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Drug Discovery and Development 2.0
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Drug Discovery and Development 2.0

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

Deadline for manuscript submissions: closed (28 February 2021) | Viewed by 19002

Special Issue Editor

Prof. Dr. William C. (Trey) Putnam

E-Mail Website
Guest Editor
1. Department of Pharmacy Practice, School of Pharmacy, Texas Tech University Health Sciences Center, 5920 Forest Park Avenue, Dallas, TX, USA
2. Department of Pharmaceutical Sciences, School of Pharmacy, Texas Tech University Health Sciences Center, 5920 Forest Park Avenue, Dallas, TX, USA
Interests: clinical pharmacology; drug discovery; drug development; drug regulatory affairs; biomarker discovery; altered metabolism of disease states; advanced analytical techniques
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The discovery and development processes, inclusive of regulatory affairs, manufacturing, and post-market operations, are cornerstones in the commercialization of innovative pharmaceutical and biotechnology products to address unmet clinical needs. Effective drug discovery processes provide a continuous pipeline of candidates for drug development, which in turn generates approvable compounds. Novel approaches across the fields of drug discovery, drug development, and regulatory affairs are of paramount interest to multiple healthcare industry stakeholders, including patients, biopharmaceutical manufacturers, clinicians, provider institutions, and payers. Examples of such innovations include enhanced drug screening protocols, in silico methodologies, computational-based toxicology, advanced manufacturing approaches, continuous manufacturing, process analytical technology, adaptive clinical trial designs, rolling marketing application submissions, and utilization of real-world evidence. The acceleration of and improvements to the drug development continuum will yield a more efficient and cost-effective pharmaceutical and biotechnology product commercialization process, as well as safer and more effective therapies, which provide improved clinical outcomes.

This Special Issue, “Drug Discovery, Drug Development, and Regulatory Affairs”, will focus on novel approaches (original research articles) as well as reviews of current practices surrounding the continuum of taking products from the beaker to the bedside. This Special Issue will present innovative research involving aspects of drug discovery and drug development for both small-molecule pharmaceuticals as well as biotechnology products.

Prof. Dr. William C. (Trey) Putnam
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 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. 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

  • drug discovery
  • drug development
  • biotechnology
  • target identification
  • target validation
  • regulatory affairs
  • regulatory sciences
  • drug commercialization
  • pharmaceutical market access
  • drug screening
  • novel nonclinical models/approaches
  • advanced manufacturing
  • continuous manufacturing
  • process analytical technology
  • adaptive clinical trials
  • in silico laboratory and clinical development
  • rolling submissions
  • accelerated approvals
  • real world evidence

Related Special Issue

Published Papers (5 papers)

