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The Future of Drug Discovery and Development

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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 (30 October 2023) | Viewed by 114659

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Prof. Dr. William C. (Trey) Putnam

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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
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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, “The Future of Drug Discovery and Development”, 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

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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

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Published Papers (9 papers)

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Research

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25 pages, 2702 KiB

Open AccessArticle

Towards Anticancer and Antibacterial Agents: Design and Synthesis of 1,2,3-Triazol-quinobenzothiazine Derivatives

by Ewa Kisiel-Nawrot, Dominika Pindjakova, Malgorzata Latocha, Andrzej Bak, Violetta Kozik, Kinga Suwinska, Alois Cizek, Josef Jampilek and Andrzej Zięba

Int. J. Mol. Sci. 2023, 24(17), 13250; https://doi.org/10.3390/ijms241713250 - 26 Aug 2023

Cited by 3 | Viewed by 1494

Abstract

In this paper, we describe a new method for synthesizing hybrid combinations of 1,2,3-triazoles with a tetracyclic quinobenzothiazinium system. The developed approach allowed for the production of a series of new azaphenothiazine derivatives with the 1,2,3-triazole system in different positions of the benzene ring. In practice, the methodology consists of the reaction of triazole aniline derivatives with thioquinanthrenediinium bis-chloride. The structure of the products was determined by ¹H-NMR, ¹³C-NMR spectroscopy, and HR-MS spectrometry, respectively. Moreover, the spatial structure of the molecule and the arrangement of molecules in the crystal (unit cell) were determined by X-ray crystallography. The anticancer activity profiles of the synthesized compounds were tested in vitro against human cancer cells of the A549, SNB-19, and T47D lines and the normal NHDF cell line. Additional tests of antibacterial activity against methicillin-sensitive and methicillin-resistant staphylococci, vancomycin-sensitive and vancomycin-resistant enterococci, and two mycobacterial strains were also performed. In fact, the dependence of anticancer and antibacterial activity on the substituent type and its position in the quinobenzothiazinium system was observed. Furthermore, the distance-guided property evaluation was performed using principal component analysis (PCA) and hierarchical clustering analysis (HCA) on the pool of the calculated descriptors. Finally, the theoretically approximated partition coefficients (clogP) were (inter-)correlated with each other and cross-compared with the empirically specified logP_TLC parameters. Full article

(This article belongs to the Special Issue The Future of Drug Discovery and Development)

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15 pages, 7458 KiB

Open AccessArticle

Selective α₃β₄ Nicotinic Acetylcholine Receptor Ligand as a Potential Tracer for Drug Addiction

by Apinan Kanasuwan, Winnie Deuther-Conrad, Sumet Chongruchiroj, Jiradanai Sarasamkan, Chanisa Chotipanich, Opa Vajragupta and Kuntarat Arunrungvichian

Int. J. Mol. Sci. 2023, 24(4), 3614; https://doi.org/10.3390/ijms24043614 - 10 Feb 2023

Cited by 2 | Viewed by 2557

Abstract

α₃β₄ Nicotinic acetylcholine receptor (nAChR) has been recognized as an emerging biomarker for the early detection of drug addiction. Herein, α₃β₄ nAChR ligands were designed and synthesized to improve the binding affinity and selectivity of two lead compounds, (S)-QND8 and (S)-T2, for the development of an α₃β₄ nAChR tracer. The structural modification was achieved by retaining the key features and expanding the molecular structure with a benzyloxy group to increase the lipophilicity for blood-brain barrier penetration and to extend the ligand-receptor interaction. The preserved key features are a fluorine atom for radiotracer development and a p-hydroxyl motif for ligand-receptor binding affinity. Four (R)- and (S)-quinuclidine-triazole (AK1-AK4) were synthesized and the binding affinity, together with selectivity to α₃β₄ nAChR subtype, were determined by competitive radioligand binding assay using [³H]epibatidine as a radioligand. Among all modified compounds, AK3 showed the highest binding affinity and selectivity to α₃β₄ nAChR with a K_i value of 3.18 nM, comparable to (S)-QND8 and (S)-T2 and 3069-fold higher affinity to α₃β₄ nAChR in comparison to α₇ nAChR. The α₃β₄ nAChR selectivity of AK3 was considerably higher than those of (S)-QND8 (11.8-fold) and (S)-T2 (294-fold). AK3 was shown to be a promising α₃β₄ nAChR tracer for further development as a radiotracer for drug addiction. Full article

