Protein kinase CK2 is the subject of numerous studies in medicinal chemistry due to its involvement in the development of several diseases, primarily cancers. Its overexpression in tumor cells is related to key processes such as tumor immune evasion and cell proliferation. The scientific approach of this study aims to investigate the thermal shift assay (TSA) as a pre-screening tool and to complement it with a co-crystallization approach in post-screening. Therefore, the synthesis of seven small-molecule CK2 inhibitors derived from indeno[1,2-b]indoles was supplemented by 18 related derivatives from our in-house compound library. The 25 molecules belong to four sub-scaffolds, namely 4b,9b-dihydroxy-4b,5,6,7,8,9b-hexahydroindeno[1,2-b]indole-9,10-dione (D-0), 5,6,7,8-tetrahydroindeno[1,2-b]indole-9,10-dione (D-1), 9-hydroxy-5H-indeno[1,2-b]indol-10-one (D-2), and 5H-indeno[1,2-b]indole-6,9,10-trione (D-3). The most active CK2 inhibitors identified by capillary electrophoresis (CE)-based assay belong to the D-1 sub-scaffold. In the TSA, these compounds also generate significant shifts of the melting temperature (Tm) of CK2, indicating a clear correlation between the results of the CE-based assay and those of the TSA. The contribution of co-crystallization in post-screening also demonstrated the effectiveness of D-1 sub-scaffold compared with D-0 sub-scaffold.
Cancer immunotherapy enhances the body's ability to recognize and eliminate tumor cells, mainly by modulating immune checkpoints such as PD-1/PD-L1 and CTLA-4. Monoclonal antibody inhibitors targeting PD-1 or PD-L1 have transformed cancer care, but their high cost, IV administration, and immune-related toxicities have encouraged the development of small-molecule alternatives. Early PD-L1 small-molecule inhibitors, pioneered by Bristol Myers Squibb, block PD-1/PD-L1 interactions by occupying hydrophobic pockets on PD-L1, and SAR studies continue to refine their potency and selectivity. This review focuses on how the structural scaffolds of small-molecule PD-L1 inhibitors determine their mechanisms of action, protein interactions, and biological performance. We examine how different chemotypes influence dimerization of PD-L1, disruption of PD-1 binding, or engagement of additional immune-modulatory pathways. Special attention is given to scaffolds capable of acting through more than one mechanism, as these may offer broader or more durable immunomodulatory effects. We also compare how scaffold design correlates with activity across in vitro assays, co-culture immune models, and in vivo tumor systems, highlighting the physicochemical features that enable or limit translatability. Finally, we discuss emerging clinical efforts, the challenges underlying trial failures, and how refined structural design may guide the next generation of small-molecule PD-L1 inhibitors.
This study reports the radiosynthesis and biological evaluation of 99mTc-Amygdalin, using a newly developed chromatographic 99Mo/99mTc generator based on alumina doped with terbium oxide. The prepared sorbent was successfully synthesized and characterized as a structurally stable oxide matrix exhibiting high Mo(VI) sorption capacity (117 mg/g), excellent adsorption selectivity at pH 4, and minimal 99Mo breakthrough, enabling the production of high-purity 99mTc suitable for radiopharmaceutical applications. Amygdalin was efficiently radiolabeled under optimized reductive conditions, achieving radiochemical purity exceeding 90%. In addition, a corresponding rhenium analogue complex was synthesized to support the proposed coordination behavior of the radiocomplex. Biodistribution studies in Ehrlich solid tumor-bearing mice demonstrated rapid blood clearance, favorable systemic distribution, and progressive tumor uptake, reaching 8.5 ± 0.65%ID/g at 120 min post-injection, with target-to-non-target ratios approaching 17 at later time points. The obtained pharmacokinetic profile highlights the potential applicability of 99mTc-Amygdalin as a promising tumor-targeting radiotracer for diagnostic imaging.
