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Special Issue "Computer Simulation for Drug Design and Medical Bioengineering"

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A special issue of Pharmaceutics (ISSN 1999-4923). This special issue belongs to the section "Drug Targeting and Design".

Deadline for manuscript submissions: 30 June 2023 | Viewed by 4795

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Special Issue Editors

Prof. Dr. Catalin Buiu
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Department of Automatic Control and Systems Engineering, Politehnica University of Bucharest, Splaiul Independentei 313, 060042 Bucharest, Romania
Interests: computational biology; bioinformatics

Prof. Dr. Speranta Avram

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Guest Editor

Department of Anatomy, Animal Physiology and Biophysics, Faculty of Biology, University of Bucharest, Splaiul Independentei, No 91‐95, 050095 Bucharest, Romania
Interests: bioinformatics; cheminformatics; drug design and discovery; QSAR; neuropsychiatry

Special Issue Information

Dear Colleagues,

The discovery of natural and synthetic chemical compounds as candidates for pharmaceutical drugs is essential scientifically, socially, and economically in medical and bioengineering fields. Improvements in bioinformatics and computational biology have increased the efficiency of many stages of the drug discovery pipeline. Computer-aided tools which are used in drug discovery are critical for many human pathologies. Special attention has been paid to drug design for cancers and brain pathologies and, in the last two years, for SARS-CoV2 infection. Bioinformatics methods such as molecular dynamics, molecular docking, fragment-based screening (FBS), and QSAR, are strategically used when new chemicals being considered for potential drugs. Pharmacological features, represented by pharmacokinetic (absorption, distribution, metabolism, and excretion), pharmacodynamic (targets discovery), and toxicity profiles are critical for assessing proposed chemical structures for new candidate drugs. Additionally, bioengineering tools being employed to develop in silico tools.

For this Special Issue of Pharmaceutics, “Computer Simulation for Drug Design and Medical Bioengineering”, we welcome the submission of primary research and review articles that are focused on drug design, molecular docking, molecular dynamics, QSAR, and pharmacology. Interdisciplinary studies are encouraged for submission.

Prof. Dr. Catalin Buiu
Prof. Dr. Speranta Avram
Guest Editors

Manuscript Submission Information

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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. Pharmaceutics is an international peer-reviewed open access monthly 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 2600 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

bioengineering in human disorders
pharmacology
toxicology
pharmacokinetic/pharmacodynamic profile
QSAR
molecular docking
molecular dynamics
drug design for cancer
drug design for brain disorders
anti-SARS-CoV2 drug design
structure-based drug design
fragment-based screening (FBS)

Published Papers (4 papers)

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Research

Open AccessArticle

Target Prediction of 5,10,15,20-Tetrakis(4′-Sulfonatophenyl)-Porphyrin Using Molecular Docking

and

Pharmaceutics 2022, 14(11), 2390; https://doi.org/10.3390/pharmaceutics14112390 - 05 Nov 2022

Cited by 1 | Viewed by 791

Abstract

Photodynamic therapy has the potential to be a new and effective cancer treatment. Even if in vitro and in vivo research show promise, the molecular mechanism remains unclear. In this study, molecular docking simulations predict the binding affinity of the 5,10,15,20-tetrakis(4′-sulfonatophenyl)-porphyrin tetraammonium photosensitizer on several potential targets in photodynamic treatment. Our results indicate that this photosensitizer binds to several receptor targets, including B-cell lymphoma 2 (BCL-2) and other related proteins BCL-xL, MCL-1, or A1. The binding affinity of the porphyrin derivative with human serum albumin was determined using UV–vis absorption spectroscopy and predicted using molecular docking. We conclude that the studied porphyrin photosensitizer binds to human serum albumin and may inhibit the cancer cell line through its interactions with HIS and MET AA residues from BCL-2, MCL-1, and β-catenin receptors or through its low estimated free energy of binding when interacting with A1 and BCL-B receptors. Full article

(This article belongs to the Special Issue Computer Simulation for Drug Design and Medical Bioengineering)

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Open AccessArticle

Scaffold Repurposing Reveals New Nanomolar Phosphodiesterase Type 5 (PDE5) Inhibitors Based on Pyridopyrazinone Scaffold: Investigation of In Vitro and In Silico Properties

Mohammed A. S. Abourehab

Mahmoud H. El-Maghrabey

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Pharmaceutics 2022, 14(9), 1954; https://doi.org/10.3390/pharmaceutics14091954 - 15 Sep 2022

