Drug Development Research[JOURNAL]
Sun
200 papers
Beyond the Forest Plot: Redefining Model-Based Meta-Analysis as a Quantitative Engine for Model-Informed Drug Development.
Sukumaran B, Xavier RM, Vs A … +4 more , Sm S, H R, Kp A, M D
Drug Dev Res · 2026 Feb · PMID 41536205 · Publisher ↗
Despite the fact that meta-analysis is a widely utilized methodology in synthesis of evidence from clinical trials, traditional methodologies have limitations with regards to informing dose selection, time-course dynamic...
Despite the fact that meta-analysis is a widely utilized methodology in synthesis of evidence from clinical trials, traditional methodologies have limitations with regards to informing dose selection, time-course dynamics and quantitative decision-making across the drug-development continuum. To overcome these limitations, a complex evidence-synthesis model, Model-Based Meta-analysis (MBMA) was proposed to combine pharmacometric modeling and the concepts of meta-analysis. MBMA provides predictive information, by explicitly considering dose-response relationships and longitudinal treatment effects, and by considering between-study heterogeneity, that goes beyond the information provided by a single-time-point summary. Although proven valuable, MBMA remains underutilized and inconsistently applied, partly due to methodological complexity, lack of standardization, and a continued misunderstanding with traditional meta-analysis. The aim of the present review is to critically assess MBMA as a quantitative engine of model-informed drug development (MIDD) and demystify the methodological underpinnings of this technique and its practical applicability. The major MBMA techniques are summarized and synthesized, namely nonlinear mixed-effects modelling, Bayesian hierarchical models and the estimation of models and validation as well as the quantification of uncertainty. The use in therapeutic areas is discussed to demonstrate how MBMA can be used in dose optimization, comparison of efficacy, paediatric extrapolation, and trial design. Regulatory considerations and emerging guidance supporting model-based approaches are also addressed. Landmarking MBMA as a significant distinction from traditional meta-analysis and highlighting its influence on clinical and regulatory decision-making, the review establishes MBMA as an undeniably imperative instrument in translating the heterogeneous clinical data into actionable insights across the lifecycle of drug-development.
Exploring CPP Enhanced Hypoxia Targeting: An Approach Using Radiolabeled 2-nitroimidazole TAT Conjugate.
Mittal S, Jain A, Babu A … +2 more , Kumar C, Mallia MB
Drug Dev Res · 2026 Feb · PMID 41536193 · Full text
Mediated by their protein transduction domain, cell-penetrating peptides (CPPs) have been widely explored for facilitating intracellular delivery of drugs and small molecules. In this study, a radiolabeled, 2-nitroimidaz...
Mediated by their protein transduction domain, cell-penetrating peptides (CPPs) have been widely explored for facilitating intracellular delivery of drugs and small molecules. In this study, a radiolabeled, 2-nitroimidazole conjugated TAT (TAT - transactivator of transcription) peptide was prepared and evaluated for targeting tumor hypoxia. The conjugate was radiolabeled with iodine-125 and comprehensive in vitro and in vivo evaluations were conducted to assess its potential to target hypoxic cells. A radiolabeled [I]I-TAT was also prepared as a control. In vitro studies carried out in CHO cells under hypoxic conditions revealed three fold uptake of [I]I-TAT-2-NIM compared to [I]I-TAT at 1 h post-incubation, which further increased sixfold at 4 h post-incubation, clearly demonstrating the role of nitroimidazole in targeting hypoxic cells. However, the study also revealed a negative influence of hypoxia in cellular uptake, wherein the radiolabeled TAT peptides showed a lower uptake in cells under hypoxic conditions than in normoxic conditions. In vivo, [I]I-TAT-2-NIM showed uptake and retention in the tumor with the tumor/muscle ratio above 2 at all time points studied. However, the tumor/blood ratio was found to decrease with time. Though [ I]I-TAT-2-NIM showed higher accumulation in hypoxic cells compared to [I]I-TAT in vitro, the negative influence of hypoxia on the cellular uptake of TAT-peptides possibly indicates their limitation for hypoxia targeting applications.
Iridium(III) Complexes for Lung Cancer Therapy: Recent Advances and Case Studies in DNA Targeting, Antioxidant Activity and Cytotoxicity.
Joshi B, Chakraborty S, Manickam V … +1 more , Shivashankar M
Drug Dev Res · 2026 Feb · PMID 41527510 · Publisher ↗
Lung cancer remains a leading cause of cancer-related mortality, and resistance to platinum-based chemotherapy necessitates the development of alternative metal-based therapeutics. In this study, two iridium(III) complex...
