Med Chem [JOURNAL]
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200 papers
Research Progress of G Protein-coupled Receptor 52 on Central Nervous System Diseases.
Wu Q, Li J, Hu X … +2 more , Zhuang Y, Zheng L
Med Chem · 2026 · PMID 40444627 · Publisher ↗
The G protein-coupled receptor 52 (GPR52) is a Gs-coupled receptor and is located principally in the striatum alongside D receptor and in the pre-frontal cortex alongside D receptor. Its stimulation leads to potentiation...
The G protein-coupled receptor 52 (GPR52) is a Gs-coupled receptor and is located principally in the striatum alongside D receptor and in the pre-frontal cortex alongside D receptor. Its stimulation leads to potentiation of intracellular cAMP levels, producing effects on cAMP levels similar to those of a Gi-coupled D receptor antagonist in the striatum and a Gscoupled D receptor agonist in the prefrontal cortex. This dual mechanism suggests that GPR52 activation could result in antipsychotic effects akin to D antagonism and pro-cognitive effects resembling D1 agonism. As a result, GPR52 has emerged as a promising therapeutic target for central nervous system (CNS) disorders, including schizophrenia and substance use disorder. Additionally, knocking out (KO) GPR52 not only significantly reduces mutant huntingtin protein (mHTT) levels in the striatum but also rescues Huntington's disease-associated behavioral phenotypes in a knock-in Huntington's disease mouse model, which provides evidence that GRP52 may also serve as a potential target for Huntington's disease. This review summarizes the current state of small-molecule ligand/drug discovery for GPR52, focusing on the latest findings about the role of GPR52 in schizophrenia and Huntington's disease.
Recent Advances in the Medicinal Chemistry of Cancer (Part 1).
Yıldırım I
Med Chem · 2025 · PMID 40377152 · Publisher ↗
Abstract loading — click title to view on PubMed.
Natural Mimetic 4,6-Dihydroxyaurone Derivatives as Tyrosinase Inhibitors: Design, Synthesis, and Biological Evaluation.
Nguyen QT, Tran GQ, Ta HT … +6 more , Do QD, Vu QX, Phung BT, Tran TD, Thai KM, Vo CT
Med Chem · 2025 · PMID 40377151 · Publisher ↗
INTRODUCTION: Tyrosinase, a key enzyme in melanin biosynthesis and food browning, has become an important target for inhibitor development. This study aimed to investigate the inhibitory potential of 4,6-dihydroxyaurone...
INTRODUCTION: Tyrosinase, a key enzyme in melanin biosynthesis and food browning, has become an important target for inhibitor development. This study aimed to investigate the inhibitory potential of 4,6-dihydroxyaurone derivatives with varied ring B substituents on mushroom tyrosinase. METHODS: A set of 4,6-dihydroxyaurone derivatives, each with varied substituent patterns on ring B, were designed and subjected to computational studies to predict their binding affinity, binding modes with tyrosinase, and drug-likeness properties. These aurone derivatives were subsequently synthesized and evaluated in vitro for their tyrosinase inhibitory activity. Enzyme kinetics studies were conducted to determine the mode of tyrosinase inhibition. RESULTS: Computational studies of the twenty designed aurone derivatives indicated their strong binding within the active site and exhibited favorable drug-likeness properties. UV-Vis spectrophotometric assays of the synthesized compounds revealed that compound 5h, featuring a 3,4-dichlorophenyl substituent on ring B, showed the most potent tyrosinase inhibitory activity (IC = 6.3 ± 0.3 μM) compared to kojic acid (IC = 136.5 ± 11.5 μM). Kinetic studies and molecular docking simulations indicated that compound 5h inhibits tyrosinase through a mixedtype inhibition mechanism, with competitive and uncompetitive inhibition constants of 21 μM and 68 μM, respectively. CONCLUSION: These findings highlight the promising potential of 4,6-dihydroxyaurone derivatives as potent tyrosinase inhibitors for applications in pharmaceuticals, cosmetics, and agriculture.
Discovering the Cholinesterase Inhibitory Potential of Thiosemicarbazone Derivatives through , Molecular Docking, Kinetics, and Dynamics Studies.
Essid M, Alam A, Fareed G … +7 more , Rahman S, Ahmad I, Zghab I, Alnakhli ZH, Ali A, Kamal M, Khan M
Med Chem · 2025 May · PMID 40357792 · Publisher ↗
BACKGROUND: The current study explored the cholinesterase inhibitory activities of some thiosemicarbazone derivatives bearing 2,4-dichloro phenylacetic acid scaffold. OBJECTIVE: This study aimed to screen the synthesized...
