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.

Spleen tyrosine kinase (SYK), a non-receptor tyrosine kinase, serves as a pivotal regulator in multiple intracellular signaling pathways, particularly those involved in immune responses. Dysregulated SYK activation has been strongly implicated in the pathogenesis of various hematological malignancies and autoimmune disorders, making it an attractive therapeutic target. Consequently, significant progress has been made in developing SYK inhibitors as a targeted treatment strategy. This article comprehensively reviews recent advances in SYK inhibitor research, focusing on their therapeutic potential in autoimmune diseases and hematologic cancers. Furthermore, we highlight representative SYK inhibitors, discuss their clinical applications, outline current challenges, and future directions in this evolving field.

Alzheimer's Disease (AD) is a neurological disorder characterized by progressive cognitive impairment and memory loss. In vitro artificial membrane permeability assays targeting the blood-brain barrier (BBB), such as the parallel artificial membrane permeability assay (PAMPA), are useful for pre-evaluating the BBB penetration of molecules during the early stages of drug development. Inhibitors of glycogen synthase kinase-3β (GSK-3β), casein kinase-1δ (CK-1δ), and acetylcholinesterase (AChE) exhibit neuroprotective effects, indicating a potential therapeutic approach for AD. This study aimed to assess the ability of 23 phenolic compounds derived from natural sources to penetrate the central nervous system (CNS) and examine their potential neuroprotective effects. Following the prediction of BBB penetration of the compounds by PAMPA, neuroprotective effects of CNS+ compounds were evaluated through in vitro inhibition of GSK-3β, CK-1δ, and AChE. Based on the data obtained, five flavonoids (hispidulin, nepetin, platanoside, apigenin, and kaempferol) and two furanocoumarins (isopimpinellin and bergapten) were predicted to penetrate the CNS. Apigenin (API) and kaempferol (KEM) exhibited the most potent dual inhibitory activity against CK-1δ and GSK-3β. Furthermore, API and KEM did not exhibit cytotoxic effects in SH-SY5Y cells. Molecular modeling studies, including molecular docking, molecular dynamics simulations, and dynophore analysis, were performed to understand the binding mechanism of these most potent compounds to their target enzymes. Overall, the current study offers a rational approach to designing new molecules inspired by natural compounds to treat Alzheimer's Disease.

Glioblastoma (GBM) is the most common and lethal primary intracranial tumor, and glycolysis has been reported to play a critical role in its progression. Formin-binding protein 1 (FNBP1) has been implicated in GBM progression; however, the precise molecular mechanisms remain unclear. In this study, we demonstrated that FNBP1 expression was significantly higher in GBM tissues compared with adjacent tissues. Elevated FNBP1 expression was correlated with higher tumor grade and reduced 5-year survival in GBM patients. In vitro, knockdown of FNBP1 inhibited proliferation, invasion, and glycolysis, while promoting apoptosis in GBM cells. Mechanistically, RNA-binding motif protein 15B (RBM15B) increased the m6A modification level of FNBP1 mRNA, and insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) recognized this m6A mark and enhanced the stability of FNBP1 mRNA. Furthermore, FNBP1 interacted with LIM and SH3 Domain Protein 1 (LASP1), upregulating LASP1 protein expression and subsequently activating the Smad3 signaling pathway to promote glycolysis. In vivo, subcutaneous xenograft models were established using U251/U87 cells, and a lung metastasis model was generated via tail vein injection of U87 cells. FNBP1 knockdown significantly suppressed tumor growth in the subcutaneous model and reduced the number of lung nodules in the metastasis model. In conclusion, FNBP1, regulated by the RBM15B-m6A-IGF2BP2 axis, promotes GBM progression by interacting with LASP1 to activate Smad3-mediated glycolysis.

Intracerebral hemorrhage (ICH) is a serious acute cerebrovascular disease with a high death and disability rate. Baicalin plays a neuroprotective role in various diseases, but its regulatory mechanism on ICH remains unclear. In this study, we investigated the protective effects and mechanisms of baicalin in ICH using an ICH mouse model. ICH mouse model was established by injection of collagenase type IV into intracranial in C57BL/6 mice. Neurological function was evaluated by neurological severity scores and the rotarod test. Hemorrhagic foci of brain was evaluated by TTC and hematoxylin-eosin staining. Iron ion deposition in brain was detected by Prussian blue staining. Ferroptosis was evaluated by measuring expression of FTH-1, SLC7A11, GPX4, and TFRC, as well as detecting iron content and levels of glutathione (GSH) and malondialdehyde (MDA). GPX4 expression and apoptosis of brain were detected by immunofluorescence staining and TUNEL assay. Results showed that baicalin improved neurological function and reduced the area of hemorrhagic foci of brain in ICH mouse model. Baicalin decreased iron ion deposition, inhibited ferroptosis and apoptosis, and upregulated GPX4 in brain of ICH mouse model. Moreover, baicalin increased AKT1 phosphorylation and the protein level of Nrf2 in brain of ICH mouse model. Notably, AKT1 inhibitor LY294002 and Nrf2 inhibitor reversed the effects of baicalin on the activation of AKT1/Nrf2/GPX4 axis and the inhibition of ferroptosis in brain of ICH mouse model. Collectively, we demonstrated that baicalin promotes ICH recovery by inhibiting ferroptosis in brain tissue through activation of AKT/Nrf2/GPX4 axis. These results may provide new insights for the study of baicalin in the treatment of ICH.