Heterotetrameric KV7.2/3 potassium channels were retrospectively identified as the target of the analgesic flupirtine and the antiepileptic retigabine (ezogabine). Clinical utility of these agents ended after decades or 6 years, respectively, before their full scope was explored. Market withdrawals in 2017 and 2018 hampered research in other medical fields and left a gap for researchers using these compounds off-label in experimental indications and for patients with KV7.2/3 malfunctions. Failure of these drugs might be regarded as a reason to abandon this class of compounds, due to the notion that toxicity might be a class effect and to competitive markets. Yet, evidence accumulated that the toxicity of both compounds is not an inherent property of modulators of KV7.2/3 channels, but rather the result of an oxidation-sensitive metabophore/toxicophore. Second, epilepsy associated with KV7.2/3 channelopathies might rationally be addressed best with modulators of this validated drug target. Employing retrometabolic drug design to remodel the enzyme-labile carbamate structure and the central highly substituted ring, azetukalner (formerly encukalner, XEN1101) emerged from the unlucky forerunners. This structural analog of retigabine exhibits improved metabolic stability, increased potency, and enhanced blood-brain barrier penetration compared with its predecessor. This review details the synthesis, physicochemical properties, and clinical results of azetukalner.
[Image: see text] The Central Role of CMR for Diagnosis and Risk Stratification in HCM
Many naturally occurring substances exhibit anti-ulcer properties. One promising area of research is the identification of terpenoid compounds with enhanced therapeutic and gastroprotective properties. The present study aimed to synthesize new terpenoid derivatives of myrtenol via biotransformation using freeze-dried Cladosporium cladosporioides mycelium or via porphyrin-based biomimetic transformation, and to evaluate their gastroprotective activity in an ethanol-induced gastric lesion model. Five myrtenyl esters (acetate, butyrate, caprylate, pelargonate, and laurate) and two oxidative derivatives (myrtenal and myrtenal oxide) were obtained with a high degree of purity (> 94%, GC). The anti-ulcer preventive effects of the compounds were evaluated in mice at doses ranging from 6.25 to 25 mg per kg of body weight. The mice were treated orally prior to the induction of ethanol-induced gastric lesions. All compounds exerted a gastroprotective effect, reducing the lesion area (mm2) compared to the negative control group. Notably, the gastroprotective effects of myrtenyl caprylate, myrtenyl pelargonate, and myrtenyl laurate were equivalent to those promoted by the clinical medicine pantoprazole.
The sinoatrial node pacemaker channel HCN4 plays a central role in cardiac automaticity, and disease-associated variants can predispose to atrial arrhythmias. Here, we investigated the functional interplay between the HCN4 variant P883R and the potassium channel β-subunit KCNE1, focusing on the common atrial fibrillation-associated KCNE1 variant G38S and its regulation by the iron-induced serine protease TMPRSS6. Electrophysiological analyses revealed that HCN4-P883R decreases net HCN4 currents If, consistent with impaired automaticity. Co-expression of KCNE1, either wild-type or polymorphic KCNE1-G38S, restored functional properties of the mutant channel, indicating that KCNE1 is a key modulator of HCN4 activity. Importantly, TMPRSS6-mediated proteolytic processing of KCNE1 reduced HCN4 currents, whereas HCN4 expressed alone was insensitive to TMPRSS6, identifying KCNE1 as the direct regulatory target. Notably, KCNE1-G38S altered the HCN4-KCNE1 complex to TMPRSS6-dependent downregulation, resulting in a reduced suppression of HCN4-P883R-mediated currents compared with wild-type KCNE1. Mechanistically, differential TMPRSS6 cleavage depended on the membrane positioning of the KCNE1-32RRSPRSS38 motif. These findings reveal a protease-dependent buffering mechanism that counteracts HCN4 loss-of-function and establish TMPRSS6 as a molecular switch controlling pacemaker activity in a KCNE1 genotype-dependent manner. This dynamic regulatory framework may contribute to the phenotypic variability of sinoatrial node dysfunction and atrial fibrillation.
A novel series of 4,5-diphenyl-imidazole-indole-N-phenylacetamide derivatives (6a-m) was designed, synthesized, and evaluated for their inhibitory activities against α-glucosidase and acetylcholinesterase (AChE). Among the thirteen derivatives, nine were more potent than the standard α-glucosidase inhibitor (acarbose), and eleven showed higher potency than the standard AChE inhibitor (tacrine). The most effective compound against α-glucosidase was compound 6l, which demonstrated a 2.1-fold higher potency compared to acarbose. The best compound against AChE was compound 6j, which was 16.9-fold more potent than tacrine. Given that the compounds showed stronger inhibitory activity against AChE than against α-glucosidase, compound 6j, identified as the best AChE inhibitor, was selected for further investigation. Kinetic studies revealed that compound 6j is a competitive inhibitor of AChE. Molecular docking and dynamics simulations confirmed the stability of compound 6j within the active site of AChE. Additionally, compound 6j demonstrated no cytotoxicity at its effective dose against AChE in the normal cell line NIH-3T3, confirming its favorable safety profile at high concentrations.