BACKGROUND: The current study explored the cholinesterase inhibitory activities of some thiosemicarbazone derivatives bearing 2,4-dichloro phenylacetic acid scaffold. OBJECTIVE: This study aimed to screen the synthesized derivatives for their acetylcholine and butyrylcholinesterase inhibition. METHODS: These compounds were synthesized by refluxing 2,4-dichloro phenylacetic acid with sulfuric acid in ethanol to get the ester, which was further refluxed with thiosemicarbazide in ethanol to get the desired compound (2). Different benzaldehydes were treated with compound (2) in ethanol having a catalytic amount of acetic acid to get thiosemicarbazones. RESULTS: In the series, seven compounds, including compounds 2c, 2a, 2b, 2d, 2g, 2e, and 2f, displayed excellent acetylcholinesterase inhibition activities in the range of IC values from 41.51 ± 3.88 to 95.48 ± 0.70 μM, surpassing than the standard galantamine (IC = 104.5 ± 1.20 μM). Also, compounds 2a, 2g, 2h, 2f, 2b, and 2d with IC values ranging from 64.47 ± 2.74 to 80.62 ± 0.73 μM exhibited potent inhibition against butyrylcholinesterase enzyme, being similar to the standard galantamine (IC = 156.8 ± 1.50 μM). The molecular docking investigation was performed to assess the binding affinity of the compounds with the active site of the enzyme. These compounds, along with the docked complexes, specifically AChE-compound 2a and BuChE-compound 2g, were chosen and subjected to 100-nanosecond molecular dynamics simulations. The simulations demonstrated strong stability of the ligands within the active pockets of AChE and BuChE enzymes. CONCLUSION: These derivatives exhibited superior acetylcholinesterase and butyrylcholinesterase inhibitory activities compared to galantamine, with molecular docking and dynamic simulations confirming their strong binding affinity with the active sites of the enzymes.
Synthesis, Characterization, and Pharmacological Evaluation of ZnO(BDC): Anticancer, Antidiabetic, and Drug Delivery Potential.
Khan S, Hameed MF, Zafar I … +5 more , Bibi R, Mohany M, Nazir S, Kamal MA, Shafiq M
Med Chem · 2025 May · PMID 40353418 · Publisher ↗
INTRODUCTION: This study presents a comprehensive exploration of the biomedical potential of the synthesized metal-organic framework ZnO(BDC), focusing on its applications in cancer and diabetes treatment and its advance...
INTRODUCTION: This study presents a comprehensive exploration of the biomedical potential of the synthesized metal-organic framework ZnO(BDC), focusing on its applications in cancer and diabetes treatment and its advanced drug delivery capabilities. METHODS: The structural and physicochemical properties of ZnO(BDC) were characterized using FTIR, TGA, H NMR, PXRD, and elemental analysis, revealing its exceptional stability and coordination properties. Molecular docking, molecular dynamics simulations (100 ns), and MM-GBSA calculations were performed to assess binding affinities and stability. RESULTS: The interactions of ZnO(BDC) with salmon sperm DNA (SSDNA) and bovine serum albumin (BSA) demonstrated significant anticancer potential, evidenced by binding constant values of 6.0 × 10M and Gibbs free energy changes of -17.93 and -19.61 kcal/mol, respectively, highlighting its ability to suppress tumor cell proliferation. With doxorubicin (DOX) loading and reloading efficiencies of 88% and 87.5%, ZnO(BDC) exhibited superior drug delivery capabilities. The anti-diabetic potential was validated by the formation of human insulin (HI) hexamers with ΔG values of 0.8 ± 0.1 and a significant decrease in absorption intensity (5.8 to 0.05 at 250 nm). Molecular docking studies revealed moderate to high binding affinities (-10.0 to -5.3 kcal/mol) with biomolecular targets, supported by molecular dynamics simulations over 100 ns and MM-GBSA calculations indicating robust stability (ΔG = -33.31 kcal/mol). CONCLUSION: These and analyses underscore the significant pharmacological promise of ZnO(BDC) as a multifunctional agent for anticancer, antidiabetic, and drug delivery applications.
Screening of Novel Inhibitors Targeting the Non-ATP-binding Domain of SecA1.
Liu Y, Su Q, Wang Z … +7 more , Liu P, Hong J, Seoh HK, Jia X, Sui SF, Tai PC, Huang X
Med Chem · 2026 · PMID 40353417 · Publisher ↗
OBJECTIVE: has been one of the pathogenic bacteria for clinical infections, and there is an urgent need for the development of novel anti-S. aureus drugs. SecA is a conserved and essential protein in bacteria and is con...
