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Pharmaceutics
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Computer Simulation for Drug Design and Medical Bioengineering
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Computer Simulation for Drug Design and Medical Bioengineering

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

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 15590

Special Issue Editors

Prof. Dr. Catalin Buiu

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Guest Editor
Department of Automatic Control and Systems Engineering, Politehnica University of Bucharest, Splaiul Independentei 313, 060042 Bucharest, Romania
Interests: computational biology; bioinformatics
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Speranta Avram

E-Mail Website
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

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 submissions that pass pre-check are 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. 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 2900 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)

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Published Papers (7 papers)

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Research

16 pages, 4607 KiB  
Article
Mechanistic Elucidation of Activation/Deactivation Signal Transduction within Neurotensin Receptor 1 Triggered by ‘Driver Chemical Groups’ of Modulators: A Comparative Molecular Dynamics Simulation
by Xun Lu, Xinchao Shi, Jigang Fan, Mingyu Li, Yuxiang Zhang, Shaoyong Lu, Guanghuan Xu and Ziqiang Chen
Pharmaceutics 2023, 15(7), 2000; https://doi.org/10.3390/pharmaceutics15072000 - 21 Jul 2023
Cited by 2 | Viewed by 1672
Abstract
Small-molecule modulators of neurotensin receptor 1 (NTSR1), a class A G-protein-coupled receptor (GPCR), has emerged as promising therapeutic agent for psychiatric disorders and cancer. Interestingly, a chemical group substitution in NTSR1 modulators can launch different types of downstream regulation, highlighting the significance of [...] Read more.
Small-molecule modulators of neurotensin receptor 1 (NTSR1), a class A G-protein-coupled receptor (GPCR), has emerged as promising therapeutic agent for psychiatric disorders and cancer. Interestingly, a chemical group substitution in NTSR1 modulators can launch different types of downstream regulation, highlighting the significance of deciphering the internal fine-tuning mechanism. Here, we conducted a synergistic application of a Gaussian accelerated molecular dynamics simulation, a conventional molecular dynamics simulation, and Markov state models (MSM) to investigate the underlying mechanism of ‘driver chemical groups’ of modulators triggering inverse signaling. The results indicated that the flexibility of the leucine moiety in NTSR1 agonists contributes to the inward displacement of TM7 through a loosely coupled allosteric pathway, while the rigidity of the adamantane moiety in NTSR1 antagonists leads to unfavorable downward transduction of agonistic signaling. Furthermore, we found that R3226.54, Y3196.51, F3537.42, R1483.32, S3567.45, and S3577.46 may play a key role in inducing the activation of NTSR1. Together, our findings not only highlight the ingenious signal transduction within class A GPCRs but also lay a foundation for the development of targeted drugs harboring different regulatory functions of NTSR1. Full article
(This article belongs to the Special Issue Computer Simulation for Drug Design and Medical Bioengineering)
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20 pages, 7007 KiB  
Article
Experimental and Computational Investigation of the Oxime Bond Stereochemistry in c-Jun N-terminal Kinase 3 Inhibitors 11H-Indeno[1,2-b]quinoxalin-11-one Oxime and Tryptanthrin-6-oxime
by Vladislava V. Matveevskaya, Dmitry I. Pavlov, Anastasia R. Kovrizhina, Taisiya S. Sukhikh, Evgeniy H. Sadykov, Pavel V. Dorovatovskii, Vladimir A. Lazarenko, Andrei I. Khlebnikov and Andrei S. Potapov
Pharmaceutics 2023, 15(7), 1802; https://doi.org/10.3390/pharmaceutics15071802 - 23 Jun 2023
Cited by 3 | Viewed by 1380
Abstract
11H-Indeno[1,2-b]quinoxalin-11-one oxime (IQ-1) and tryptanthrin-6-oxime are potent c-Jun N-terminal kinase 3 (JNK-3) inhibitors demonstrating neuroprotective, anti-inflammatory and anti-arthritic activity. However, the stereochemical configuration of the oxime carbon–nitrogen double bond (E- or Z-) in these [...] Read more.
11H-Indeno[1,2-b]quinoxalin-11-one oxime (IQ-1) and tryptanthrin-6-oxime are potent c-Jun N-terminal kinase 3 (JNK-3) inhibitors demonstrating neuroprotective, anti-inflammatory and anti-arthritic activity. However, the stereochemical configuration of the oxime carbon–nitrogen double bond (E- or Z-) in these compounds was so far unknown. In this contribution, we report the results of the determination of the double bond configuration in the solid state by single crystal X-ray diffraction and in solution by 1D and 2D NMR techniques and DFT calculations. It was found that both in the solid state and in solution, IQ-1 adopts the E-configuration stabilized by intermolecular hydrogen bonds, in contrast to previously assumed Z-configuration that could be stabilized only by an intramolecular hydrogen bond. Full article
(This article belongs to the Special Issue Computer Simulation for Drug Design and Medical Bioengineering)