Lung cancer remains a leading cause of cancer-related mortality, and resistance to platinum-based chemotherapy necessitates the development of alternative metal-based therapeutics. In this study, two iridium(III) complexes were synthesized and systematically investigated for their photophysical and biological properties. Spectroscopic characterisation confirmed effective ligand coordination and metal-to-ligand charge transfer behaviour. Both complexes exhibited significant interaction with calf thymus DNA, with intrinsic binding constants of 5.01 × 10M and 1.08 × 10M, and showed strong affinity towards human serum albumin (K up to 8.30 × 10M). Antioxidant activity assessed by the DPPH assay revealed moderate radical scavenging ability. Cytotoxicity studies using an MTT assay demonstrated concentration-dependent antiproliferative activity against A549 lung cancer cells, with IC values of 57.6 µM and 36.0 µM, while maintaining low toxicity towards normal HEK 293 cells.
Desmopressin Induces Mitochondrial Fragmentation and Dysfunction in Human U87 MG Glioma Cells via CaMKII-Drp1 Signaling Pathway.
Liang S, Zhu Y, Su J … +2 more , Luo C, Yang C
Drug Dev Res · 2026 Feb · PMID 41527347 · Publisher ↗
Mitochondrial dynamics play a crucial role in glioma progression by regulating cellular metabolism, proliferation, and survival. This study investigated the effects of desmopressin (dDAVP), a synthetic vasopressin analog...
Mitochondrial dynamics play a crucial role in glioma progression by regulating cellular metabolism, proliferation, and survival. This study investigated the effects of desmopressin (dDAVP), a synthetic vasopressin analog, on mitochondrial function in human U87 MG glioma cells. Our results demonstrate that dDAVP treatment induces dose-dependent cytotoxicity while upregulating vasopressin type 2 receptor expression. The compound significantly increased oxidative stress markers and impaired mitochondrial function, as evidenced by reduced ATP production, compromised respiratory chain activity, and decreased oxygen consumption. Furthermore, dDAVP promoted mitochondrial fragmentation through Drp1 activation, enhancing its phosphorylation at Ser616 and subsequent mitochondrial translocation. Mechanistically, dDAVP was found to activate CaMKII signaling, which mediated the observed changes in Drp1 phosphorylation and mitochondrial dynamics. The CaMKII inhibitor KN-93 effectively reversed dDAVP-induced mitochondrial fragmentation, Drp1 phosphorylation, and energy metabolism impairment. The AVPR2 antagonist tolvaptan blocked dDAVP effects, confirming receptor specificity. These findings reveal that dDAVP disrupts mitochondrial homeostasis in glioma cells through AVPR2-mediated CaMKII-dependent regulation of Drp1 activity, leading to mitochondrial dysfunction and cell damage. The study provides new insights into the molecular mechanisms underlying dDAVP's effects on glioma cells and suggests potential therapeutic applications targeting the CaMKII-Drp1 axis in glioma treatment.
Mitochondrial Dysfunction in Inflammatory Skin Diseases: Mechanisms, Biomarkers, and Emerging Therapeutic Strategies.
Li M, Zhao G, Zhao GW … +1 more , Shen J
Drug Dev Res · 2026 Feb · PMID 41508288 · Publisher ↗
Mitochondrial dysfunction critically underpins the pathogenesis of inflammatory skin diseases such as psoriasis, vitiligo, atopic dermatitis, and impaired wound healing. This comprehensive review synthesizes recent evide...
Mitochondrial dysfunction critically underpins the pathogenesis of inflammatory skin diseases such as psoriasis, vitiligo, atopic dermatitis, and impaired wound healing. This comprehensive review synthesizes recent evidence to elucidate mechanisms, including compromised bioenergetics, excessive reactive oxygen species (ROS), mitochondrial DNA (mtDNA) damage, and aberrant mitochondrial dynamics. Distinct from prior work, this analysis uncovers novel findings: mtDNA acts as a damage-associated molecular pattern, activating cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathways to drive type I interferon in vitiligo and IL-17A in psoriasis; succinate-mediated immune-metabolic signaling amplifies type 2 inflammation in atopic dermatitis; and subclinical mitochondrial impairments in non-lesional skin serve as early indicators of disease susceptibility across these conditions. Preclinical studies have shown that emerging therapies, including antioxidants (e.g., NMN), mitochondrial modulators (e.g., SS31), senotherapeutics, and mitochondrial transplantation, are promising strategies for restoring cellular function. Future research should focus on multi-omics to dissect mitochondrial-epigenetic interactions, validate mitochondrial metabolites like succinate as diagnostic biomarkers, and explore synergistic combination therapies. This integrative framework of mitochondrial-driven pathology provides fresh perspectives to advance diagnostic and therapeutic innovation in dermatology.
Protective Effects of Herbacetin in Experimental Colitis: Targeting NF-κB and NLRP3 Pathways.
Bseiso Y, Alotaibi BS, Aljabali AAA … +5 more , Gammoh O, Rabeh ME, Rabi AM, Qnais E, Alqudah A
Drug Dev Res · 2026 Feb · PMID 41486523 · Publisher ↗
Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD) resulting from a dysregulation of immune responses. Herbacetin, a flavonoid of natural origin, has been found to exert an anti-inflammatory action, th...