OBJECTIVE: has been one of the pathogenic bacteria for clinical infections, and there is an urgent need for the development of novel anti-S. aureus drugs. SecA is a conserved and essential protein in bacteria and is considered as an ideal target for development. Current screening of inhibitors against SecA has focused on the ATP-binding structural domain, which increases the risk of drug side effects, so a novel screening strategy based on the non-ATP-binding structural domain was chosen in this paper. METHODS: A three-dimensional structural model of S. aureus SecA1N75 was constructed, and molecular docking was utilized to screen small molecules with strong interactions with the non- ATP binding domains from a compound library, and four candidate compounds were finally targeted. Molecular dynamics simulations of the candidate molecules were performed to evaluate their drug potential. RESULTS: The four candidate compounds formed stable interactions with key residues of the SecA binding pocket. Molecular dynamics simulations further showed that the candidate molecules bound to the receptor in a stable conformation with nM-level inhibition constants, displaying potent SecA inhibitory activity. It lays the foundation of a lead compound for the development of antimicrobial drugs targeting SecA. CONCLUSION: In this thesis, an inhibitor screening strategy based on non-ATP binding structural domains was successfully constructed, which breaks through the limitations of traditional methods to screen candidate molecules with high activity and low risk of potential side effects, and provides an innovative solution to meet the challenge of S. aureus drug resistance.
Design and Synthesis of (2,3-dichloro-4-(3-(substituted Phenyl)acryloyl) phenoxy) Substituted Carboxylic Acid as Potent Glutathione-s-transferase Inhibitors, Anti-breast-cancer Agents and Enhancing Therapeutic Efficacy of Anticancer Agents.
Qayyum ABA, Ali SA, Mokale SN
Med Chem · 2025 · PMID 40351070 · Publisher ↗
BACKGROUND: Ethacrynic acid is a dynamic agent holding alpha-beta unsaturated carbonyl unit in its structure which imparts superiority and extraordinary advantage of displaying multiple biological activities such as anti...
BACKGROUND: Ethacrynic acid is a dynamic agent holding alpha-beta unsaturated carbonyl unit in its structure which imparts superiority and extraordinary advantage of displaying multiple biological activities such as anticancer, antiviral, anti-malarial effect, diuretic effect and inhibits the Glutathione-s-transferase p1-1 enzyme which produces hindrance in the pathway of apoptosis. Ethacrynic acid is an inhibitor of Glutathione-s-transferases. EtA by itself act as an anticancer agent at higher concentration and also increases effectiveness of other compounds used in cancer treatment by preventing their detoxification, all these facts attracted our attention to develop and evaluate novel structural analogues of ethacrynic acid for their inhibitory effect on GSTs and anti-cancer activity in breast cancer. OBJECTIVE: By attending rational drug design perspectives the research is aimed to develop and evaluate novel structural analogues of ethacrynic acid as Inhibitors of GSTs enzyme and with antibreast cancer activity. METHODS: Designed compounds were synthesized as per convenient route shown in the scheme of synthesis. Molecular docking studies were done against GSTP1-1 (PDB:3HJO). Structures of novel synthesized molecules were confirmed by spectral characterization such as FTIR, HNMR, CNMR and Mass spectrometry. ADME studies were done to ensure safety and drug like properties of the compounds. Ten structural analogues of ethacrynic acid were synthesized and evaluated for their inhibitory effect on activity of Glutathione-s-transferases which was measured by performing assay method. anti-breast cancer activity was done on MCF-7 and MDAMB-231 cell line by MTT assay. RESULTS: Compound A3, A5 and A6 were found with greater inhibition of the activity of GSTs and maximum anti-proliferative activity in breast cancer. CONCLUSION: We have effectively developed novel compounds possessing structural resemblance with ethacrynic acid Compounds of the series has shown moderate to higher inhibitory effect on GSTs and anti-proliferative activity in breast cancer. The compound A3 was found to be promising agent with high level of potency in each biological response. The research studies presented here may be an enlightening path in development of novel therapeutic agents with high level of inhibition in the activity of GSTs and anti-breast cancer effect.
Synthesis, Characterization, and and Studies of New Triazole Derivatives as Aromatase Inhibitors.
Uzmez ZL, Osmaniye D, Ozkay Y … +1 more , Kaplancıklı ZA
Med Chem · 2025 · PMID 40351069 · Full text
INTRODUCTION: Breast cancer is the most common type of cancer among women. Steroidal or non-steroidal aromatase inhibitors (NSAIs) are used clinically, and in most cancer diseases, resistance is the most important proble...
