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Special Issue "Computational Methods in Drug Design"

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Biology".

Deadline for manuscript submissions: 31 October 2021.

Special Issue Editor

Dr. Giulio Poli
E-Mail Website
Guest Editor
Department of Pharmacy, University of Pisa, Via Bonanno 6, 56126 Pisa, Italy
Interests: drug design; molecular modeling; virtual screening; hit identification; lead optimization; molecular docking; molecular dynamics

Special Issue Information

Dear Colleagues,

Molecular modeling and computational chemistry have become essential in the medicinal chemistry field today. In silico strategies represent powerful weapons commonly applied to accelerate drug discovery, design, and optimization campaigns, as well as to improve the knowledge and understanding of the biological processes implied in the mechanism of action of known drugs. Virtual screening protocols combining receptor-based and ligand-based techniques, such as molecular docking, pharmacophore modeling, and various types of ligand-similarity strategies, can speed up the identification of novel hit compounds endowed with inhibitory activity toward the targets of interest. Computational studies employing these and other techniques can help the rationalization of structure–activity relationships among chemical series of pharmacologically active compounds and guide hit-to-lead and lead optimization studies aimed at improving both the activity and pharmacokinetic properties of the ligands, in the search for suitable drug candidates. Moreover, advanced in silico methods based on molecular dynamics simulations and related techniques, in combination with experimental studies, can help to shed light on drug–target interactions, thus facilitating the design of more potent compounds. Finally, machine learning and artificial intelligence models have recently attracted interest for their application in the prediction of various ligand properties and biological activities, as well as in the prediction of potential receptors for active compounds with unknown molecular target (target-fishing).

On these basis, this Special Issue is focused on the development of valuable and innovative computer-aided drug design approaches, as well as on successful applications of in silico techniques and strategies in all aspects and stages of the drug design process. Scientists are thus invited to submit original research articles and reviews dealing with all kinds of molecular modeling studies applied to drug design, such as virtual screening studies, computer-aided hit-to-lead and lead optimization campaigns, molecular modeling studies focused on drug–target interactions and dynamics, development and application of target-fishing approaches, generation of innovative computational tools and models for the prediction of pharmacodynamics, and pharmacokinetic ligand properties.

Dr. Giulio Poli
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 papers will be 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. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. 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

  • virtual screening
  • molecular docking
  • molecular dynamics
  • pharmacophore modeling
  • target-fishing
  • ligand-based similarity
  • chemoinformatic
  • artificial intelligence
  • computer-aided drug design
  • QSAR/QSPR

Published Papers (4 papers)