Ulcerative colitis (UC) is a type of inflammatory bowel disease (IBD) resulting from a dysregulation of immune responses. Herbacetin, a flavonoid of natural origin, has been found to exert an anti-inflammatory action, though its actions in experimental colitis are unknown. Colitis was induced in BALB/c mice with 2,4,6-trinitrobenzenesulfonic acid (TNBS). Mice were administered with herbacetin (25, 50, 100 mg/kg) or sulfasalazine (100 mg/kg) orally for 7 days. The disease activity index (DAI), colon length, weight/length ratio, histopathology, MPO and NO contents, and inflammatory gene expression (NF-κB, iNOS, COX-2, NLRP3, IL-1β, IL-18) were evaluated. TNBS induced marked weight loss and increased DAI (p < 0.01 vs. NC). Body weight (p < 0.01) and DAI (p < 0.01) were significantly ameliorated by herbacetin, especially at 50 and 100 mg/kg. TNBS significantly reduced the colon length (p < 0.001) and increased the weight/length ratio (p < 0.001), which were significantly counteracted by herbacetin (p < 0.01-0.001). TNBS mice presented with mucosal injury and inflammatory infiltration were demonstrated by histopathology (p < 0.001) and a dose-dependent healing effect was observed in herbacetin-treated mice. TNBS mice had higher levels of MPO and NO (p < 0.001), which were significantly attenuated by herbacetin (p < 0.01-0.001). Herbacetin decreased the mRNA expression levels of NF-κB, iNOS, COX-2, NLRP3, IL-1β, and IL-18 in a dose-dependent (p < 0.05-0.001). Herbacetin exerts a protective effect in colitis by suppressing neutrophil infiltration, oxidative stress, and NF-κB-NLRP3-mediated inflammation, highlighting the potential of herbacetin-based treatment for UC and related inflammatory bowel diseases.
Polydatin Protects Against the Formation of PPE-Induced Abdominal Aortic Aneurysms in Mice by Activating Nuclear Factor Erythroid 2-Related Factor 2.
Liu Z, Zhu J, Zhou Q … +2 more , Qian H, Cui F
Drug Dev Res · 2026 Feb · PMID 41486502 · Full text
Sudden death resulting from abdominal aortic aneurysm (AAA) rupture is a highly fatal cardiovascular condition. There remains an urgent need to identify innovative therapeutic strategies capable of decelerating AAA progr...
Sudden death resulting from abdominal aortic aneurysm (AAA) rupture is a highly fatal cardiovascular condition. There remains an urgent need to identify innovative therapeutic strategies capable of decelerating AAA progression and rupture. Although polydatin (PLD) has been consistently shown to exert potent anti-inflammatory effects in diverse pathological contexts, its regulatory role in AAA has not yet been investigated. Using a porcine pancreatic elastase (PPE) infusion-induced AAA mouse model, we comprehensively evaluated PLD's influence on NRF2 signaling by Western blot (WB) analysis, immunohistochemistry (IHC), immunofluorescence (IF), flow cytometry (FC), and real-time quantitative PCR (RT-qPCR) tests. Our findings demonstrate that PLD robustly activates NRF2 pathway, thereby attenuating AAA formation by curbing smooth muscle cell (SMCs) phenotypic transformation and apoptosis, as well as suppressing macrophage-mediated inflammatory responses.
Overcoming Resistance in EGFR-Mutant Cancers: A Comprehensive Review of Inhibitor Evolution and SAR-Based Design.
Naykwadi H, Alavala RR
Drug Dev Res · 2026 Feb · PMID 41486501 · Publisher ↗
The epidermal growth factor receptor (EGFR) is a key target in cancer therapy, mainly in non-small cell lung cancer (NSCLC). Though, the efficacy of EGFR-targeted therapies is limited by the development of resistance. Th...
The epidermal growth factor receptor (EGFR) is a key target in cancer therapy, mainly in non-small cell lung cancer (NSCLC). Though, the efficacy of EGFR-targeted therapies is limited by the development of resistance. This comprehensive review details the structural biology of EGFR and its role in oncogenic signaling, elucidating the major activating mutations, particularly exon 19 deletions and L858R point mutations, and acquired resistance. The progressive development of EGFR tyrosine kinase inhibitors (TKIs), from first-generation ATP-competitive inhibitors (e.g., gefitinib, erlotinib) to third-generation covalent agents (e.g., osimertinib) and emerging fourth-generation allosteric and degradation approaches, are critically examined for their mechanisms, efficacy, and clinical limitations. We have also discussed about the intrinsic and acquired resistance mechanisms, including alternative oncogenic drivers (KRAS, ALK), bypass pathway activations (MET, HER2), and phenotypic changes like epithelial-mesenchymal transition. Additionally, we emphasize the role of computational modeling, high-throughput SAR studies, and preclinical models, including patient-derived xenografts and organoids, in guiding rational drug design. Emerging approaches integrating artificial intelligence, machine learning, and precision oncology hold potential to accelerate EGFR-targeted drug discovery. The combination strategies with immunotherapy, and anti-angiogenic agents are considered in the context of improving patient outcomes. Together, ongoing advances in understanding EGFR signaling and resistance mechanisms are driving the development of next-generation inhibitors and personalized therapies, with the ultimate goal of overcoming drug resistance and improve patient outcomes in EGFR-mutant cancers.