INTRODUCTION: Breast cancer is the most common type of cancer among women. Steroidal or non-steroidal aromatase inhibitors (NSAIs) are used clinically, and in most cancer diseases, resistance is the most important problem. METHODS: The nitrogenous heterocyclic ring is noteworthy in the structure of non-steroidal aromatase inhibitors. This is the pharmacophore structure for aromatase inhibition. Because the enzyme interacts with the Fe cation of the HEM structure in its active site, the most used agents in the clinic, such as anastrozole and letrozole, contain triazoles in their structures. Within the scope of this study, hybrid compounds containing both imidazole and triazole were synthesized. RESULTS: The synthesis was carried out by a 4-step reaction. The anticancer effects of the compounds were evaluated by MTT assay performed on A549 and MCF-7 cancer cells. Compound 4d showed anticancer activity against the MCF-7 cell line with IC=6.7342 uM value. This compound exhibited anticancer activity against the A549 cell line with an IC = 17.1761 μM. In the MTT test performed on a healthy cell line to determine the cytotoxic effects of the compounds, the compound showed activity with a value of 4d IC=13.2088 uM. This indicates that the compound is not cytotoxic. Additionally, BrdU analysis was performed to evaluate whether the compound inhibits DNA synthesis. These selective effects of the compounds on breast cancer strengthened their aromatase enzyme inhibitor potential. For this reason, experiments conducted with both and methods revealed a compound with high aromatase inhibitor potential. CONCLUSION: The interactions observed as a result of molecular docking and dynamics studies are in harmony with activity studies. In particular, interactions with HEM600 demonstrate the activity potential of the compound.
Analysis and Molecular Docking of Human Antimicrobial Peptides for Targeting Monkeypox Virus: Potential Therapeutic Implications of Histatin 5 Peptide.
Radhakumar DSD, Thiyagarajan S, Rajaram K … +1 more , Parsanathan R
Med Chem · 2025 · PMID 40351068 · Publisher ↗
BACKGROUND: Monkeypox, a viral zoonotic disease akin to smallpox, has posed significant public health challenges, particularly in Africa. Recent outbreaks, including those in India, underscore the global threat it poses....
BACKGROUND: Monkeypox, a viral zoonotic disease akin to smallpox, has posed significant public health challenges, particularly in Africa. Recent outbreaks, including those in India, underscore the global threat it poses. OBJECTIVE: In this study, we explore a novel approach to combat monkeypox virus (MPXV) infection by targeting its surface proteins, crucial for viral entry and fusion. METHODS: Employing advanced computational techniques, we predict and refine the 3D structures of MPXV surface proteins and human antimicrobial peptides (hAMPs), specifically Histatin 1, 3, and their cleaved product, Histatin 5 (HIS 5). Further, molecular docking was carried out for MPXV surface proteins with hAMP HIS using HDOCK and Cluspro 2.0. Protein-peptide interactions were analyzed using PdbSum. Finally, the physicochemical properties of HIS peptides were determined using CamSol. RESULTS: Our findings suggest HIS 5 as a potential therapeutic peptide against MPXV, warranting further investigation through and studies. CONCLUSION: This study sheds light on the efficacy of the HIS family in targeting MPXV and advocates for continued exploration of HIS 5's antiviral effects.
Pharmacological Evaluation of Bioisosterically Replaced and Triazole- Tethered Derivatives for Anticancer Therapy.
Kumar D, Salahuddin, Mazumder A … +6 more , Kumar R, Ahsan MJ, Yar MS, Abbussalam, Tyagi PK, Chaitanya MVNL
Med Chem · 2025 · PMID 40351067 · Publisher ↗
Cancer has been the cause of the highest number of deaths in the human population despite the development and advancement in treatment therapies. The toxicity, drug resistance, and side effects of the current medicaments...
Cancer has been the cause of the highest number of deaths in the human population despite the development and advancement in treatment therapies. The toxicity, drug resistance, and side effects of the current medicaments and therapies have left the void for more research and development. One of the possibilities to fill this void is by incorporating Triazole moieties within existing anticancer pharmacophores to develop new hybrid drugs with less toxicity and more potency. The placement of nitrogen in the triazole ring has endowed its characterization of being integrated with anticancer pharmacophores via bioisosteric replacement, click chemistry and organocatalyzed approaches. This review paper emphasizes the discussions from articles published from the early 2000s to the current 2020s about the triazole-based derivatives used in anticancer therapy, elaborating more on their chemical structures, target receptors or enzymes, mechanism of action, structure-activity relationships, different triazole-derived hybrid drugs under clinical and nonclinical trials, and recent advancements toward developing more potent and less toxic anticancer agents.
One-Pot Synthesis of Benzoxazoles: A Promising Approach to Aromatic Heterocyclic Compounds Preparation.
Chauhan M, Nain S
Med Chem · 2025 · PMID 40351066 · Publisher ↗
Considering the necessity for broad synthetic operations, integrating various reactions into a single pot operation is an intriguing approach to improve synthetic efficiency. One-pot operations may serve as an effective...
Considering the necessity for broad synthetic operations, integrating various reactions into a single pot operation is an intriguing approach to improve synthetic efficiency. One-pot operations may serve as an effective way to minimize the amount of chemical waste generated, save time, avoid multiple purification processes, accomplish numerous transformations, and make multiple bonds in one pot. Therefore, "pot economy" should be considered while designing a synthesis process, since a one-pot reaction can be effective and environmentally safe. Outstanding synthesis has rapidly increased over the last ten years. This study's main goal was to illustrate various one-pot methods that lead to advantageous synthesis.