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Research

Article
Sources of Variability in the Response of Labeled Microspheres and B Cells during the Analysis by a Flow Cytometer
Int. J. Mol. Sci. 2021, 22(15), 8256; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22158256 - 31 Jul 2021
Viewed by 360
Abstract
A stochastic model of the flow cytometer measurement process was developed to assess the nature of the observed coefficient of variation (CV%) of the mean fluorescence intensity (MFI) from a population of labeled microspheres (beads). Several sources of variability were considered: the total [...] Read more.
A stochastic model of the flow cytometer measurement process was developed to assess the nature of the observed coefficient of variation (CV%) of the mean fluorescence intensity (MFI) from a population of labeled microspheres (beads). Several sources of variability were considered: the total number of labels on a bead, the path through the laser beam, the optical absorption cross-section, the quantum yield, the numerical aperture of the collection optics, and the photoelectron conversion efficiency of the photomultiplier (PMT) cathode. The variation in the number of labels on a bead had the largest effect on the CV% of the MFI of the bead population. The variation in the path of the bead through the laser beam was minimized using flat-top lasers. The variability in the average optical properties of the labels was of minor importance for beads with sufficiently large number of labels. The application of the bead results to the measured CV% of labeled B cells indicated that the measured CV% was a reliable measure of the variability of antibodies bound per cell. With some modifications, the model can be extended to multicolor flow cytometers and to the study of CV% from cells with low fluorescence signal. Full article
(This article belongs to the Special Issue Computational Methods in Drug Design)
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Article
Discovery of a Novel Triazolopyridine Derivative as a Tankyrase Inhibitor
Int. J. Mol. Sci. 2021, 22(14), 7330; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22147330 - 08 Jul 2021
Cited by 2 | Viewed by 683
Abstract
More than 80% of colorectal cancer patients have adenomatous polyposis coli (APC) mutations, which induce abnormal WNT/β-catenin activation. Tankyrase (TNKS) mediates the release of active β-catenin, which occurs regardless of the ligand that translocates into the nucleus by AXIN degradation via the ubiquitin-proteasome [...] Read more.
More than 80% of colorectal cancer patients have adenomatous polyposis coli (APC) mutations, which induce abnormal WNT/β-catenin activation. Tankyrase (TNKS) mediates the release of active β-catenin, which occurs regardless of the ligand that translocates into the nucleus by AXIN degradation via the ubiquitin-proteasome pathway. Therefore, TNKS inhibition has emerged as an attractive strategy for cancer therapy. In this study, we identified pyridine derivatives by evaluating in vitro TNKS enzyme activity and investigated N-([1,2,4]triazolo[4,3-a]pyridin-3-yl)-1-(2-cyanophenyl)piperidine-4-carboxamide (TI-12403) as a novel TNKS inhibitor. TI-12403 stabilized AXIN2, reduced active β-catenin, and downregulated β-catenin target genes in COLO320DM and DLD-1 cells. The antitumor activities of TI-12403 were confirmed by the viability of the colorectal cancer cells and its lack of visible toxicity in DLD-1 xenograft mouse model. In addition, combined 5-FU and TI-12403 treatment synergistically inhibited proliferation to a greater extent than that in a single drug treatment. Our observations suggest that TI-12403, a novel selective TNKS1 inhibitor, may be a suitable compound for anticancer drug development. Full article
(This article belongs to the Special Issue Computational Methods in Drug Design)
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Article
Structure-Based Design, Docking and Binding Free Energy Calculations of A366 Derivatives as Spindlin1 Inhibitors
Int. J. Mol. Sci. 2021, 22(11), 5910; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22115910 - 31 May 2021
Viewed by 1558
Abstract
The chromatin reader protein Spindlin1 plays an important role in epigenetic regulation, through which it has been linked to several types of malignant tumors. In the current work, we report on the development of novel analogs of the previously published lead inhibitor A366 [...] Read more.
The chromatin reader protein Spindlin1 plays an important role in epigenetic regulation, through which it has been linked to several types of malignant tumors. In the current work, we report on the development of novel analogs of the previously published lead inhibitor A366. In an effort to improve the activity and explore the structure–activity relationship (SAR), a series of 21 derivatives was synthesized, tested in vitro, and investigated by means of molecular modeling tools. Docking studies and molecular dynamics (MD) simulations were performed to analyze and rationalize the structural differences responsible for the Spindlin1 activity. The analysis of MD simulations shed light on the important interactions. Our study highlighted the main structural features that are required for Spindlin1 inhibitory activity, which include a positively charged pyrrolidine moiety embedded into the aromatic cage connected via a propyloxy linker to the 2-aminoindole core. Of the latter, the amidine group anchor the compounds into the pocket through salt bridge interactions with Asp184. Different protocols were tested to identify a fast in silico method that could help to discriminate between active and inactive compounds within the A366 series. Rescoring the docking poses with MM-GBSA calculations was successful in this regard. Because A366 is known to be a G9a inhibitor, the most active developed Spindlin1 inhibitors were also tested over G9a and GLP to verify the selectivity profile of the A366 analogs. This resulted in the discovery of diverse selective compounds, among which 1s and 1t showed Spindlin1 activity in the nanomolar range and selectivity over G9a and GLP. Finally, future design hypotheses were suggested based on our findings. Full article
(This article belongs to the Special Issue Computational Methods in Drug Design)
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Article
Synthesis, Biological Activity, and Molecular Dynamics Study of Novel Series of a Trimethoprim Analogs as Multi-Targeted Compounds: Dihydrofolate Reductase (DHFR) Inhibitors and DNA-Binding Agents
Int. J. Mol. Sci. 2021, 22(7), 3685; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073685 - 01 Apr 2021
Cited by 3 | Viewed by 855
Abstract
Eighteen previously undescribed trimethoprim (TMP) analogs containing amide bonds (1–18) were synthesized and compared with TMP, methotrexate (MTX), and netropsin (NT). These compounds were designed as potential minor groove binding agents (MGBAs) and inhibitors of human dihydrofolate reductase (hDHFR). [...] Read more.
Eighteen previously undescribed trimethoprim (TMP) analogs containing amide bonds (1–18) were synthesized and compared with TMP, methotrexate (MTX), and netropsin (NT). These compounds were designed as potential minor groove binding agents (MGBAs) and inhibitors of human dihydrofolate reductase (hDHFR). The all-new derivatives were obtained via solid phase synthesis using 4-nitrophenyl Wang resin. Data from the ethidium displacement test confirmed their DNA-binding capacity. Compounds 13–14 (49.89% and 43.85%) and 17–18 (41.68% and 42.99%) showed a higher binding affinity to pBR322 plasmid than NT. The possibility of binding in a minor groove as well as determination of association constants were performed using calf thymus DNA, T4 coliphage DNA, poly (dA-dT)2, and poly (dG-dC)2. With the exception of compounds 9 (IC50 = 56.05 µM) and 11 (IC50 = 55.32 µM), all of the compounds showed better inhibitory properties against hDHFR than standard, which confirms that the addition of the amide bond into the TMP structures increases affinity towards hDHFR. Derivatives 2, 6, 13, 14, and 16 were found to be the most potent hDHFR inhibitors. This molecular modelling study shows that they interact strongly with a catalytically important residue Glu-30. Full article
(This article belongs to the Special Issue Computational Methods in Drug Design)
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