Novel 4-chlorophenyl and 3/4-chlorophenoxy Based Triazole/Thiazole Derivatives: Synthesis and Investigation of Their Effects on Neurodegenerative Disorders-Related Enzymes via In Vitro and In Silico.
Dawbaa S, Nuha D, Evren AE … +2 more , Sağlik BN, Yurttaş L
Drug Dev Res · 2026 Feb · PMID 41476393 · Publisher ↗
In this study, nine new synthesized compounds were investigated for their enzyme inhibition activity and evaluated for their ADME parameters and DFT-based properties. The compounds were classified into two main structure...
In this study, nine new synthesized compounds were investigated for their enzyme inhibition activity and evaluated for their ADME parameters and DFT-based properties. The compounds were classified into two main structures: derivatives of 2-(3/4-chlorophenoxy)-N-(3-(4-chlorophenyl)-4-(4-substituted phenyl)thiazol-2(3H)-ylidene)propanehydrazide (4a-4f) and N-(6-substituted benzothiazol-2-yl)-2-((5-(1-(3-chlorophenoxy)ethyl)-4-(4-chlorophenyl)-4H-1,2,4-triazol-3-yl)thio)acetamide (6a-6c). The inhibitory effects of these compounds on cholinesterase and MAO enzymes were studied, and their percentages of inhibition were determined. It was found that the compounds exhibited higher inhibition of AChE than BChE, with compounds 4e, 6a, and 6b showing the highest percentage inhibition against AChE. In terms of MAO inhibition, compounds 6a and 6b demonstrated significant potency against MAO-A, while compounds 4a, 4 d, 4 f, and 6c exhibited inhibition against MAO-A above 55.372%. The compounds also showed notable inhibition against MAO-B, with compounds 4a, 4 f, 6a, and 6b displaying the highest inhibitory activity. DFT studies revealed the optimized molecular structures and the energy difference between the HOMO and LUMO orbitals. Compound 4a exhibited greater activity and compound 4 f showed nucleophilic character, while compound 6a displayed higher electronegativity and nucleophilic character. In silico analyses indicated that the benzothiazole moiety was localized at the outer region of the MAOs, whereas the phenoxy and 4-chlorophenyl moieties were positioned near the FAD cofactor within the inner pocket. It was also suggested that the acyl moiety is pivotal in forming H-bonds with the key residues. These findings contribute to the understanding of the enzyme inhibition activity and molecular properties of the azole-based ether derivatives in modulation of neuroprotective enzymes.
3-Substituted Triazolone-Benzoate Hybrids: Synthesis, Enzyme Inhibition, Anticancer Activity and ADMET Evaluation by Molecular Docking and Dynamics Studies.
Beytur M, Tarmaşır E, Oguz E … +6 more , Bayrakdar A, Sabancılar İ, Akyildirim O, Türkan F, Aras A, Yüksek H
Drug Dev Res · 2026 Feb · PMID 41467324 · Publisher ↗
In this study, eight 3-substitued -4-amino-4,5-dihydro-1H-1,2,4-triazol-5-one compounds were synthesized. The reactions of these compounds with 2-ethoxy-4-formylphenyl benzoate, which was synthesized by the reaction of 3...
In this study, eight 3-substitued -4-amino-4,5-dihydro-1H-1,2,4-triazol-5-one compounds were synthesized. The reactions of these compounds with 2-ethoxy-4-formylphenyl benzoate, which was synthesized by the reaction of 3-ethoxy-4-hydroxy benzaldehyde with benzoyl chloride by using triethylamine, were investigated. Eight novel 2-ethoxy-4-(((3-substitued-5-oxo-1,5-dihydro-4H-1,2,4-triazol-4-yl)imino)methyl)phenyl benzoate compounds were obtained in order to identify the new synthesized compounds by spestroscopic methods including IR, H-NMR and C-NMR used. Concentration ranges of 25, 50, 120, 200, and 400 µg/mL were applied to determine the compund's anti-cancer properties. The human ovarian cancer cell line (OVCAR-3) compared with human umbilical vein endothelial cells (HUVEC) and significant results were obtained against the OVCAR-3 cell line. The enzyme inhibitory effect of compound on glutathione S-transferase (GST), acetylcholinesterase (AChE) enzymes were studied. Ki and IC values were found in the range of 1.1143 ± 0.2402 µM-7.9100 ± 1.9107 µM and 1.840 µM-4.149 µM for AChE; 2.0733 ± 0.8199 µM-8.2120 ± 1.5720 µM and 1.320 µM-3.223 µM for GST. In silico ADMET and drug-likeness analyses confirmed favorable pharmacokinetic and drug-like profiles for the compounds. Additionally, molecular docking and 100 ns molecular dynamics (MD) simulations revealed stable binding modes and dynamic stability of the most active compounds with the target enzymes.