Inhibitors of Phosphatidylinositol-specific Phospholipase C wit h -inositol Scaffold.
Bierkamp C, Hanekamp W, Arenz C … +1 more , Lehr M
Med Chem · 2026 · PMID 40325542 · Publisher ↗
BACKGROUND: Phosphatidylinositol-specific phospholipase C (PI-PLC) enzymes catalyze the conversion of phosphatidylinositol-4,5-bisphosphate into the second messengers diacylglycerol and inositol- 1,4,5-trisphosphate, bot...
BACKGROUND: Phosphatidylinositol-specific phospholipase C (PI-PLC) enzymes catalyze the conversion of phosphatidylinositol-4,5-bisphosphate into the second messengers diacylglycerol and inositol- 1,4,5-trisphosphate, both of which play crucial roles in regulating biochemical processes. Despite the wellestablished link between elevated PI-PLC activity and pathophysiological conditions, no PI-PLC inhibitors are currently in clinical development. Moreover, existing inhibitors demonstrate only limited potency. OBJECTIVE: Due to the structural similarity with known inhibitors with a -inositol backbone, DL-1-Ododecylsulfonyl- -inositol-3,5-bisphosphate, designated as acid sphingomyelinase inhibitor, and derivatives thereof should be tested for inhibition of PI-PLC activity. METHODS: The newly synthesized compounds were evaluated for their ability to inhibit PI-PLC activity in porcine platelet lysate and porcine brain homogenate, as well as their inhibitory potency against the recombinant isoenzymes PLCγ1 and PLCγ2. The assay measured the release of diacylglycerol from L-α- phosphatidylinositol using HPLC coupled with MS detection. Furthermore, the specificity of selected compounds was assessed by determining their inhibitory potency against other surface-active enzymes through HPLC-based assays. RESULTS: It was found that DL-1-O-dodecylsulfonyl-myo-inositol-3,5-bisphosphate inhibits PI-PLC activity at micromolar concentrations. However, its maximum achievable inhibitory effect was limited to approximately 70%. Through structural modifications, inhibitors were developed that led to near complete inhibition of PIPLC activity. The study also revealed that the alleged PI-PLC inhibitor U73122, still frequently cited in the literature to demonstrate PI-PLC involvement in biochemical processes, is unsuitable for this purpose. Consistent with observations by others, its inhibitory activity in bionucleophile-containing cell or tissue preparations was found to be significantly lower than its activity against purified PI-PLC enzymes. Additionally, U73122 was shown to inhibit other enzymes, such as cytosolic phospholipase Aα, fatty acid amide hydrolase, and monoacylglycerol lipase, which, like PI-PLC, metabolize lipophilic substrates. In contrast, the newly developed -inositol derivatives exhibited reduced sensitivity to bionucleophiles and significantly improved selectivity against the tested surface-active enzymes compared to U73122. CONCLUSION: New compounds exhibiting significant inhibitory activity against PI-PLC have been identified. The findings could prove valuable in the development of clinically applicable PI-PLC inhibitors, particularly for the treatment of cancer. Additionally, the -inositol derivatives developed demonstrated greater suitability for studying PI-PLC's role in physiological processes in tissue homogenates compared to the maleimide derivative U73122, which is commonly used for this purpose in scientific research. This advantage arises from the fact that U73122 is a non-specific 'pan-assay interference compound' (PAIN).
Design, Synthesis, and Biological Evaluation of a Novel Series of Thiazolidinediones as Dual GSK-3β and Tau Aggregation Inhibitors.
Abdollahi Z, Abnous K, Kalani MR … +4 more , Taghdisi SM, Soltani S, Nejabat M, Hadizadeh F
Med Chem · 2026 · PMID 40325541 · Publisher ↗
INTRODUCTION: Glycogen synthase kinase-3β (GSK-3β) is a serine/threonine kinase that is involved in the synthesis of glycogen. Among the inhibitors, thiazolidinediones (TZDs) can specifically bind to GSK-3β. They act non...