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Research

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22 pages, 5005 KiB  
Article
Systems Medicine Design for Triple-Negative Breast Cancer and Non-Triple-Negative Breast Cancer Based on Systems Identification and Carcinogenic Mechanisms
by Shan-Ju Yeh, Bo-Jie Hsu and Bor-Sen Chen
Int. J. Mol. Sci. 2021, 22(6), 3083; https://doi.org/10.3390/ijms22063083 - 17 Mar 2021
Cited by 2 | Viewed by 2289
Abstract
Triple-negative breast cancer (TNBC) is a heterogeneous subtype of breast cancers with poor prognosis. The etiology of triple-negative breast cancer (TNBC) is involved in various biological signal cascades and multifactorial aberrations of genetic, epigenetic and microenvironment. New therapeutic for TNBC is urgently needed [...] Read more.
Triple-negative breast cancer (TNBC) is a heterogeneous subtype of breast cancers with poor prognosis. The etiology of triple-negative breast cancer (TNBC) is involved in various biological signal cascades and multifactorial aberrations of genetic, epigenetic and microenvironment. New therapeutic for TNBC is urgently needed because surgery and chemotherapy are the only available modalities nowadays. A better understanding of the molecular mechanisms would be a great challenge because they are triggered by cascade signaling pathways, genetic and epigenetic regulations, and drug–target interactions. This would allow the design of multi-molecule drugs for the TNBC and non-TNBC. In this study, in terms of systems biology approaches, we proposed a systematic procedure for systems medicine design toward TNBC and non-TNBC. For systems biology approaches, we constructed a candidate genome-wide genetic and epigenetic network (GWGEN) by big databases mining and identified real GWGENs of TNBC and non-TNBC assisting with corresponding microarray data by system identification and model order selection methods. After that, we applied the principal network projection (PNP) approach to obtain the core signaling pathways denoted by KEGG pathway of TNBC and non-TNBC. Comparing core signaling pathways of TNBC and non-TNBC, essential carcinogenic biomarkers resulting in multiple cellular dysfunctions including cell proliferation, autophagy, immune response, apoptosis, metastasis, angiogenesis, epithelial-mesenchymal transition (EMT), and cell differentiation could be found. In order to propose potential candidate drugs for the selected biomarkers, we designed filters considering toxicity and regulation ability. With the proposed systematic procedure, we not only shed a light on the differences between carcinogenetic molecular mechanisms of TNBC and non-TNBC but also efficiently proposed candidate multi-molecule drugs including resveratrol, sirolimus, and prednisolone for TNBC and resveratrol, sirolimus, carbamazepine, and verapamil for non-TNBC. Full article
(This article belongs to the Special Issue Drug Discovery and Development 2.0)
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16 pages, 3610 KiB  
Article
Potential Enhancement of Metformin Hydrochloride in Lipid Vesicles Targeting Therapeutic Efficacy in Diabetic Treatment
by Emmanuel Chekwube Ossai, Augustine Chidi Madueke, Benjamin Emenike Amadi, Martins Obinna Ogugofor, Audu Mumuni Momoh, Charles Odilichukwu R. Okpala, Chioma Assumpta Anosike and Obioma Uzoma Njoku
Int. J. Mol. Sci. 2021, 22(6), 2852; https://doi.org/10.3390/ijms22062852 - 11 Mar 2021
Cited by 5 | Viewed by 2566
Abstract
The potential enhancement of metformin hydrochloride (MH) loaded in lipid vesicles targeting therapeutic efficacy on alloxan-induced diabetic rats was investigated. This involved lipid vesicles formulated with homogenously distributed nano-sized particles by a novel integrated process of multiple emulsification by membrane and solvent evaporation. [...] Read more.
The potential enhancement of metformin hydrochloride (MH) loaded in lipid vesicles targeting therapeutic efficacy on alloxan-induced diabetic rats was investigated. This involved lipid vesicles formulated with homogenously distributed nano-sized particles by a novel integrated process of multiple emulsification by membrane and solvent evaporation. The average diameter of the water-in-oil (W1/O), W1/O/W2 emulsion droplets, and lipid vesicles was 192 nm, 52 µm, and 173 nm, respectively. The entrapment yield of metformin hydrochloride (MH) in the prepared lipid vesicles was 40.12%. The metformin hydrochloride-loaded lipid vesicles (MH-LLVs) sustained the release of the entrapped drug over a 12-h period and reduced the plasma glucose level of diabetic rats by 77.4% compared with free MH solution (2-h period and 58.2%, respectively) after one week post-diabetic treatment through oral administration of MH-LLV and the free drug. The remarkable improvement in the biochemical parameters recorded in the MH-LLV-treated animals compared with those that received free MH solutions depicted an enhanced kidney function, liver function, as well as oxidative stress status. Pancreatic histology depicted a pancreas with intralobular ducts (ID) and exocrine secretory acini that characterize an intact pancreas, which suggests the ability of the MH-LLVs to restore pancreatic cells to normal, on a continued treatment. Overall, MH-LLV appears an encouraging extended-release formulation with enhanced bioavailability, sustained release, and improved antihyperglycemic potentials. Full article
(This article belongs to the Special Issue Drug Discovery and Development 2.0)
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10 pages, 1542 KiB  
Article
Establishment of Novel Protein Interaction Assays between Sin3 and REST Using Surface Plasmon Resonance and Time-Resolved Fluorescence Energy Transfer
by Masamitsu Harada, Jun Nagai, Riho Kurata, Xiaofeng Cui, Takayuki Isagawa, Hiroaki Semba, Yasuhiro Yoshida, Norihiko Takeda, Koji Maemura and Tomo Yonezawa
Int. J. Mol. Sci. 2021, 22(5), 2323; https://doi.org/10.3390/ijms22052323 - 26 Feb 2021
Cited by 2 | Viewed by 2241
Abstract
Repressor element-1 (RE-1) or neural restrictive silencer element (NRSE) bound with a zinc finger transcription repressor, RE-1 silencing transcription factor (REST, also known as neural restrictive silencer factor, NRSF) has been identified as a fundamental repressor element in many genes, including neuronal genes. [...] Read more.
Repressor element-1 (RE-1) or neural restrictive silencer element (NRSE) bound with a zinc finger transcription repressor, RE-1 silencing transcription factor (REST, also known as neural restrictive silencer factor, NRSF) has been identified as a fundamental repressor element in many genes, including neuronal genes. Genes regulated by REST/NRSF regulate multifaceted neuronal phenotypes, and their defects in the machinery cause neuropathies, disorders of neuron activity), autism and so on. In REST repressions, the N-terminal repressor domain recruits Sin3B via its paired amphipathic helix 1 (PAH1) domain, which plays an important role as a scaffold for histone deacetylase 1 and 2. This machinery has a critical role in maintaining neuronal robustness. In this study, in order to establish protein–protein interaction assays mimicking a binding surface between Sin3B and REST, we selected important amino acids from structural information of the PAH1/REST complex and then tried to reconstitute it using recombinant short peptides derived from PAH1/REST. Initially, we validated whether biotinylated REST interacts with glutathione S-transferase (GST)-tagged PAH1 and whether another PAH1 peptide (PAH1-FLAG) competitively binds with biotinylated REST using surface plasmon resonance (SPR). We observed a direct interaction and competitive binding of two PAH1 peptides. Secondly, in order to establish a high-throughput and high-dynamic-range assay, we utilized an easily performed novel time-resolved fluorescence energy transfer (TR-FRET) assay, and closely monitored this interaction. Finally, we succeeded in establishing a novel high-quality TR-FRET assay and a novel interaction assay based on SPR. Full article
(This article belongs to the Special Issue Drug Discovery and Development 2.0)
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15 pages, 2513 KiB  
Article
In Silico/In Vitro Hit-to-Lead Methodology Yields SMYD3 Inhibitor That Eliminates Unrestrained Proliferation of Breast Carcinoma Cells
by Ilham M. Alshiraihi, Dillon K. Jarrell, Zeyad Arhouma, Kelly N. Hassell, Jaelyn Montgomery, Alyssa Padilla, Hend M. Ibrahim, Debbie C. Crans, Takamitsu A. Kato and Mark A. Brown
Int. J. Mol. Sci. 2020, 21(24), 9549; https://doi.org/10.3390/ijms21249549 - 15 Dec 2020
Cited by 7 | Viewed by 2381
Abstract
SMYD3 is a lysine methyltransferase that regulates the expression of over 80 genes and is required for the uncontrolled proliferation of most breast, colorectal, and hepatocellular carcinomas. The elimination of SMYD3 restores normal expression patterns of these genes and halts aberrant cell proliferation, [...] Read more.
SMYD3 is a lysine methyltransferase that regulates the expression of over 80 genes and is required for the uncontrolled proliferation of most breast, colorectal, and hepatocellular carcinomas. The elimination of SMYD3 restores normal expression patterns of these genes and halts aberrant cell proliferation, making it a promising target for small molecule inhibition. In this study, we sought to establish a proof of concept for our in silico/in vitro hit-to-lead enzyme inhibitor development platform and to identify a lead small molecule candidate for SMYD3 inhibition. We used Schrodinger® software to screen libraries of small molecules in silico and the five compounds with the greatest predicted binding affinity within the SMYD3 binding pocket were purchased and assessed in vitro in direct binding assays and in breast cancer cell lines. We have confirmed the ability of one of these inhibitors, Inhibitor-4, to restore normal rates of cell proliferation, arrest the cell cycle, and induce apoptosis in breast cancer cells without affecting wildtype cell behavior. Our results provide a proof of concept for this fast and affordable small molecule hit-to-lead methodology as well as a promising candidate small molecule SMYD3 inhibitor for the treatment of human cancer. Full article
(This article belongs to the Special Issue Drug Discovery and Development 2.0)
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Review