Multitargeted Anti-Inflammatory Agents: Novel Pyrazole and Pyrazolo[1,5-a]Pyrimidine Carbonic Anhydrase and COX-2 Inhibitors With Optimal In Vivo Efficacy and Low Toxicity.
Fakhry MM, Said MA, Ammara A … +4 more , Bouajila J, Supuran CT, Abdel-Aziz HA, Abou-Seri SM
Drug Dev Res · 2026 Feb · PMID 41459651 · Publisher ↗
In this study, three series of pyrazole and pyrazolo[1,5-a]pyrimidine derivatives 6a-f, 8a-f, and 10a-f were designed and synthesized in response to the global need to safe and potent anti-inflammatory agents. A rational...
In this study, three series of pyrazole and pyrazolo[1,5-a]pyrimidine derivatives 6a-f, 8a-f, and 10a-f were designed and synthesized in response to the global need to safe and potent anti-inflammatory agents. A rational design strategy was employed to synthesize compounds that inhibit inflammation-related carbonic anhydrase isoforms (II, IX, and XII) alongside achieving selective inhibition of cyclooxygenase-2 (COX-2). Remarkably, the sulfonamide derivatives 6f, 8d, and 10e displayed high activity as carbonic anhydrase inhibitors against isoforms II, IX and XII in addition to their potent and selective COX-2 inhibition effect (IC = 57-87 nM; SI = 175-100). Among them, the multitargeted inhibitor 10e (COX-2, IC = 57 nM; CA II, K = 49.9 nM; CA IX, K = 67.5 nM; CA XII, K = 54.6 nM) was further evaluated in vivo and demonstrated strong dual anti-inflammatory and analgesic properties, with a rapid onset of action within the first hour and sustained efficacy over 5 h. Toxicological studies revealed that compound 10e possessed a favorable safety profile, showing no significant adverse effects on liver, kidney, or cardiac functions and minimal ulcerogenic potential. Molecular docking studies further supported these findings by confirming key binding interactions with CA II, IX, XII, and COX-2 active sites.
Discovery of 1-(arylacetyl)-2-phenyl-pyrrolidine Derivatives as Novel POLθ-pol Inhibitors via Structure-Based Virtual Screening and Fragment Fusion.
Fan W, Qiu M, Wang Z … +3 more , Chen G, Yu Y, Sheng R
Drug Dev Res · 2026 Feb · PMID 41459625 · Publisher ↗
DNA polymerase theta (POLθ) has been regarded as a promising therapeutic target for the treatment of BRCA-deficient tumors. In this study, 1-(arylacetyl)-2-phenyl-pyrrolidine derivative VS-13 was identified as a POLθ-pol...
DNA polymerase theta (POLθ) has been regarded as a promising therapeutic target for the treatment of BRCA-deficient tumors. In this study, 1-(arylacetyl)-2-phenyl-pyrrolidine derivative VS-13 was identified as a POLθ-pol inhibitor hit with an IC value of 1.47 μM through virtual screening. The followed similarity research obtained a more potent analogue SS-5, which was hybridized with RP-6685 to get 1-(phenylacetyl)-2-phenyl-pyrrolidine derivative F-1. It showed potent POLθ inhibitory activity with an IC value of 170 nM, and good anti-proliferative activity against BRCA2-deficient DLD1 and HCT116 cell lines, with IC values of 4.39 μM and 4.79 μM, respectively. Further MD simulations and interaction analysis disclosed the possible binding mode of F-1 with POLθ-pol.
Lansbermin-I: A Snake Venom Disintegrin With Selective Cytotoxicity and Anti-Adhesive Effects Against Glioblastoma Cells.
Orozco-Mera J, Montoya-Gómez A, Sevilla-Sánchez MJ … +3 more , Borrero AMA, Escudero MM, Jiménez-Charris E
Drug Dev Res · 2026 Feb · PMID 41451885 · Publisher ↗
Glioblastoma is the most common and aggressive malignant brain tumor, characterized by poor response to current therapies and inevitable recurrence. Novel therapeutic strategies are urgently needed. Lansbermin-I, a disin...
Glioblastoma is the most common and aggressive malignant brain tumor, characterized by poor response to current therapies and inevitable recurrence. Novel therapeutic strategies are urgently needed. Lansbermin-I, a disintegrin isolated from the venom of Porthidium lansbergii lansbergii, was purified, sequenced, structurally modeled, and evaluated for its antitumor potential against the human Glioblastoma cell line T98G. Cytotoxicity assays revealed a dose-dependent effect, with Lansbermin-I inducing up to 38.1% cell death at 100 μg/mL, surpassing the activity of temozolomide (34.9%) while exhibiting lower toxicity on non-tumorigenic human astrocytes (28% vs. 37%). Lansbermin-I also inhibited T98G adhesion to fibronectin by nearly 80% (p < 0.0001), suggesting interference with integrin-mediated interactions. Flow cytometry demonstrated a significant increase in apoptotic cells (60% vs. 36% in control) and cell cycle arrest at the G1 phase. In silico docking studies supported a strong interaction of Lansbermin-I with integrin αvβ3, comparable to that of fibronectin, reinforcing its potential mechanism of action through the disruption of adhesion and survival signaling. Collectively, these findings highlight Lansbermin-I as a promising selective prototype for Glioblastoma therapy. Further studies are warranted to elucidate its molecular targets and evaluate its efficacy in preclinical models.