Although first-line pharmacological treatments for neuropathic pain are often ineffective, cannabidiol has shown promise. However, the analgesic effects of orally administered, cannabidiol are limited by low bioavailability and a short half-life. Therefore, this study investigated the effects of intrathecal (i.t.), cannabidiol administration on neuropathic pain, focusing on spinal 5-HT1A receptors and microglial modulation. Male C57BL/6 mice were subjected to neuropathic pain-induced by chronic constriction injury (CCI). Mechanical nociceptive thresholds were assessed using von Frey filaments. The involvement of spinal 5-HT1A receptors was examined by i.t. administration of the selective antagonist WAY-100635. mRNA expression, IL-10, and TNF-α levels, and microglial activation were evaluated. Intrathecal, cannabidiol significantly reversed mechanical allodynia, producing a more potent and prolonged antinociceptive effect than oral administration. This effect was abolished by WAY-100635, indicating spinal 5-HT1A receptor involvement. Moreover, i.t. cannabidiol increased spinal IL-10 levels and 5-HT1A receptor mRNA expression, while reducing microglial activation. In vitro, cannabidiol attenuated microglial activation and significantly reduced TNF-α production. In conclusion, i.t. cannabidiol effectively alleviates neuropathic pain in mice, with findings that may suggest the involvement of spinal mechanisms associated with 5-HT1A receptor-related signaling and modulation of microglial activation.
The KCa2.2 and KCa3.1 channels are fundamental regulators of membrane potential and calcium signalling and promising targets to treat diseases such as spinocerebellar ataxia and cancer. To fully exploit their therapeutic potential, and to continue studying their pathophysiological role, it is crucial to develop selective modulators for each of these two channels. Here, we present a computational study to identify the molecular determinants behind the selectivity of two recently reported KCa2.2 modulators, namely, N-(2,1,3-benzoxadiazol-4-yl)-3-(4-methoxybenzene-1-sulfonamido)benzamide and N-(2,1,3-benzoxadiazol-4-yl)-4-(trifluoromethyl)benzamide. We leveraged a protocol combining in silico mutagenesis, molecular dynamics simulations, and protein-ligand docking to analyse the pockets targeted by these ligands. We identified the Ser353/Pro245 substitution to be the main driver of the distinct pocket shapes in KCa2.2 and KCa3.1 channels, ultimately defining modulator selectivity. This approach provides novel insights into the structural differences of this binding site across potassium channel subtypes, proposing potential selectivity determinants of the modulators targeting this pocket.
SPINK5-syndromic epidermal differentiation disorder (also known as Netherton syndrome [NS]) is a severe chronic genetic disorder characterized by skin inflammation, severe atopy, and trichorrhexis invaginata (TI). Causative SPINK5 gene mutations result in defective serine protease inhibitor LEKTI, leading to unopposed serine protease activity and resulting in impaired skin barrier and type 2 inflammation. TI is the result of an intermittent keratinization defect of the hair cortex, a problem without specific treatment available to date. We diagnosed NS in a 67-year-old woman who had severe skin manifestations and a hair-growth defect since childhood. Scalp hair was sparse in the nuchal and temporoparietal regions. Trichoscopy of these areas showed numerous "bamboo" hairs that broke off during contact with the dermatoscope. We initiated treatment with dupilumab and optimized the topical therapy. At a 3-month follow-up, improvement of rash, pruritus, and quality of life was reported. Furthermore, the previously brittle short hair was replaced with longer hair and normal hair shafts in the previously affected areas. TI, as part of NS, has a variable presentation, biologics currently treating cutaneous inflammation, but little is known about their effects on hair biology. In this report, we show that dupilumab treatment not only proved efficient for control of skin inflammation and pruritus but was also associated with near-complete resolution of "bamboo" hair and promoted hair growth. Especially how alterations in the inflammatory response in NS can be linked to a structural defect have not been addressed in the current literature so far.
