegra-García, Isidro Palos, Nuria E. Campillo and Gildardo Rivera

Int. J. Mol. Sci. 2021, 22(11), 5943; https://doi.org/10.3390/ijms22115943 - 31 May 2021

Cited by 14 | Viewed by 3261

Abstract

Infectious diseases caused by intestinal protozoan, such as Entamoeba histolytica (E. histolytica) and Giardia lamblia (G. lamblia) are a worldwide public health issue. They affect more than 70 million people every year. They colonize intestines causing primarily diarrhea; nevertheless, [...] Read more.

Infectious diseases caused by intestinal protozoan, such as Entamoeba histolytica (E. histolytica) and Giardia lamblia (G. lamblia) are a worldwide public health issue. They affect more than 70 million people every year. They colonize intestines causing primarily diarrhea; nevertheless, these infections can lead to more serious complications. The treatment of choice, metronidazole, is in doubt due to adverse effects and resistance. Therefore, there is a need for new compounds against these parasites. In this work, a structure-based virtual screening of FDA-approved drugs was performed to identify compounds with antiprotozoal activity. The glycolytic enzyme triosephosphate isomerase, present in both E. histolytica and G. lamblia, was used as the drug target. The compounds with the best average docking score on both structures were selected for the in vitro evaluation. Three compounds, chlorhexidine, tolcapone, and imatinib, were capable of inhibit growth on G. lamblia trophozoites (0.05–4.935 μg/mL), while folic acid showed activity against E. histolytica (0.186 μg/mL) and G. lamblia (5.342 μg/mL). Full article

(This article belongs to the Special Issue New Avenues in Molecular Docking for Drug Design 2021)

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22 pages, 23956 KiB

Open AccessArticle

Computational Investigation Identified Potential Chemical Scaffolds for Heparanase as Anticancer Therapeutics

by Shraddha Parate, Vikas Kumar, Danishuddin, Jong Chan Hong and Keun Woo Lee

Int. J. Mol. Sci. 2021, 22(10), 5311; https://doi.org/10.3390/ijms22105311 - 18 May 2021

Cited by 11 | Viewed by 3557

Abstract

Heparanase (Hpse) is an endo-β-D-glucuronidase capable of cleaving heparan sulfate side chains. Its upregulated expression is implicated in tumor growth, metastasis and angiogenesis, thus making it an attractive target in cancer therapeutics. Currently, a few small molecule inhibitors have been reported to inhibit [...] Read more.

Heparanase (Hpse) is an endo-β-D-glucuronidase capable of cleaving heparan sulfate side chains. Its upregulated expression is implicated in tumor growth, metastasis and angiogenesis, thus making it an attractive target in cancer therapeutics. Currently, a few small molecule inhibitors have been reported to inhibit Hpse, with promising oral administration and pharmacokinetic (PK) properties. In the present study, a ligand-based pharmacophore model was generated from a dataset of well-known active small molecule Hpse inhibitors which were observed to display favorable PK properties. The compounds from the InterBioScreen database of natural (69,034) and synthetic (195,469) molecules were first filtered for their drug-likeness and the pharmacophore model was used to screen the drug-like database. The compounds acquired from screening were subjected to molecular docking with Heparanase, where two molecules used in pharmacophore generation were used as reference. From the docking analysis, 33 compounds displayed higher docking scores than the reference and favorable interactions with the catalytic residues. Complex interactions were further evaluated by molecular dynamics simulations to assess their stability over a period of 50 ns. Furthermore, the binding free energies of the 33 compounds revealed 2 natural and 2 synthetic compounds, with better binding affinities than reference molecules, and were, therefore, deemed as hits. The hit compounds presented from this in silico investigation could act as potent Heparanase inhibitors and further serve as lead scaffolds to develop compounds targeting Heparanase upregulation in cancer. Full article

(This article belongs to the Special Issue New Avenues in Molecular Docking for Drug Design 2021)

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30 pages, 12617 KiB

Open AccessArticle

SARS-CoV-2 Papain-Like Protease Potential Inhibitors—In Silico Quantitative Assessment

by Adam Stasiulewicz, Alicja W. Maksymiuk, Mai Lan Nguyen, Barbara Bełza and Joanna I. Sulkowska

Int. J. Mol. Sci. 2021, 22(8), 3957; https://doi.org/10.3390/ijms22083957 - 12 Apr 2021

Cited by 24 | Viewed by 7939

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes the papain-like protease (PLpro). The protein not only plays an essential role in viral replication but also cleaves ubiquitin and ubiquitin-like interferon-stimulated gene 15 protein (ISG15) from host proteins, making it an important target for [...] Read more.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes the papain-like protease (PLpro). The protein not only plays an essential role in viral replication but also cleaves ubiquitin and ubiquitin-like interferon-stimulated gene 15 protein (ISG15) from host proteins, making it an important target for developing new antiviral drugs. In this study, we searched for novel, noncovalent potential PLpro inhibitors by employing a multistep in silico screening of a 15 million compound library. The selectivity of the best-scored compounds was evaluated by checking their binding affinity to the human ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), which, as a deubiquitylating enzyme, exhibits structural and functional similarities to the PLpro. As a result, we identified 387 potential, selective PLpro inhibitors, from which we retrieved the 20 best compounds according to their IC₅₀ values toward PLpro estimated by a multiple linear regression model. The selected candidates display potential activity against the protein with IC₅₀ values in the nanomolar range from approximately 159 to 505 nM and mostly adopt a similar binding mode to the known, noncovalent SARS-CoV-2 PLpro inhibitors. We further propose the six most promising compounds for future in vitro evaluation. The results for the top potential PLpro inhibitors are deposited in the database prepared to facilitate research on anti-SARS-CoV-2 drugs. Full article

(This article belongs to the Special Issue New Avenues in Molecular Docking for Drug Design 2021)

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