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23 pages, 7177 KiB  
Article
Design of a Synthetic Long Peptide Vaccine Targeting HPV-16 and -18 Using Immunoinformatic Methods
by Alexandru Tîrziu, Speranța Avram, Leonard Mada, Mihaela Crișan-Vida, Casiana Popovici, Dan Popovici, Cosmin Faur, Corina Duda-Seiman, Virgil Păunescu and Corina Vernic
Pharmaceutics 2023, 15(7), 1798; https://doi.org/10.3390/pharmaceutics15071798 - 23 Jun 2023
Cited by 4 | Viewed by 2458
Abstract
Human papillomavirus types 16 and 18 cause the majority of cervical cancers worldwide. Despite the availability of three prophylactic vaccines based on virus-like particles (VLP) of the major capsid protein (L1), these vaccines are unable to clear an existing infection. Such infected persons [...] Read more.
Human papillomavirus types 16 and 18 cause the majority of cervical cancers worldwide. Despite the availability of three prophylactic vaccines based on virus-like particles (VLP) of the major capsid protein (L1), these vaccines are unable to clear an existing infection. Such infected persons experience an increased risk of neoplastic transformation. To overcome this problem, this study proposes an alternative synthetic long peptide (SLP)-based vaccine for persons already infected, including those with precancerous lesions. This new vaccine was designed to stimulate both CD8+ and CD4+ T cells, providing a robust and long-lasting immune response. The SLP construct includes both HLA class I- and class II-restricted epitopes, identified from IEDB or predicted using NetMHCPan and NetMHCIIPan. None of the SLPs were allergenic nor toxic, based on in silico studies. Population coverage studies provided 98.18% coverage for class I epitopes and 99.81% coverage for class II peptides in the IEDB world population’s allele set. Three-dimensional structure ab initio prediction using Rosetta provided good quality models, which were assessed using PROCHECK and QMEAN4. Molecular docking with toll-like receptor 2 identified potential intrinsic TLR2 agonist activity, while molecular dynamics studies of SLPs in water suggested good stability, with favorable thermodynamic properties. Full article
(This article belongs to the Special Issue Computer Simulation for Drug Design and Medical Bioengineering)
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19 pages, 3645 KiB  
Article
Target Prediction of 5,10,15,20-Tetrakis(4′-Sulfonatophenyl)-Porphyrin Using Molecular Docking
by Ana-Maria Udrea, Andra Dinache, Angela Staicu and Speranta Avram
Pharmaceutics 2022, 14(11), 2390; https://doi.org/10.3390/pharmaceutics14112390 - 5 Nov 2022
Cited by 6 | Viewed by 1939
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 [...] Read more.
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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17 pages, 3876 KiB  
Article
Scaffold Repurposing Reveals New Nanomolar Phosphodiesterase Type 5 (PDE5) Inhibitors Based on Pyridopyrazinone Scaffold: Investigation of In Vitro and In Silico Properties
by Kamelia M. Amin, Ossama M. El-Badry, Doaa E. Abdel Rahman, Magda H. Abdellattif, Mohammed A. S. Abourehab, Mahmoud H. El-Maghrabey, Fahmy G. Elsaid, Mohamed A. El Hamd, Ahmed Elkamhawy and Usama M. Ammar
Pharmaceutics 2022, 14(9), 1954; https://doi.org/10.3390/pharmaceutics14091954 - 15 Sep 2022
Cited by 4 | Viewed by 2096
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 [...] Read more.
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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16 pages, 9073 KiB  
Article
Mechanistic Understanding of the Palmitoylation of Go Protein in the Allosteric Regulation of Adhesion Receptor GPR97
by Hao Zhang, Guojun Chu, Gaoming Wang, Min Yao, Shaoyong Lu and Ting Chen
Pharmaceutics 2022, 14(9), 1856; https://doi.org/10.3390/pharmaceutics14091856 - 2 Sep 2022
Cited by 12 | Viewed by 2564
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 [...] Read more.
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 Go protein is essential for Go’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−Go complex in the presence or absence of Go 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 Go protein. Structural and energetic analyses indicated that the palmitoylation of Go 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 Go not only allosterically strengthens the internal interactions between Gαo and Gβγ, but also enhances the coupling between Go and GPR97. Our study provides mechanistic insights into the regulation of aGPCRs via post-translational modifications of the Go 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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22 pages, 4322 KiB  
Article
Antiproliferative Copper(II) Complexes Bearing Mixed Chelating Ligands: Structural Characterization, ROS Scavenging, In Silico Studies, and Anti-Melanoma Activity
by Rodica Olar, Catalin Maxim, Mihaela Badea, Mihaela Bacalum, Mina Raileanu, Speranta Avram, Nataša Čelan Korošin, Teodora Burlanescu and Arpad Mihai Rostas
Pharmaceutics 2022, 14(8), 1692; https://doi.org/10.3390/pharmaceutics14081692 - 14 Aug 2022
Cited by 4 | Viewed by 2075
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 [...] Read more.
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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