(This article belongs to the Special Issue The Future of Drug Discovery and Development)

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11 pages, 583 KiB

Open AccessArticle

HPLC Method Validation for the Estimation of Lignocaine HCl, Ketoprofen and Hydrocortisone: Greenness Analysis Using AGREE Score

by Tariq Mehmood, Sana Hanif, Faiza Azhar, Ijaz Ali, Ahmed Alafnan, Talib Hussain, Afrasim Moin, Mubarak A. Alamri and Muhammad Ali Syed

Int. J. Mol. Sci. 2023, 24(1), 440; https://doi.org/10.3390/ijms24010440 - 27 Dec 2022

Cited by 11 | Viewed by 3608

Abstract

In the current study, the reversed-phased high-pressure liquid chromatography (RP-HPLC) method was proposed for the estimation of lignocaine hydrochloride (LIG), hydrocortisone (HYD) and Ketoprofen (KET) according to International Conference for Harmonization (ICH) Q2 R1 guidelines, in a gel formulation. The chromatographic evaluation was executed using Shimadzu RP-HPLC, equipped with a C8 column and detected using UV at 254 nm wavelength, using acetonitrile and buffer (50:50) as a mobile phase and diluent, at flow rate 1 mL/min and n injection volume of 20 μL. The retention time for LIG, HYD, and KET were 1.54, 2.57, and 5.78 min, correspondingly. The resultant values of analytical recovery demonstrate accuracy and precision of the method and was found specific in identification of the drugs from dosage form and marketed products. The limit of detection (LOD) for LIG, HYD, and KET were calculated to be 0.563, 0.611, and 0.669 ppm, while the limit of quantification (LOQ) was estimated almost at 1.690, 1.833, and 0.223 ppm, respectively. The AGREE software was utilized to evaluate the greenness score of the proposed method, and it was found greener in score (0.76). This study concluded that the proposed method was simple, accurate, precise, robust, economical, reproducible, and suitable for the estimation of drugs in transdermal gels. Full article

(This article belongs to the Special Issue The Future of Drug Discovery and Development)

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23 pages, 3928 KiB

Open AccessArticle

ES-Screen: A Novel Electrostatics-Driven Method for Drug Discovery Virtual Screening

by Naiem T. Issa, Stephen W. Byers and Sivanesan Dakshanamurthy

Int. J. Mol. Sci. 2022, 23(23), 14830; https://doi.org/10.3390/ijms232314830 - 27 Nov 2022

Cited by 1 | Viewed by 1782

Abstract

Electrostatic interactions drive biomolecular interactions and associations. Computational modeling of electrostatics in biomolecular systems, such as protein-ligand, protein–protein, and protein-DNA, has provided atomistic insights into the binding process. In drug discovery, finding biologically plausible ligand-protein target interactions is challenging as current virtual screening and adjuvant techniques such as docking methods do not provide optimal treatment of electrostatic interactions. This study describes a novel electrostatics-driven virtual screening method called ‘ES-Screen’ that performs well across diverse protein target systems. ES-Screen provides a unique treatment of electrostatic interaction energies independent of total electrostatic free energy, typically employed by current software. Importantly, ES-Screen uses initial ligand pose input obtained from a receptor-based pharmacophore, thus independent of molecular docking. ES-Screen integrates individual polar and nonpolar replacement energies, which are the energy costs of replacing the cognate ligand for a target with a query ligand from the screening. This uniquely optimizes thermodynamic stability in electrostatic and nonpolar interactions relative to an experimentally determined stable binding state. ES-Screen also integrates chemometrics through shape and other physicochemical properties to prioritize query ligands with the greatest physicochemical similarities to the cognate ligand. The applicability of ES-Screen is demonstrated with in vitro experiments by identifying novel targets for many drugs. The present version includes a combination of many other descriptor components that, in a future version, will be purely based on electrostatics. Therefore, ES-Screen is a first-in-class unique electrostatics-driven virtual screening method with a unique implementation of replacement electrostatic interaction energies with broad applicability in drug discovery. Full article

(This article belongs to the Special Issue The Future of Drug Discovery and Development)