INTRODUCTION: Glycogen synthase kinase-3β (GSK-3β) is a serine/threonine kinase that is involved in the synthesis of glycogen. Among the inhibitors, thiazolidinediones (TZDs) can specifically bind to GSK-3β. They act non-competitively with ATP, and as a result, they are very specific and have fewer side effects. In this research, new TZDs were designed and synthesized, and then their inhibitory effects on GSK-3β enzyme and tau aggregation were investigated. MATERIALS AND METHODS: The structure of the compounds was confirmed using 1H-NMR, 13CNMR, and LC-MASS. The inhibitory activities of the compounds 5a-p, against GSK-3β were evaluated using Z'-LYTE technique, and the IC50 values were determined. RESULTS: Compound 5l (R1 = Me, R2 = 4-F-benzyl, R3 = butyl) with IC50 of 16.1 μM exhibited the most potent inhibition. Also, the binding with tau protein and their inhibitory effects on the accumulation of recombinant human tau protein (1N4R, htau34) were evaluated using the Surface Plasmon Response (SPR) method. In this study also the impact of TZDs on tau aggregation using the Thioflavin T (ThT) assay was investigated. PC12 cells viability study confirmed the neuroprotective effects of compounds against tau aggregates. MD simulation studies showed the interaction of 5l with the active site of GSK-3β (PDB ID: 2OW3) and also its destructive effect on tau aggregate (PDB ID: 5O3L) was studied. CONCLUSION: Overall, the study identified three promising TZDs with potential as inhibitors of GSK-3β and tau proteins, highlighting compound 5l as particularly effective in stabilizing GSK- 3β and disrupting tau aggregation.
Curcumin-Based Virtual Screening Identifies Inhibitors of SARS-CoV-2 Spike Protein and ACE2 Receptor Binding.
Delgado-Maldonado T, Gonzalez-Morales LD, Vargas-Salas G … +4 more , Rojas-Verde G, Ortíz-Pérez E, Paz-Gonzalez AD, Rivera G
Med Chem · 2026 · PMID 40277059 · Publisher ↗
BACKGROUND: To date, COVID-19 has caused over 772 million cases, with approximately 7 million deaths, according to the World Health Organization. Therefore, there is a need to develop new drugs to address the challenges...
BACKGROUND: To date, COVID-19 has caused over 772 million cases, with approximately 7 million deaths, according to the World Health Organization. Therefore, there is a need to develop new drugs to address the challenges posed by this disease. OBJECTIVE: To propose new antiviral agents based on the natural product curcumin as potential protein-protein interaction inhibitors between the SARS-CoV-2 spike receptor binding domain (RBD) and the ACE2 receptor. METHODS: A curcumin-based virtual screening was performed (Tanimoto coefficient= 0.9), and molecular docking analysis were carried out using the RBD as a receptor. Molecular dynamics (MD) using GROMACS were conducted for 120 ns. The SwissADME server was used to predict pharmacokinetics properties. To validate predictions, an in vitro enzyme assay measuring the relative inhibition of the interaction between the RBD and the ACE2 receptor was performed. RESULTS: More than 1300 ligands were evaluated through molecular docking. The docking results were analyzed, and the ligands were classified according to their score and profile of interactions with residues of the RBD of the SARS-CoV-2 S glycoprotein. The top ten with the best scores and interactions were selected to verify the commercial availability. The lead compound Cu-1 demonstrated significant interactions with the RBD and stability in MD simulations, was acquired and evaluated in vitro. Compound Cu-1 inhibited 36 ± 0.7% the interaction between the SARSCoV- 2 spike and the ACE2 receptor. In addition, Cu-1 was shown to have an acceptable druglikeness and pharmacokinetic profile. CONCLUSION: Curcumin provides a scaffold for identifying novel compounds with potential antiviral activity. Further studies on compound Cu-1 could yield on optimizing its structure to increase activity targeting the RBD of the S glycoprotein.
Scaffold Hopping and Optimization of Thiazole Hybrids as Selective PIN1 Inhibitors: A Computational Study.
Chellappan MC, Vasu S, Mahadevan S … +4 more , Kathiravan MK, Jayaraman S, Naik S, Thachil KK
Med Chem · 2026 · PMID 40265424 · Publisher ↗
BACKGROUND: Protein Interacting with NIMA1 (PIN1) is a distinct enzyme, known as a peptidyl-prolyl cis-trans isomerase (PPIase), which catalyzes the cis-trans isomerization of amide bonds in proteins containing phosphose...
BACKGROUND: Protein Interacting with NIMA1 (PIN1) is a distinct enzyme, known as a peptidyl-prolyl cis-trans isomerase (PPIase), which catalyzes the cis-trans isomerization of amide bonds in proteins containing phosphoserine/threonine-proline (pSer/Thr-Pro) motifs, presenting a unique therapeutic opportunity for addressing multiple disorders. METHODS: A series of 140 thiazole compounds were created using the shape similarity technique with the intention of discovering effective PIN1 inhibitors with a new scaffold. The designed compounds were docked into the enzyme's ATP binding site, and the binding free energies for all docked conformations were calculated. The compounds were evaluated for their ADMET and drug-likeness properties. Following the identification of top candidates, molecular dynamics simulations were conducted to investigate the binding dynamics of the highest-scoring compound. RESULTS: Based on computational findings, sixteen compounds were identified as potential PIN1 inhibitors. Among the sixteen compounds, four (S8Ba, S8Bb, S8Bc, and S8Bd) exhibited the most favorable ADMET profiles and robust interactions with key PIN1 residues. Molecular dynamics simulations confirmed that S8Ba and S8Bc exhibited the most promising activity over 100ns. CONCLUSION: The results corroborated the docking outcomes, validating the selected hits as potential PIN1 inhibitors. This breakthrough could influence the development of therapeutic leads for combating diabetes, cancer, and Alzheimer's disease.