Mathematical and Artificial Intelligence Techniques in Modern Drug Discovery: A Review.
Agrwal A, Kumar R, Maheshwari S … +4 more , Sharma M, Batra CM, Sharma S, Gaur V
Drug Dev Res · 2026 Feb · PMID 41431184 · Publisher ↗
The future of drug research is intrinsically connected to the continuous advancement and prudent integration of Artificial intelligence (AI) and mathematics. By addressing challenges and leveraging possibilities, the pha...
The future of drug research is intrinsically connected to the continuous advancement and prudent integration of Artificial intelligence (AI) and mathematics. By addressing challenges and leveraging possibilities, the pharmaceutical industry may fully harness the potential of AI to develop innovative and effective treatments for diverse diseases. In our opinion, finding new drugs takes long time and funds, and in the past, it was mostly done manually. AI has changed this sector completely, making drug manufacturing faster, cheaper, and more specific. This review presents the pertinent literature on drug discovery utilizing mathematical modeling and AI tools and methodologies implemented at every stage of drug development to expedite the research process and mitigate risk and costs in clinical trials, it also presents that how mathematical modeling and AI algorithms can be used together at several stages of drug development. There is a lot of focus on how mathematical frameworks like Linear Algebra, optimization, statistical modeling, graph theory and differential equations may operate along with the techniques of AI like machine learning (ML), deep learning (DL), reinforcement learning (RL), natural language processing (NLP) and transfer learning (TL) and the problems that are now being faced, the tools and datasets that are accessible, and what the future holds for this field, which is changing quickly.
Interface-Engineered Nanocarriers for Translational and Patient-Centric Topical Therapy in Psoriasis.
Singh V, Rehman U, Alqahtani T … +4 more , Shmrany HA, Gupta G, Goh KW, Kesharwani P
Drug Dev Res · 2026 Feb · PMID 41431180 · Publisher ↗
Psoriasis is a chronic, immune-mediated dermatological disorder characterized by keratinocyte hyperproliferation and persistent inflammation, representing a significant therapeutic challenge. Conventional topical therapi...
Psoriasis is a chronic, immune-mediated dermatological disorder characterized by keratinocyte hyperproliferation and persistent inflammation, representing a significant therapeutic challenge. Conventional topical therapies are often limited by inadequate skin penetration, poor drug stability, and systemic toxicity, necessitating the development of advanced drug delivery platforms. Recent progress in colloid and interface science has enabled the design of nanocarrier systems including solid lipid nanoparticles, nanostructured lipid carriers, nanoemulsions, and liposomes that optimize drug-skin interactions at the nanoscale. Through interface engineering, these carriers improve drug solubility, stability, and controlled release, while enhancing epidermal localization and minimizing off-target exposure. Lipid-based nanosystems, in particular, leverage the skin's lipid pathways to achieve higher drug accumulation in psoriatic lesions, thereby improving therapeutic outcomes and patient compliance. Preclinical and early clinical studies with drugs such as methotrexate and cyclosporine have demonstrated enhanced lesion resolution, reduced side effects, and superior safety profiles when delivered via nanocarriers. Nevertheless, the clinical translation of these systems is often hindered by challenges such as large-scale reproducibility, formulation stability, and regulatory complexity. Interface-engineered nanocarriers address these limitations by employing biocompatible materials, scalable synthesis techniques, and targeted design strategies that enhance safety, efficacy, and translational feasibility. This review integrates mechanistic insights from colloid and interface engineering with translational perspectives on formulation scalability, regulatory pathways, and long-term safety evaluation. Collectively, interface-tailored nanocarriers represent a transformative approach for precision-driven, effective, and patient-centered topical therapy of psoriasis.
Pharmacological Evaluation of Novel N- and C-Modified Peptide Analogues of VV-hemorphin-5 and VV-hemorphin-7 as Potential Agents With Anti-Seizure Activity.
Tchekalarova J, Rangelov M, Todorova N … +2 more , Stoyanova T, Todorov P
Drug Dev Res · 2026 Feb · PMID 41431144 · Publisher ↗
Recently, a series of N- and C-modified hemorphins have been synthesized, characterized and evaluated for their antibacterial potency. These analogues included amino acids such as cysteine (Cys), glutamic acid (Glu), and...