This review presents the first complete comprehensive analysis of the crown-of-thorns starfish Acanthaster planci (A. planci), highlighting its biological activities and therapeutic potential. A. planci, a well-known member of the phylum Echinodermata and class Asteroidea, is a widespread marine invertebrate found in Indo-Pacific coral reef environments. It has garnered increasing scientific attention not only due to its ecological significance but also for its rich diversity of bioactive compounds. Research has revealed that its tissues, particularly the dermal layer, contain a diverse array of biologically active metabolites, including saponins, steroids, terpenoids, alkaloids, fatty acids, and sphingolipids, many of which exhibit anti-inflammatory, cytotoxic, antioxidant, and antimicrobial properties. These bioactive metabolites have highlighted A. planci as a potentially valuable source for novel natural product discovery. Furthermore, its exceptional regenerative abilities make it a promising organism for studies in regenerative biology and marine biotechnology. The present review compiles up-to-date findings on A. planci's pharmacologically significant metabolites and underscores its emerging role in biomedical and pharmaceutical research.
Indazole tautomers (1H- and 2H-) have emerged as privileged scaffolds in drug discovery due to their unique hydrogen-bonding properties, aromatic stability and ability to interact with many oncogenic targets. These structural characteristics of indazole derivatives make them a promising chemical moiety for the development of anticancer drugs. This review aims to elucidate the structural features of indazole derivatives that contribute to their anticancer potential while summarising recent advances in their biological evaluation. Recent studies have revealed that an indazole derivative exhibits several anticancer activities, including kinase inhibition, cell-cycle arrest, apoptosis, DNA interactions and modulation of critical oncogenic pathways. Computational studies supporting structural validation were also discussed to correlate the substitution pattern with biological potency. Discussed patents may highlight innovative synthetic strategies and hybrid molecular designs. In this review, the most active indazole-based compounds are discussed, along with their IC50 values, key structural features and supporting biological evaluations (cell line studies, molecular targets: AURKs, CDKs, EGFR, FGFR, HIF-1, ER-α, MAPKs, PDKs and in vivo studies). Indazole derivatives with potent activity exhibit nano- to micromolar IC50 values, with strategic substitutions markedly improving efficacy and selectivity, highlighting indazole as a potential anticancer scaffold.
The metadherin (MTDH)-staphylococcal nuclease domain-containing protein 1 (SND1) interaction is a functionally important protein-protein interaction implicated in tumor progression, making it an attractive but challenging therapeutic target. In this study, we employed an integrated in silico-to-in vitro virtual screening workflow to identify small-molecule disruptors of the MTDH-SND1 interface from a focused library of 1487 N-aryl-N'-heteroaryl ureas. After sequential filtering, four compounds (C1-C4) were prioritized for long-timescale evaluation. Docking showed that all four hits occupied the targeted SND1 interfacial hot-spot pocket with binding modes consistent with disruption of MTDH recognition. The 1000 ns MD simulations, together with MM/PBSA, protein-protein disruption metrics, and free energy landscape analyses, revealed ligand-dependent destabilization of the complex, with C3 producing the strongest weakening of the MTDH-SND1 interface and the broadest conformational redistribution, while C4 showed a somewhat weaker but still favorable profile. ADMET prediction indicated that all compounds satisfied basic drug-likeness criteria, although C3 displayed greater developability liabilities, whereas C4 showed the most balanced predicted pharmacokinetic and toxicity profile. Experimental validation using split-luciferase complementation assays confirmed concentration-dependent inhibition of the MTDH-SND1 interaction by all four compounds in both cell-free and cell-based formats, with C3 showing the greatest potency (cell-free IC50 = 2.81 ± 0.31 μM; cell-based IC50 = 11.30 ± 1.80 μM), followed by C4, C1, and C2, and with minimal activity in the linked-luciferase counter-screen. Collectively, these findings identify N-aryl-N'-heteroaryl ureas as a promising scaffold for MTDH-SND1 PPI disruption, establish C3 as the leading hit, and support C4 as a valuable secondary scaffold for future optimization.
