基于药效团和分子对接的FLT3抑制剂筛选方法

目的 建立虚拟筛选与生物检测相结合的方法来筛选FLT3抑制剂。方法 建立了基于药效团和对接的虚拟筛选方法用于筛选靶向FLT3的化合物,并建立FLT3-ITD过表达的细胞模型进一步验证抑制剂的药效及作用机制。结果 通过筛选商业化合物库,成功发现了1个含有3-苯基吡唑并[1,5-a]嘧啶骨架的化合物（命名74）,可以选择性地抑制表达FLT3-ITD的BaF3细胞和AML细胞增殖。进一步研究表明,在细胞实验中,74也能克服FLT3-ITD -D835V、-D835Y、-F691L、-N676K等二次突变。机制研究表明,74通过抑制FLT3介导的通路抑制AML细胞的生长。结论 74是1个潜在的抑制FLT3-ITD的苗头分子,它的发现验证了FLT3筛选方法的准确性,并可用来寻找海洋来源的FLT3抑制剂。     

噻唑-吡唑啉衍生物作为EGFR抑制剂的3D-QSAR和分子对接模型研究

目的 建立EGFR抑制剂结构和活性之间的关系模型,基于对分子活性产生影响的重要结构性因素的信息,设计新的抑制剂分子并预测其活性,为抑制剂分子的设计提供依据。方法 使用Discovery Studio 2019软件进行3D-QSAR的研究以及偏最小二乘的计算;利用Autodock进行分子对接;使用LigPlot研究二维相互作用。结果 模型具有较高的q²(0.521),和r²(r²_training=0.993,r²_test=0.916,r²_blind=0.940),表明模型具有较高的预测能力和拟合能力。结论 预测结果表明,新设计的化合物活性较高,为EGFR抑制剂分子的设计提供了参考。     

蛋白酪氨酸磷酸酶1B抑制剂的分子对接及三维定量构效关系研究

目的对文献报道的一系列芳环取代噻唑类蛋白酪氨酸磷酸酶1B(PTP1B)抑制剂进行分子对接及三维定量构效关系(3D-QSAR)研究。方法应用Surflex-Dock进行分子对接结合模式研究,并用比较分子力场分析(CoMFA)和比较分子相似性指数分析(CoMSIA)方法进行三维定量构效关系研究,建立具有良好预测能力的3D-QSAR模型。结果对接结果表明,该类结构可以很好地占据PTP1B的3个关键结合位点,大大提高了抑制剂与酶的亲和力。所建立的CoMFA模型交叉验证系数q~2为0.644,CoMSIA模型交叉验证系数q~2为0.719。结论获得的CoMFA和CoMSIA模型具有可靠的预测能力,可应用于指导该类化合物的设计。     

Docking and 3D-QSAR studies of N-benzyl isatin oximes as JNK3 inhibitors

The c-Jun N-terminal kinase (JNK) is involved in a variety of important cellular processes and aberrant JNK activity is associated with many human diseases. The ligand-based and receptor-based alignment rules were used to build 3D-QSAR models for a series of N-benzyl isatin oximes JNK inhibitors. The best models were obtained for the receptor-based alignment with CoMSIA combining steric (S), electrostatic (E), and hydrogen bond donor (D) and hydrogen bond acceptor (A) fields (q² = 0.759, r² = 0.966, r²_pred = 0.703). Based on the contour maps of RB CoMSIA model, some key structural factors responsible for inhibitory activity were investigated. Large groups at N-substituent or R6 position are preferred to interact with hydrophobic residues Ile70, Asp150, Ala151, Asn152 and Ser193. Electron-donating or hydrogen bond donor groups on the isatin ring would form polar and hydrogen bond with the negative-charged residue Glu147. In addition, electron-withdrawing groups or hydrogen bond acceptor group near the N-substituent would enhance inhibitory activity. The results are in good accordance and complementary to each other. The developed models could provide guidance in the rational design of more potent and selective JNK inhibitors.     

Discovery of HIV‐1 Integrase Inhibitors: Pharmacophore Mapping,Virtual Screening,Molecular Docking,Synthesis, and Biological Evaluation

HIV‐1 integrase enzyme plays an important role in the life cycle of HIV and responsible for integration of virus into human genome. Here, both computational and synthetic approaches were used to design and synthesize newer HIV‐1 integrase inhibitors. Pharmacophore mapping was performed on 20 chemically diverse molecules using DISCOtech, and refinement was carried out using GASP. Ten pharmacophore models were generated, and model 2, containing four features including two donor sites, one acceptor atom, and one hydrophobic region, was considered the best model as it has the highest fitness score. It was used as a query in NCI and Maybridge databases. Molecules having more than 99% Q_fit value were used to design 30 molecules bearing pteridine ring and were docked on co‐crystal structure of HIV‐1 integrase enzyme. Among these, six molecules, showing good docking score compared with the reference standards, were synthesized by conventional as well as microwave‐assisted methods. All compounds were characterized by physical and spectral data and evaluated for in vitro anti‐HIV activity against the replication of HIV‐1 (IIIB) in MT‐4 cells. The used approach of molecular docking and anti‐HIV activity data of designed molecules will provide significant insights to discover novel HIV‐1 Integrase Inhibitors.     