Reducing Cabozantinib Toxicity in Renal Cell Carcinoma Treatment through Structural Modifications.
Guo J, Yin X, Lu Y … +1 more , Yang Y
Med Chem · 2025 · PMID 40257021 · Full text
BACKGROUND AND OBJECTIVES: Cabozantinib, a Tyrosine Kinase Inhibitor (TKI), is widely used in Renal Cell Carcinoma (RCC) therapy but often causes serious side effects such as myelosuppression, immunosuppression, and angi...
BACKGROUND AND OBJECTIVES: Cabozantinib, a Tyrosine Kinase Inhibitor (TKI), is widely used in Renal Cell Carcinoma (RCC) therapy but often causes serious side effects such as myelosuppression, immunosuppression, and angiopathy. This study aims to identify key protein targets responsible for the therapeutic efficacy and adverse reactions of cabozantinib and to explore structural modifications to reduce toxicity while preserving efficacy. METHODS: A non-randomized computational approach was employed, screening 400 potential protein targets using SwissTargetPrediction and ChemBL databases. Molecular docking and Structure-Activity Relationship (SAR) analysis were performed to assess interactions between cabozantinib and identified targets, focusing on structural elements contributing to toxicity. RESULTS: Three primary proteins were identified as responsible for the anti-tumor effects of cabozantinib, while three others were linked to its side effects. Docking analysis revealed that the methoxyphenyl group in cabozantinib formed undesirable hydrogen bonds with toxicity-related proteins. Modulating these off-target interactions by minimizing hydrogen bonding in this region could significantly reduce adverse effects. CONCLUSION: These findings provide structural insights into cabozantinib's dual effects and suggest optimization strategies for TKI design, offering a pathway toward safer and more effective RCC treatments.
Expanding Therapeutic Horizons with Indazole-Based Compounds: A Review of Anticancer, Antimicrobial, and Neuroprotective Applications.
Bhane PD, Pawar SS
Med Chem · 2026 · PMID 40257020 · Publisher ↗
Indazole-based compounds have recently developed and physiologically evaluated as diverse agents for antibacterial, anticancer, anti-inflammatory, anti-obesity, and neurological therapies. This review highlights these ad...
Indazole-based compounds have recently developed and physiologically evaluated as diverse agents for antibacterial, anticancer, anti-inflammatory, anti-obesity, and neurological therapies. This review highlights these advancements. Through molecular docking and experimental tests, scientists have created distinct indazole analogs that exhibit significant inhibitory effects on various biological targets, including 1,2,3-triazolyl-indazoles, carbothioamides, and carboxamides. Key compounds have demonstrated strong bactericidal and antifungal properties against microbes such as , and ; their effectiveness was enhanced by halogenated and electron-withdrawing substituents. In models including positive HER2 breast cancer and hepatocellular tumors, indazole derivatives have shown efficacy against targets such as CDK2, EGFR, c-Met, HSP90, and VEGFR2 in oncology, resulting in successful anticancer responses. The pharmacokinetics, solubility, and specificity of these compounds have been further improved through structural alterations, such as piperazine ring modifications and C-terminal changes. Additionally, the LRRK2 antagonist MLi-2 demonstrated remarkable efficacy in treating neurodegenerative diseases, while indazole-5-carboxamides exhibited a strong affinity for monoamine oxidases, potentially offering new therapeutic options for Parkinson's disease. Inhibition of COX-2 and FGFR resulted in anti-inflammatory effects, with minimal off-target damage observed in vivo. Collectively, our findings underscore the therapeutic versatility of indazole frameworks across various disease pathways, suggesting their potential for developing innovative treatments for cancer, infections, metabolic disorders, and neurological conditions.
Pyrazole and Pyrazoline-Based EGFR TK Inhibitors: A Review Study Emphasizing Structure-Activity Relationship (SAR).
Mittal S, Alam O, Singh L … +8 more , Kannan, Shakuli A, Mathur V, Jha M, Ilyas A, Ali S, Naim MJ, Tanweer S
Med Chem · 2025 Apr · PMID 40248933 · Publisher ↗
Unusual cell growth patterns, metastasis (the spread of tumors to other parts of the body), and potential death are all hallmarks of cancerResearch in oncology clearly shows that abnormalities in EGFR expression directly...