Chronic obstructive pulmonary disease (COPD) remains a significant global health challenge, which urges the discovery of novel drugs. In this article, we investigated the therapeutic potential and action mechanism of a new benzoxazolone derivative, 4-(5'-dimethylamino)-naphthalenesulfonyl-2(3H)-benzoxazolone (W3D), synthesized by our research team, against COPD both in vivo and in vitro. The results demonstrated that W3D could down-regulate inflammatory cytokines such as interleukin-6 (IL-6), interleukin-1 beta (IL-1β), tumor necrosis factor-alpha (TNF-α), and MMP-9, thereby reducing airway inflammation and improving lung function, which together alleviated lung injury in COPD. Meanwhile, W3D increased the expression of tight junction proteins claudin-1 and occludin and attenuated the activation of the Toll-like receptor 4/nuclear factor kappa B (TLR4)/NF-κB) signaling pathway to maintain the integrity of bronchial epithelial cells. Additionally, W3D restored the expression of glycolytic enzymes such as LDHA, PKM2, and HK2 to modulate lactate levels, thereby correcting glycolytic pathway dysregulation. W3D decreased intracellular lactate content, down-regulated global Kla levels and H3K18la expression, and regulated macrophage polarization in cigarette smoke extract (CSE)-induced macrophages. Furthermore, these therapeutic effects of W3D were compromised in the presence of the glycolytic inhibitor 2-deoxy-d-glucose (2-DG), indicating that W3D regulated macrophage polarization by inhibiting glycolysis. Our results demonstrated that glycolysis was activated in macrophages exposed to CSE and served as a key role in the macrophage polarization process. Inhibiting glycolysis in macrophages might be a potential therapeutic direction for COPD. In addition, given the confirmed protective effect against COPD, W3D could serve as a promising lead compound for further structural modifications of innovative drugs.
Cancer poses a devastating global threat, inflicting immense physical suffering, high mortality rates, severe psychological distress, and substantial economic burdens on individuals, families, and healthcare systems worldwide while gravely compromising quality of life and leaving long-lasting impacts on affected communities. As a fundamental and versatile modality for cancer treatment, chemotherapy exerts a pivotal effect in shrinking tumors, eliminating residual cancer cells, alleviating symptoms, and improving survival rates across various cancer types, whether utilized as monotherapy or in combination with surgery, radiotherapy, or targeted therapies. However, chemotherapy is hampered by several key limitations. The primary drawbacks are tumor cell multidrug resistance, which culminates in impaired drug responsiveness and ultimately treatment failure, and non-specific cytotoxicity, which elicits off-target adverse effects in normal tissues. Accordingly, the development of novel anticancer agents remains an indispensable research priority in contemporary oncology. Natural indole alkaloids, a diverse class of natural secondary metabolites, exhibit notable advantages for cancer therapy, including high target selectivity, multiple anticancer mechanisms, favorable biocompatibility, and ample sources for lead compound discovery. Their structural diversity enables specific binding to cancer-associated molecular targets, while their structural modifiability further optimizes pharmacokinetic profiles, rendering them promising candidates for advancing the development of novel anticancer therapeutics. This review summarizes the recent research progress on natural indole alkaloids with anticancer therapeutic potential, developed over the period 2021 to the present, aiming to provide novel insights for the discovery of innovative anticancer agents.
A new series of extended-functionality triazole-substituted chalcone derivatives was synthesized, and their in vitro anti-proliferative and cytotoxic profiles were evaluated using cancer and non-cancer cell models. First, all compounds were screened in the FaDu head and neck squamous cell carcinoma cell line to identify the most active candidates with comparatively lower IC50 values. Compounds 6c, 6e, and 6f reduced FaDu cell viability to 42.62 ± 12.21%, 34.49 ± 4.99%, and 31.13 ± 4.76% of control, respectively. These three compounds also decreased viability of CaCo-2 human colon cancer cells and A549 human lung adenocarcinoma cells, showing micromolar-range activity (IC50 < 50 µM) across cancer cell lines of different origins. To obtain a preliminary indication of selectivity, we additionally tested a non-cancer, immortalized prostate epithelial cell line (PNT1a). In this model, 6c/6e/6f displayed relatively lower cytotoxicity than in cancer cells, suggesting a preliminary selectivity window within the tested assay framework. Among them, 6f the most active compound in our series-significantly reduced colony formation, comparable to paclitaxel. In apoptosis-related assessments, 6f increased apoptosis-associated readouts in cancer cells relative to control, although further confirmation is needed with additional orthogonal assays. Overall, our results identify 6c, 6e, and especially 6f as moderately active lead compounds for further optimization of triazole-chalcone hybrids and support continued structure-activity-guided development to improve potency and selectivity.