Molecular Docking and 3D QSAR Studies of Chk2 Inhibitors

Isothiazole‐carboxamidines are potent ATP competitive checkpoint kinases (Chk2) inhibitors. Three‐dimensional quantitative structure–activity relationship models were developed using comparative molecular field analysis and comparative molecular similarity indices analysis. The study was performed using three different geometrical methods. In geometrical method‐1, molecules were fully optimized by PM3 Hamiltonian and aligned using common substructure. This alignment was subsequently used for Ligand‐based comparative molecular field analysis and comparative molecular similarity indices analysis. In receptor‐guided analyses, the receptor coordinates were obtained from public domine (PDB 2cn8). The molecule‐7 was docked into receptor protein using FlexX and two plausible binding modes were identified. These modes were used as templates for geometrical method‐2 and 3. These methods were used for 3D QSAR. The geometrical method‐3‐based comparative molecular field analysis (q ² = 0.75, r ² = 0.87 and r ²_predict = 0.81) and comparative molecular similarity indices analysis (q ² = 0.90, r ² = 0.96 and r ²_predict = 0.75) gave better result. The steric, hydrophobic and hydrogen bond donor fields effects significantly contribute to activity. In this way, the receptor‐guided study presents a more detailed understanding about chk2 active site interactions. The study indicated some modifications to the active molecule which might be valuable to improve the activity.     

Combined 3D‐QSAR Modeling and Molecular Docking Study on Quinoline Derivatives as Inhibitors of P‐selectin

P‐selectin is a promising target for developing novel atherosclerosis drugs. To understand the structure–activity correlation of quinolines‐based P‐selectin inhibitors, we have carried out a combined molecular docking and three‐dimensional quantitative structure–activity relationship (3D‐QSAR) modeling study. The study has resulted in two types of satisfactory 3D‐QSAR models, including the CoMFA model (r², 0.863; q², 0.589) and CoMSIA model (r², 0.866; q², 0.636), to predict the biological activity of new compounds. The detailed microscopic structures of P‐selectin binding with inhibitors have been studied by molecular docking. We have also developed docking based 3D‐QSAR models (CoMFA with r², 0.934; q², 0.591; CoMSIA with r², 0.896; q², 0.573). The contour maps obtained from the 3D‐QSAR models in combination with the docked binding structures help to better interpret the structure–activity relationship. All of the structural insights obtained from both the 3D‐QSAR contour maps and molecular docking are consistent with the available experimental activity data. The satisfactory results strongly suggest that the developed 3D‐QSAR models and the obtained P‐selectin‐inhibitor binding structures are reasonable for the prediction of the activity of new inhibitors and in future drug design.     

Synthesis,In vitro and Docking Studies of New Flavone Ethers as α‐Glucosidase Inhibitors

We report herein the synthesis, α‐glucosidase inhibition and docking studies for a series of 3–15 new flavones. A simple nucleophilic substitution reaction takes place between 3′hydroxyflavone ( 2 ) with halides to afford the new flavones. Chalcone ( 1 ), 3′hydroxyflavone ( 2 ) and the newly synthesized flavones ( 3–15 ) were being evaluated for their ability to inhibit activity of α ‐glucosidase. Compounds 2 , 3 , 5 , 7 – 10 and 13 showed good inhibitory activity with IC₅₀ values ranging between 1.26 and 36.44 μ m as compared to acarbose (IC₅₀ = 38.25 ± 0.12 μ m ). Compounds 5 (5.45 ± 0.08 μ m ), 7 (1.26 ± 0.01 μ m ) and 8 (8.66 ± 0.08 μ m ) showed excellent inhibitory activity, and this may be due to trifluoromethyl substitution that is common for these compounds. Compound 7 , a 2,5‐trifluoromethyl‐substituted compound, recorded the highest inhibition activity, and it is thirty times better than the standard drug. Docking studies for compound 7 suggest that both trifluoromethyl substituents are well positioned in a binding pocket surrounded by Phe300, Phe177, Phe157, Ala278, Asp68, Tyr71 and Asp214. The ability of compound 7 to interact with Tyr71 and Phe177 is extremely significant as they are found to be important for substrates recognition by α ‐glucosidase.     

3D-QSAR and molecular docking for the discovery of ketolide derivatives

Introduction: There is an urgent need to discover novel antibiotics to overcome the growing problem of antibiotic resistance, which has become a serious concern in current medicine. Ketolides, the third generation of macrolide antibiotics, have shown promising effect against macrolide-resistant pathogens in respiratory diseases. Currently, a number of ketolide derivatives with excellent antibacterial activities have been reported, while their structure–activity relationships (SARs) were rarely explored systematically. Computer-aided drug design (CADD) such as 3D-QSAR and molecular docking are useful tools to study drug SARs in medicinal chemistry. Using these technologies, ketolide derivatives were systemically analyzed revealing important useful information about their SARs, providing useful information which can guide new drug design and optimization.