Unusual cell growth patterns, metastasis (the spread of tumors to other parts of the body), and potential death are all hallmarks of cancerResearch in oncology clearly shows that abnormalities in EGFR expression directly contribute to uncontrolled cell growth and division, resulting in the development of carcinomas.. People with cancer have developed resistance due to mutations in several EGFR-associated genes. Tyrosine kinase inhibitors (TKIs) and other cancer treatments must, therefore, undergo continuous improvement. Currently, fourth-generation tyrosine kinase inhibitors (TKIs) that act allosterically against the C797S mutation are the most widely used class of medications that target EGFR mutations. To help researchers better understand how to optimize pyrazole and pyrazoline-based derivatives as antiproliferative agents, this review summarises the work done in the last fifteen years on different anti-cancer agents representing 31 most potential compounds along with their activity characteristics, with a particular emphasis on the structure-activity relationship (SAR) of possible pyrazole and pyrazoline derivatives as EGFR tyrosine kinase inhibitors.
Integrated Artificial Intelligence and Physics-Based Methods for the Design of Spleen Tyrosine Kinase (SYK) Inhibitors.
Pawar AD, Abdelghani HTM, Deka H … +5 more , Battula MS, Maiti S, Patil PC, Bhowmick S, Chikhale RV
Med Chem · 2025 · PMID 40143396 · Publisher ↗
INTRODUCTION: SYK (Spleen Tyrosine Kinase) regulates immune response and is a promising target for cancer, sepsis, and allergy therapies. This study aims to create novel compounds that serve as alternative inhibitors for...
INTRODUCTION: SYK (Spleen Tyrosine Kinase) regulates immune response and is a promising target for cancer, sepsis, and allergy therapies. This study aims to create novel compounds that serve as alternative inhibitors for cancer treatments targeting SYK. METHODS: A thorough combination of machine learning (ML) and physics-based methods was employed to achieve these goals, encompassing design, multitier molecular docking, absolute binding affinity computation, and molecular dynamics (MD) simulation. RESULTS: A total of 5576 novel molecules with key pharmacophoric features were generated using an ML-driven de novo approach against 21 diaminopyrimidine carboxamide analogs. Pharmacokinetic and toxicity evaluation assisted by the ML approach revealed that 4353 chemical entities fulfilled the acceptable pharmacokinetic and toxicity profiles. By screening through binding energy threshold from the physics-based multitier molecular docking, and ML-assisted absolute binding affinity identified the top four molecules such as RI809 (2-([1,1'-biphenyl]-3-ylmethyl)-4-((2- aminocyclohexyl)oxy)benzamide), RI1393 (4-((2-aminocyclohexyl)amino)-2-(3-(1-methyl-1Hpyrazol- 5-yl)-4-(trifluoromethyl)benzyl)benzamide), RI2765 (2-([1,1'-biphenyl]-3-ylmethyl)-4-((4- aminocyclohexyl)methyl)benzamide), and RI3543 (2-([1,1'-biphenyl]-2-ylmethyl)-4-(piperidin-3- yloxy)benzamide). The final molecules identified exhibit a strong affinity for SYK, attributed to their structural diversity and notable pharmacophoric characteristics. All-atom MD simulations showed that each final molecule retained significant binding interactions with SYK and stability in dynamic states, indicating their potential as anticancer agents. Calculated binding free energy for selected molecules using molecular mechanics with generalized Born and surface area (MMGBSA) ranged from -6 to -35 kcal/mol, indicating strong SYK affinity. CONCLUSION: In conclusion, the integration of AI and physics-based methods successfully developed promising SYK inhibitors with significant potential. The molecules reported could be vital anticancer agents subjected to experimental validation.
Pyrimidine-Based Compounds in Tuberculosis Management: A Review of their Biological and Medicinal Importance.
Singh D, Singh V, Moin A … +3 more , Gangadhar M, Revanasiddappa BC, Dixit SR
Med Chem · 2026 · PMID 40129152 · Publisher ↗
Pyrimidine derivatives are a class of chemically and biologically active heterocyclic compounds promising for developing anti-tubercular, anti-viral, anti-malarial, anti-inflammatory, and enzyme-inhibiting drugs. To cure...
Pyrimidine derivatives are a class of chemically and biologically active heterocyclic compounds promising for developing anti-tubercular, anti-viral, anti-malarial, anti-inflammatory, and enzyme-inhibiting drugs. To cure TB, scientists were driven to establish novel pyrimidine derivatives. The main objective of the current review is to identify and develop new pyrimidine moiety- containing derivatives that have been assessed for their structure-activity relationship (SAR). Several drug-resistant MTB infections have emerged and spread worldwide, which has rendered first-line medication ineffective. It is crucial to develop new anti-TB drugs that are extremely effective against both drug-sensitive and drug-resistant TB. The development of pyrimidine therapeutic methods will thus benefit from the current review. Three medications-GSK-286, TBA-7371, and SPR-720 are now undergoing clinical testing. This study aims to emphasize the structural variety of anti-tuberculosis pyrimidine-containing compounds by providing an overview of current developments in drug discovery investigations.
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