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Review

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25 pages, 4518 KiB

Open AccessReview

Tetrazoles and Related Heterocycles as Promising Synthetic Antidiabetic Agents

by Rostislav E. Trifonov and Vladimir A. Ostrovskii

Int. J. Mol. Sci. 2023, 24(24), 17190; https://doi.org/10.3390/ijms242417190 - 6 Dec 2023

Cited by 3 | Viewed by 1941

Abstract

Tetrazole heterocycle is a promising scaffold in drug design, and it is incorporated into active pharmaceutical ingredients of medications of various actions: hypotensives, diuretics, antihistamines, antibiotics, analgesics, and others. This heterocyclic system is metabolically stable and easily participates in various intermolecular interactions with different biological targets through hydrogen bonding, conjugation, or van der Waals forces. In the present review, a systematic analysis of the activity of tetrazole derivatives against type 2 diabetes mellitus (T2DM) has been performed. As it was shown, the tetrazolyl moiety is a key fragment of many antidiabetic agents with different activities, including the following: peroxisome proliferator-activated receptors (PPARs) agonists, protein tyrosine phosphatase 1B (PTP1B) inhibitors, aldose reductase (AR) inhibitors, dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) agonists, G protein-coupled receptor (GPCRs) agonists, glycogen phosphorylases (GP) Inhibitors, α-glycosidase (AG) Inhibitors, sodium glucose co-transporter (SGLT) inhibitors, fructose-1,6-bisphosphatase (FBPase) inhibitors, IkB kinase ε (IKKε) and TANK binding kinase 1 (TBK1) inhibitors, and 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). In many cases, the tetrazole-containing leader compounds markedly exceed the activity of medications already known and used in T2DM therapy, and some of them are undergoing clinical trials. In addition, tetrazole derivatives are very often used to act on diabetes-related targets or to treat post-diabetic disorders. Full article

(This article belongs to the Special Issue The Future of Drug Discovery and Development)

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19 pages, 1394 KiB

Open AccessReview

Investigational Drugs for the Treatment of Postherpetic Neuralgia: Systematic Review of Randomized Controlled Trials

by Miguel Á. Huerta, Miguel M. Garcia, Beliu García-Parra, Ancor Serrano-Afonso and Nancy Paniagua

Int. J. Mol. Sci. 2023, 24(16), 12987; https://doi.org/10.3390/ijms241612987 - 20 Aug 2023

Cited by 7 | Viewed by 6607

Abstract

The pharmacological treatment of postherpetic neuralgia (PHN) is unsatisfactory, and there is a clinical need for new approaches. Several drugs under advanced clinical development are addressed in this review. A systematic literature search was conducted in three electronic databases (Medline, Web of Science, Scopus) and in the ClinicalTrials.gov register from 1 January 2016 to 1 June 2023 to identify Phase II, III and IV clinical trials evaluating drugs for the treatment of PHN. A total of 18 clinical trials were selected evaluating 15 molecules with pharmacological actions on nine different molecular targets: Angiotensin Type 2 Receptor (AT2R) antagonism (olodanrigan), Voltage-Gated Calcium Channel (VGCC) α2δ subunit inhibition (crisugabalin, mirogabalin and pregabalin), Voltage-Gated Sodium Channel (VGSC) blockade (funapide and lidocaine), Cyclooxygenase-1 (COX-1) inhibition (TRK-700), Adaptor-Associated Kinase 1 (AAK1) inhibition (LX9211), Lanthionine Synthetase C-Like Protein (LANCL) activation (LAT8881), N-Methyl-D-Aspartate (NMDA) receptor antagonism (esketamine), mu opioid receptor agonism (tramadol, oxycodone and hydromorphone) and Nerve Growth Factor (NGF) inhibition (fulranumab). In brief, there are several drugs in advanced clinical development for treating PHN with some of them reporting promising results. AT2R antagonism, AAK1 inhibition, LANCL activation and NGF inhibition are considered first-in-class analgesics. Hopefully, these trials will result in a better clinical management of PHN. Full article

(This article belongs to the Special Issue The Future of Drug Discovery and Development)

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20 pages, 375 KiB

Open AccessReview

mRNA: Vaccine or Gene Therapy? The Safety Regulatory Issues

by Helene Banoun

Int. J. Mol. Sci. 2023, 24(13), 10514; https://doi.org/10.3390/ijms241310514 - 22 Jun 2023