Nanoparticle-mediated transdermal systems can bypass the skin's natural outer barrier (stratum corneum), allowing drugs to enter the body more effectively. This technology improves how much drug reaches the bloodstream and how long it acts, which can make drug delivery noninvasive and more comfortable for patients. These technologies are engineered to markedly enhance drug permeability and bioavailability, while improving patient adherence and reducing systemic side effects. The incorporation of nanocarriers into transdermal systems can augment drug permeability across the skin by 2- to 10-fold, contingent upon the physicochemical characteristics of both the drug and the nanocarrier type, as demonstrated in multiple preclinical investigations. This review rigorously analyzes various nanocarriers, including liposomes, niosomes, solid lipid nanoparticles (SLNs), nanostructured lipid carriers (NLCs), polymeric nanoparticles, and inorganic nanostructures, and their effects on cutaneous and transdermal drug delivery. Improvements in entrapment efficiency of up to 90% and a three- to fivefold enhancement in drug retention within the epidermis have been recorded. Optimized nanoparticle-based formulations have also demonstrated sustained release characteristics lasting up to 72 h. Additionally, innovative technologies such as dissolving microneedles, nanoneedle arrays, luminous patches, and 3D-printed transdermal systems are examined regarding their capacity to enhance dosage accuracy, bioadhesion, and therapeutic efficacy. The study examines formulation characteristics such as polymer matrices, rate-controlling membranes, excipient compatibility, and penetration enhancers that affect the clinical efficacy and stability of nanoparticle-integrated patches. Significant attention is directed towards the impact of formulation choices on drug loading, release kinetics, and skin interaction patterns. Notwithstanding advancements, no nanoparticle-encapsulated transdermal patch has attained FDA approval to yet. The review delineates the principal translational obstacles-regulatory ambiguity, safety assessment, and GMP-scale production-and emphasizes the necessity for cohesive pharmacokinetic modeling, human skin correlation investigations, and real-time stability data to enhance clinical translation.

The chlorophyll-derived diterpenoid phytol (PHY) is evident for its diverse biological effects, including neuroprotective activities in experimental animals. This study aims at the evaluation of anticonvulsant effects along with the possible mechanism of action of PHY through animal and in silico studies. For this, we performed pentylenetetrazole (PTZ)-induced convulsion tests in chicks and in silico studies against GABAA receptor subunits and voltage-gated sodium channel (VGSC) receptors. PHY was tested at 25, 50, and 75 mg/kg with or without the standard drugs diazepam (DZP: 5 mg/kg) and carbamazepine (CAR: 80 mg/kg) using a vehicle as a control. Acute oral toxicity was evaluated in chicks per OECD guidelines by administering PHY (500-2000 mg/kg, p.o.) and monitoring for 48 h for mortality, toxicological signs, and behavioral changes. PHY exhibited a dose-dependent anticonvulsant effect, significantly increasing latency and reducing convulsion frequency and duration at 75 mg/kg. PHY (75 mg/kg) combined with CAR and DZP showed the most potent reduction in convulsion frequency and duration, indicating a synergistic effect. Acute toxicity tests in chicks confirmed safety up to 2000 mg/kg. In silico studies demonstrated that PHY had good binding affinity with both the GABAA receptor (-6.5 kcal/mol) and VGSC (-7.0 kcal/mol), potentially contributing to its anticonvulsant action through GABAergic and sodium channel modulation. PHY showed significant anticonvulsant activity, likely via GABAA and VGSC modulation, warranting further studies to clarify its mechanisms and assess its adjunct potential in drug-resistant convulsion management.

The structural modification and derivatization of natural products represent an essential pathway for pharmaceutical innovation in the management of depression. The 8-phenyl tetrahydroisoquinoline, as a parent core, was obtained from magnoflorine by a structural simplification strategy. The present report details the synthesis and antidepressant activity studies of 8-phenyl-THIQ analogs. Among them, compounds 1e and 1j exhibited significant antidepressant activity in addition to high synthetic accessibility and adequate predictive ADME/T properties.

A novel series of 1,1-disubstituted cyclohexane 7a-e, 8a-e, and 9a-e were designed, synthesized, and evaluated for their anticonvulsant activities. Compounds 7c, 8c, 8d, and 9a displayed significant anticonvulsant activity in both maximum electroshock seizure (MES) and pentylenetetrazol (PTZ) induced seizure during the preliminary screening with no neurotoxicity. The phase II quantitative anticonvulsant activity revealed that compound 8c demonstrated the most potent activity as compared to the conventional drugs phenobarbital. The expression of nuclear factor erythroid 2-related factor- antioxidant response element (Nrf2-ARE) signaling pathways, oxidative stress parameters were also observed. Additionally, histopathological examination of brain of animals treated with compounds 7c, 8c, 8d, and 9a was performed and the results were corroborated the neuroprotective properties. Further neurochemical investigation was performed to unravel the effect of the most active compounds, compounds 7c, 8c, 8d, and 9a demonstrated significant protection by ameliorating GABA levels, which were initially reduced to 61% by PTZ administration, suggesting enhanced GABAergic neurotransmission. Computational parameters including docking analysis on GABAA exhibiting good binding on the active site, Moreover, In silico prediction was carried out indicating that most of compounds have favorable oral bioavailability and BBB permeability they might be viewed as helpful models for future research and derivatization.