Chronic inflammation, arising from unregulated inflammatory responses to tissue damage, is linked to 25% of all cancers. Some new benzofuran-thiazole hybrids, H1-H4, were prepared herein and assessed as dual anticancer and anti-inflammatory agents. All hybrids tested displayed good potency against Caco2 cells. Particularly, H4 outperformed doxorubicin in potency, with an IC50 of 0.24 μM. Moreover, H2 and H3 exhibited excellent antiproliferative activity against RAW 264.7 cells, which was found comparable to celecoxib, with IC50 values of 160.75 and 115.76 μM, respectively. The safety of the new hybrids was evaluated against HFB4 cells, as we found that H2 and H3 showed superior selectivity against cancer cells. H2 and H3 were found to significantly increase apoptosis in RAW 264.7 cells, confirming their potential as cytotoxic agents. The anti-inflammatory efficacy of some hybrids was screened. The inhibition of nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells was measured to assess the anti-inflammatory effects, where H2 showed significant inhibition at a dose of 100 µM. Also, H3 exhibited comparable cyclooxygenase-2 (COX-2) inhibitory potency to celecoxib with an IC50 of 0.69 μM. At a dose of 1/20 LD50, both H2 and H3 were safe for kidney function in an animal model. However, H2 was safer for gastric tissue, while H3 showed adverse gastric effects at this same concentration. The molecular docking of both hybrids displayed important binding modes with the mouse COX-2 (PDB ID: 7O37).
Baicalin is a bioactive flavonoid compound extracted from plants of the Scutellaria genus, such as Scutellaria baicalensis, and exhibits a wide range of pharmacological effects. Studies have shown that it has antibacterial activity against a variety of clinically common pathogens. Meanwhile, it can inhibit the development of antimicrobial resistance, thereby enhancing the antibacterial activity of traditional antibiotics. This highlights the potential of baicalin as an antimicrobial agent and antibiotic adjuvant. This review systematically summarizes the antibacterial activity, antibiofilm effects, beneficial properties, and underlying mechanisms of baicalin, both when used alone and in combination with antibiotics, in in vitro and in vivo models. At the same time, the pharmacokinetic properties and cytotoxicity studies of baicalin were also reviewed. Given its relatively low bioavailability in vivo, the development of baicalin-based nanoformulations and other dosage forms has been highlighted as a promising strategy to enhance its bioavailability and expand its potential applications. Finally, this article discusses the limitations and shortcomings of current research and outlines future research directions. We emphasize the need to evaluate the medication strategies, clinical efficacy, and safety of baicalin in the treatment of microbial infections through higher-quality research. This review aims to provide new insights and references for the further development and clinical application of baicalin.
Small-molecule-based therapeutics play a vital role in drug discovery. These molecules are preferred owing to their oral bioavailability, ease of tuning the physicochemical properties, and broad target accessibility. In this review article, we have explored the small molecules approved by the US Food and Drug Administration (USFDA) in 2025. Through the analysis, we found 44 drug approvals, out of which 30 candidates were approved as new molecular entities (NMEs), while the remaining 14 were approved in the category of biologics, including 10 approved as biosimilars. Considering the therapeutic area distribution of 30 NMEs, 28 drugs are approved as monotherapy, with 10 drugs as anticancer agents, 4 drugs for genetic disorders, 2 drugs each for the conditions of immunological, respiratory, ophthalmic, and endocrine disorders, along with the treatment of cardiac and infectious diseases. The structural diversity analysis revealed that 29 approved drugs were aromatic (azaheterocycles) in nature, and 13 drugs possess at least one stereogenic center. Considering the elemental diversity, the near-universal presence of nitrogen in the form of amines, amides, and as a heteroatom, followed by the oxygen atom. Additionally, the prevalence of 3- or 4-membered carbocyclic or heterocyclic rings was found in five approved drugs. For metabolism, most drugs rely on CYP3A-mediated metabolism, primarily through CYP3A4, CYP2D6, and CYP2C8. Collectively, the analysis and compilation of the drugs presented are expected to provide practical insights and offer guidance to medicinal chemists, biologists, and scientists associated with current drug-discovery paradigms, making continuous strides for future medicinal chemistry innovations and evolutions.