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21 pages, 1612 KiB  
Review
Advancing Drug Discovery for Neurological Disorders Using iPSC-Derived Neural Organoids
by Gianluca Costamagna, Giacomo Pietro Comi and Stefania Corti
Int. J. Mol. Sci. 2021, 22(5), 2659; https://doi.org/10.3390/ijms22052659 - 6 Mar 2021
Cited by 35 | Viewed by 8645
Abstract
In the last decade, different research groups in the academic setting have developed induced pluripotent stem cell-based protocols to generate three-dimensional, multicellular, neural organoids. Their use to model brain biology, early neural development, and human diseases has provided new insights into the pathophysiology [...] Read more.
In the last decade, different research groups in the academic setting have developed induced pluripotent stem cell-based protocols to generate three-dimensional, multicellular, neural organoids. Their use to model brain biology, early neural development, and human diseases has provided new insights into the pathophysiology of neuropsychiatric and neurological disorders, including microcephaly, autism, Parkinson’s disease, and Alzheimer’s disease. However, the adoption of organoid technology for large-scale drug screening in the industry has been hampered by challenges with reproducibility, scalability, and translatability to human disease. Potential technical solutions to expand their use in drug discovery pipelines include Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) to create isogenic models, single-cell RNA sequencing to characterize the model at a cellular level, and machine learning to analyze complex data sets. In addition, high-content imaging, automated liquid handling, and standardized assays represent other valuable tools toward this goal. Though several open issues still hamper the full implementation of the organoid technology outside academia, rapid progress in this field will help to prompt its translation toward large-scale drug screening for neurological disorders. Full article
(This article belongs to the Special Issue Drug Discovery and Development 2.0)
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