Recently, a series of N- and C-modified hemorphins have been synthesized, characterized and evaluated for their antibacterial potency. These analogues included amino acids such as cysteine (Cys), glutamic acid (Glu), and histidine (His), as well as 1-adamantanecarboxylic acid (Adam), and niacin (nicotinic acid) (Nic). The current study aimed to explore the anti-seizure potential of these compounds in mice. The role of opioid receptors (ORs) in their mechanism of action was evaluated both pharmacologically and through in silico methods. A battery of tests were used, including the 6-Hz and maximal electroshock seizures (MES) tests, as well as kainate (KA)-induced status epilepticus (SE), pentylenetetrazol (PTZ) and corneal kindling models. The intracerebroventricular infusion of peptide analogues, specifically those containing Cys, Glu, His and Adam but not Nic, showed reduced psychomotor seizures and seizure spread. The effective dosages were as follows: C-V (25 μg/5 μl-6 Hz and MES), H-V (6 and 12 μg/5 μl-6 Hz and MES), AC-V (12 μg/5 μl-MES) and AH-V (25 μg/5 μl-6 Hz). The efficacy of the compounds in preventing clonic seizures in PTZ-kindled mice was observed, except NCH7. Furthermore, C-V and AC-V were found to be effective in corneal-kindled mice and C-V against the KA-induced SE. Naloxone blocked the anti-seizure effect of C-V and AC-V, which was also confirmed by docking analysis. Our findings suggest that insertion of Cys and Glu (C-V and AC-V) and Cys, Adam, and Glu (AC-V) enhances the potential of these novel hemorphin analogues as effective anti-seizure agents.
Targeted Delivery of Thymoquinone-Encapsulated Polyethyleneimine/Poly (Lactic Acid) Nanoparticles Into Breast Cancer Cells.
Pandi JS, Pavadai P, Babkiewicz E … +5 more , Panneerselvam T, Maszczyk P, Sankaranarayanan M, Ramar M, Kunjiappan S
Drug Dev Res · 2026 Feb · PMID 41416651 · Publisher ↗
Breast cancer is the most commonly diagnosed cancer globally, predominantly affecting older women. Thymoquinone (TQ) is a natural therapeutic agent that exerts anticancer efficacy. However, its pharmacological effects ar...
Breast cancer is the most commonly diagnosed cancer globally, predominantly affecting older women. Thymoquinone (TQ) is a natural therapeutic agent that exerts anticancer efficacy. However, its pharmacological effects are restricted by inadequate aqueous solubility and bioavailability. The present study aimed to develop TQ-encapsulated polyethyleneimine/poly(lactic acid) nanoparticles (TQ-PEI/PLA-NPs) to enhance the delivery of TQ into breast cancer cells. The solvent evaporation-emulsification method was employed to synthesize TQ-PEI/PLA-NPs, and their physicochemical properties were subsequently examined. TQ-PEI/PLA-NPs had a crystalline structure, a zeta potential of +1 mV, and a spherical shape with a diameter of 80-90 nm. The encapsulation efficiency was 85.77 ± 2.21% (w/w), while the drug loading capacity was 9.32 ± 1.14% (w/w). The release rate of TQ from TQ-PEI/PLA-NPs was marginally elevated at pH: 5.8 (81.21 ± 0.87%) compared to pH 3.5 and 7.2. MTT assay using TQ-PEI/PLA-NPs confirmed concentration-dependent cytotoxicity against MCF-7 cells after 24 h of treatment, and IC was found to be 21.99 μg/mL. The intracellular delivery of TQ in MCF-7 cells caused cell death, as indicated by AO/EBr staining, mitochondrial transmembrane potential assay, and Caspase-3 and -9 investigations. The observed MCF-7 cell death attributed to TQ was induced by reactive oxygen species (ROS) and impaired mitochondrial membrane potential. The ROS potentially damaged the mitochondrial membrane, and further studies supported the induction of apoptosis. Our results indicated that TQ-PEI/PLA-NPs, which cause cytotoxicity to breast cancer cells, as evidenced by the decreased MCF-7 cell counts, may exhibit significant therapeutic potential for breast cancer therapies.
Next-Generation Therapies for Bone Cancer: Targeted Therapy, Immunotherapy, and Nanomedicine Innovations.
Wang K, Silli EK, Lv H … +1 more , Song R
Drug Dev Res · 2026 Feb · PMID 41408957 · Publisher ↗
Bone cancer remains a challenging malignancy, with high mortality rates in advanced or metastatic stages. Recent therapeutic advances have increasingly focused on integrating targeted therapy, immunotherapy, and chemothe...