Cited by 14 | Viewed by 87381

Abstract

COVID-19 vaccines were developed and approved rapidly in response to the urgency created by the pandemic. No specific regulations existed at the time they were marketed. The regulatory agencies therefore adapted them as a matter of urgency. Now that the pandemic emergency has passed, it is time to consider the safety issues associated with this rapid approval. The mode of action of COVID-19 mRNA vaccines should classify them as gene therapy products (GTPs), but they have been excluded by regulatory agencies. Some of the tests they have undergone as vaccines have produced non-compliant results in terms of purity, quality and batch homogeneity. The wide and persistent biodistribution of mRNAs and their protein products, incompletely studied due to their classification as vaccines, raises safety issues. Post-marketing studies have shown that mRNA passes into breast milk and could have adverse effects on breast-fed babies. Long-term expression, integration into the genome, transmission to the germline, passage into sperm, embryo/fetal and perinatal toxicity, genotoxicity and tumorigenicity should be studied in light of the adverse events reported in pharmacovigilance databases. The potential horizontal transmission (i.e., shedding) should also have been assessed. In-depth vaccinovigilance should be carried out. We would expect these controls to be required for future mRNA vaccines developed outside the context of a pandemic. Full article

(This article belongs to the Special Issue The Future of Drug Discovery and Development)

33 pages, 6595 KiB

Open AccessReview

Roles of Virtual Screening and Molecular Dynamics Simulations in Discovering and Understanding Antimalarial Drugs

by Searle S. Duay, Rianne Casey Y. Yap, Arturo L. Gaitano III, June Alexis A. Santos and Stephani Joy Y. Macalino

Int. J. Mol. Sci. 2023, 24(11), 9289; https://doi.org/10.3390/ijms24119289 - 26 May 2023

Cited by 8 | Viewed by 3838

Abstract

Malaria continues to be a global health threat, with approximately 247 million cases worldwide. Despite therapeutic interventions being available, patient compliance is a problem due to the length of treatment. Moreover, drug-resistant strains have emerged over the years, necessitating urgent identification of novel and more potent treatments. Given that traditional drug discovery often requires a great deal of time and resources, most drug discovery efforts now use computational methods. In silico techniques such as quantitative structure-activity relationship (QSAR), docking, and molecular dynamics (MD) can be used to study protein-ligand interactions and determine the potency and safety profile of a set of candidate compounds to help prioritize those tested using assays and animal models. This paper provides an overview of antimalarial drug discovery and the application of computational methods in identifying candidate inhibitors and elucidating their potential mechanisms of action. We conclude with the continued challenges and future perspectives in the field of antimalarial drug discovery. Full article

(This article belongs to the Special Issue The Future of Drug Discovery and Development)

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9 pages, 2936 KiB

Open AccessBrief Report

Cannabidiol and Beta-Caryophyllene in Combination: A Therapeutic Functional Interaction

by Henry Blanton, Linda Yin, Joshua Duong and Khalid Benamar

Int. J. Mol. Sci. 2022, 23(24), 15470; https://doi.org/10.3390/ijms232415470 - 7 Dec 2022

Cited by 8 | Viewed by 3854

Abstract

Cannabis contains over 500 distinct compounds, which include cannabinoids, terpenoids, and flavonoids. However, very few of these compounds have been studied for their beneficial effects. There is an emerging concept that the constituents of the cannabis plant may work in concert to achieve better therapeutic benefits. This study is aimed at determining if the combination of a minor cannabinoid (cannabidiol, CBD) and a terpene (beta-caryophyllene, BCP) works in concert and if this has any therapeutic value. We used an inflammatory pain model (formalin) in mice to test for any functionality of CBD and BCP in combination. First, we determined the analgesic effect of CBD and BCP individually by establishing dose-response studies. Second, we tested the analgesic effect of fixed-ratio combinations and monitored any adverse effects. Finally, we determined the effect of this combination on inflammation. The combination of CBD and BCP produces a synergistic analgesic effect. This effect was without the cannabinoid receptor-1 side effects. The analgesic effect of CBD and BCP in combination involves an inflammatory mechanism. The combination of these two constituents of the cannabis plant, CBD and BCP, works in concert to produce a therapeutic effect with safety profiles through an inflammatory mechanism. Full article

(This article belongs to the Special Issue The Future of Drug Discovery and Development)

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