Cited by 1 | Viewed by 1063

Abstract

Inhibition of PDE5 results in elevation of cGMP leading to vascular relaxation and reduction in the systemic blood pressure. Therefore, PDE5 inhibitors are used as antihypertensive and antianginal agents in addition to their major use as male erectile dysfunction treatments. Previously, we developed a novel series of 34 pyridopyrazinone derivatives as anticancer agents (series A–H). Herein, a multi-step in silico approach was preliminary conducted to evaluate the predicted PDE5 inhibitory activity, followed by an in vitro biological evaluation over the enzymatic level and a detailed SAR study. The designed 2D-QSAR model which was carried out to predict the IC₅₀ of the tested compounds revealed series B, D, E and G with nanomolar range of IC₅₀ values (6.00–81.56 nM). A further docking simulation model was performed to investigate the binding modes within the active site of PDE5. Interestingly, most of the tested compounds showed almost the same binding modes of that of reported PDE5 inhibitors. To validate the in silico results, an in vitro enzymatic assay over PDE5 enzyme was performed for a number of the promising candidates with different substitutions. Both series E and G exhibited a potent inhibitory activity (IC₅₀ = 18.13–41.41 nM). Compound 11b (series G, oxadiazole-based derivatives with terminal 4-NO₂ substituted phenyl ring and rigid linker) was the most potent analogue with IC₅₀ value of 18.13 nM. Structure–activity relationship (SAR) data attained for various substitutions were rationalized. Furthermore, a molecular dynamic simulation gave insights into the inhibitory activity of the most active compound (11b). Accordingly, this report presents a successful scaffold repurposing approach that reveals compound 11b as a highly potent nanomolar PDE5 inhibitor worthy of further investigation. Full article

(This article belongs to the Special Issue Computer Simulation for Drug Design and Medical Bioengineering)

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Open AccessArticle

Mechanistic Understanding of the Palmitoylation of G_o Protein in the Allosteric Regulation of Adhesion Receptor GPR97

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Pharmaceutics 2022, 14(9), 1856; https://doi.org/10.3390/pharmaceutics14091856 - 02 Sep 2022

Cited by 2 | Viewed by 1137

Abstract

Adhesion G-protein-coupled receptors (aGPCRs)—a major family of GPCRs—play critical roles in the regulation of tissue development and cancer progression. The orphan receptor GPR97, activated by glucocorticoid stress hormones, is a prototypical aGPCR. Although it has been established that the palmitoylation of the C-terminal G_o protein is essential for G_o’s efficient engagement with the active GPR97, the detailed allosteric mechanism remains to be clarified. Hence, we performed extensive large-scale molecular dynamics (MD) simulations of the GPR97−G_o complex in the presence or absence of G_o palmitoylation. The conformational landscapes analyzed by Markov state models revealed that the overall conformation of GPR97 is preferred to be fully active when interacting with palmitoylated G_o protein. Structural and energetic analyses indicated that the palmitoylation of G_o can allosterically stabilize the critical residues in the ligand-binding pocket of GPR97 and increase the affinity of the ligand for GPR97. Furthermore, the community network analysis suggests that the palmitoylation of G_o not only allosterically strengthens the internal interactions between G_αo and G_βγ, but also enhances the coupling between G_o and GPR97. Our study provides mechanistic insights into the regulation of aGPCRs via post-translational modifications of the G_o protein, and offers guidance for future drug design of aGPCRs. Full article

(This article belongs to the Special Issue Computer Simulation for Drug Design and Medical Bioengineering)

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Open AccessArticle

Antiproliferative Copper(II) Complexes Bearing Mixed Chelating Ligands: Structural Characterization, ROS Scavenging, In Silico Studies, and Anti-Melanoma Activity

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Pharmaceutics 2022, 14(8), 1692; https://doi.org/10.3390/pharmaceutics14081692 - 14 Aug 2022

Cited by 1 | Viewed by 1007

Abstract

Melanoma is a skin cancer characterized by rapid growth and spread for which current therapies produce both resistance and increased risk of infection. To develop new anti-melanoma biocompatible species, the series of complexes Cu(N-N)(bzac)(X)⋅nH₂O (N-N: 1,10-phenanthroline/2,2′-bipyridine, Hbzac: 1-phenyl-1,3-butanedione, X: NO₃/ClO₄, and n = 0, 1) was studied. Single-crystal X-ray diffraction revealed a mononuclear structure for all complexes. The ability of the complexes to scavenge or trap reactive oxygen species such as O₂⋅⁻ and HO⋅ was proved by EPR spectroscopy experiments. All complexes inhibited B16 murine melanoma cells in a dose-dependent and nanomolar range, but the complexes with 1,10-phenanthroline were more active. Moreover, comparative activity on B16 and healthy BJ cells revealed a therapeutic index of 1.27–2.24. Bioinformatic methods were used to calculate the drug-likeness, pharmacokinetic, pharmacogenomic, and pharmacodynamic profiles of the compounds. The results showed that all compounds exhibit drug-likeness features, as well as promising absorption, distribution, metabolism, and excretion (ADME) properties, and no toxicity. The pharmacodynamics results showed that the neutral species appear to be good candidates for antitumor molecular targets (Tyrosyl-DNA phosphodiesterase 1, DNA-(apurinic or apyrimidinic site) lyase or Kruppel-like factor 5). Furthermore, the pharmacogenomic results showed a good affinity of the copper(II) complexes for the human cytochrome. These results recommend complexes bearing 1,10-phenanthroline as good candidates for developing drugs to melanoma alternative treatment. Full article

(This article belongs to the Special Issue Computer Simulation for Drug Design and Medical Bioengineering)

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