Bone cancer remains a challenging malignancy, with high mortality rates in advanced or metastatic stages. Recent therapeutic advances have increasingly focused on integrating targeted therapy, immunotherapy, and chemotherapy with nanodrug delivery systems (NDDS) to enhance treatment efficacy. Chemotherapy remains a cornerstone, with optimized regimens improving outcomes while reducing systemic toxicity. Immunotherapy (including checkpoint inhibitors, adoptive T-cell transfer, and CAR-T cell therapy) has demonstrated promising clinical potential. Targeted therapy disrupts key molecular pathways critical for tumor progression, offering a more selective approach with fewer adverse effects. NDDS amplify these strategies by improving drug bioavailability, enabling sustained and controlled release, enhancing tumor penetration, and overcoming drug resistance within the bone tumor microenvironment. They also facilitate the co-delivery of multiple agents for synergistic effects. This review provides a comprehensive analysis of the clinical applications of targeted therapy and immunotherapy in primary and secondary bone cancers, critically evaluates recent advances in NDDS, and highlights their transformative potential in precise drug targeting and multimodal regimens. By bridging established treatment modalities with emerging nanodelivery innovations, it offers an integrated framework to guide future translational research in bone cancer therapy.
Rational Design of Triazole Hydrazide Derivatives With Imidazo[2,1-b]thiazole Scaffolds as Targeted EGFR Inhibitors in NSCLC.
Elgohary MK, Elkotamy MS, Elsayed ZM … +9 more , Abdelraheem AM, Radwan IT, Darweish E, Almehizia AA, Naglah AM, Almehizia FA, Fares M, Eldehna WM, Abdel-Aziz HA
Drug Dev Res · 2026 Feb · PMID 41405156 · Publisher ↗
A novel series of triazole hydrazide derivatives 8a-o was rationally designed, synthesized, and systematically evaluated for their anticancer potential. Cytotoxicity screening against A549 lung adenocarcinoma cells ident...
A novel series of triazole hydrazide derivatives 8a-o was rationally designed, synthesized, and systematically evaluated for their anticancer potential. Cytotoxicity screening against A549 lung adenocarcinoma cells identified compounds 8a-d as the most potent, exhibiting IC values of 3.15-4.93 µM, which are comparable to doxorubicin (IC = 2.77 µM). Mechanistic studies revealed that lead compound 8a induced apoptosis through upregulation of Bax and caspase-3 and downregulation of Bcl-2. Additionally, 8a significantly inhibited A549 cell migration (34.46% wound closure vs. 61.61% in controls) and reduced clonogenic survival (surviving fraction = 0.5725). Importantly, 8a displayed low cytotoxicity toward normal lung fibroblasts (WI-38, IC = 47.21 µM). Enzyme inhibition assays demonstrated potent EGFR kinase inhibition by 8a and 8 d (IC = 74.85 and 75.87 nM, respectively), comparable to erlotinib (IC = 34.89 nM). Moreover, in silico ADMET profiling predicted favorable drug-likeness and oral bioavailability, while molecular docking supported the stable binding of 8a within the EGFR active site. These findings identify compound 8a as a promising therapeutic lead for the development of targeted EGFR inhibitors in non-small cell lung cancer (NSCLC) therapy.
Esketamine Protects the Blood-Brain Barrier Against Sepsis-Associated Brain Injury by Regulating the BDNF/TrkB Pathway.
Wei W, Wu G, Ge Y … +1 more , Lu J
Drug Dev Res · 2026 Feb · PMID 41396715 · Publisher ↗
This study was designed to explore the effects of esketamine on cognitive deficits and blood-brain barrier (BBB) dysfunction in sepsis-associated encephalopathy (SAE). An in vivo SAE model was generated through the admin...
This study was designed to explore the effects of esketamine on cognitive deficits and blood-brain barrier (BBB) dysfunction in sepsis-associated encephalopathy (SAE). An in vivo SAE model was generated through the administration of lipopolysaccharide (LPS), and LPS-induced cognitive impairment in rats was evaluated using the Morris water maze (MWM) test. BBB disruption in vivo was assessed by measuring brain water content together with Evans blue dye penetration, while LPS-induced endothelial hyperpermeability in vitro was examined through FITC-dextran leakage. The protein expression of claudin-3 and ZO-1 was determined by western blotting. In addition, the levels of pro-inflammatory cytokines, cell apoptosis, autophagy, and the activity of the BDNF/TrkB pathway were examined. Rapamycin (Rap, an autophagy inducer) and K252a (a BDNF inhibitor) were used to determine whether the protective effects of esketamine were associated with autophagy and BDNF/TrkB signaling. Esketamine treatment significantly improved the LPS-induced cognitive dysfunction and neurological injury observed in vivo, and it also inhibited the production of pro-inflammatory cytokines and reduced cell apoptosis both in vivo and in LPS-treated hCMEC/D3 cells. Importantly, esketamine alleviated BBB hyperpermeability in vivo and prevented LPS-induced endothelial leakage in vitro. Moreover, esketamine suppressed LPS-induced autophagy, and the influence of esketamine on claudin-3 and ZO-1 expression was reversed when Rap was applied. Esketamine activated the BDNF/TrkB pathway, and the protective effects of esketamine on BBB integrity and autophagy in response to LPS were abolished by K252a. Taken together, these findings indicate that esketamine protects the BBB against SAE by activating the BDNF/TrkB pathway and inhibiting autophagy, providing a potential therapeutic strategy for SAE.
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