Areas covered: The authors provide an overview of the currently reported 3D-QSAR models of ketolide derivatives. The authors present a comprehensive SAR model obtained from in-depth 3D-QSAR and molecular docking analysis for all kinds of ketolide derivatives.

Expert opinion: 3D-QSAR has been shown to be a reliable tool that had successfully assisted the design of several new antibiotics with improved activity and reduced toxicity. By applying 3D-QSAR and molecular docking, a comprehensive and systematic SAR model for ketolide derivative discovery was formed, which is important to guide future drug design for the discovery of better ketolides with lower toxicity.     

Synthesis,in vitro Biological Evaluation and Molecular Docking Studies of Benzimidamides as Potential BACE1 Inhibitors

A series of 3, 5‐disubstituted benzimidamides were synthesized and biologically evaluated as potential BACE1 inhibitors. Both the targeted compounds (benzimidamides) and the synthetic intermediates (benzonitriles) were tested for their BACE1 inhibitory activities in a cell‐free FRET assay. All the synthesized benzimidamides were active as BACE1 inhibitors and compound 6d showed the lowest IC₅₀ value of 3.35 μm . Molecular docking study proposed a binding mode, which would help to the further optimization on 6d to achieve more potent, BBB penetrant BACE1 inhibitors.     

Docking and 3D-QSAR investigations of pyrrolidine derivatives as potent neuraminidase inhibitors

Docking studies of pyrrolidine derivatives indicated that Trp178, Arg371, and Tyr406 were the key residues in the active pocket of influenza neuraminidase (NA). Hydrogen bond and electrostatic factors mainly influenced interactions between pyrrolidine derivatives and NA. Moreover, there was a significant correlation between binding affinity (total scores) and the experimental pIC(50) . Meanwhile, 3D-QSAR models of 87 pyrrolidine derivatives were developed to understand chemical-biological interactions governing their activities toward NA. Furthermore, R(2) , Q(2) , , and of the models were from 0.731 to 0.830, from 0.560 to 0.611, from 0.762 to 0.875, and from 0.649 to 0.856, respectively. QSAR modeling results elucidated that hydrogen bonds and electrostatic factors highly contributed to inhibitory activity, which was unanimous in the docking results.     

Design,Synthesis, Biological Evaluation,and Molecular Docking of Novel Benzopyran and Phenylpyrazole Derivatives as Akt Inhibitors

By inspiration of good Akt1 inhibitory and cytotoxic activity of our previously screened hits 1 and 2 , a series of novel benzopyrans 3a – c , 4 and phenylpyrazoles 5a – c , 6a – b , and 7 were designed, synthesized, and biologically evaluated for their in vitro Akt1 inhibitory and cytotoxic activity. The results revealed that all of these compounds showed moderate‐to‐excellent antiproliferative effects against the tested cancer cell lines (i.e. HL‐60, OVCAR, PC‐3, and HepG2). Among them, compounds 3a and 3c exhibited preferable Akt1 inhibitory activities (IC₅₀ of 3a and 3c are 6.18 and 5.28 μm , respectively), while compounds 4 , 5a – c , 6a – b , and 7 only showed weak Akt1 inhibitory activities. Consequently, we used molecular docking and dynamic simulation to propose a mode of binding between Akt1 and the 3c compound.     

Synthesis,Evaluation and Molecular Docking of Prolyl‐Fluoropyrrolidine Derivatives as Dipeptidyl Peptidase IV Inhibitors

A series of prolyl‐fluoropyrrolidine derivatives were designed, synthesized and screened for in vitro inhibition of dipeptidyl peptidase IV. The SAR study revealed the influence of substituted chemical modifications on dipeptidyl peptidase IV inhibitory activity. Among all the compounds screened, compound 9 (IC₅₀ = 0.83 μm ) and 10 (IC₅₀ = 0.43 μm ) possessing aryl substituted piperazine with acetamide linker resulted as most potent dipeptidyl peptidase IV inhibitors. Both the compounds 9 and 10 resulted significant reduction in glucose excursion during oral glucose tolerance test in streptozotocin‐induced diabetic rat model at single dose of 10 mg/kg. Molecular docking studies were performed to illustrate the probable binding mode and interactions of prolyl‐fluoropyrrolidine nucleus and its derivatives at binding site of receptor. The fluoropyrrolidine moiety of prolyl‐fluoropyrrolidine derivatives occupied S1 pocket as observed in the crystal structure (PDB id: 2FJP). The compounds 9 and 10 were observed to occupy S2 binding pocket and were observed to have interaction with Arg125, Tyr547 and Ser630 acquired through hydrogen bond. The aryl moiety at piperazine ring was found to extend into the cavity and interacted with Arg358. The observed interactions signalled that occupancy of the highly hydrophobic S2 pocket is very crucial for dipeptidyl peptidase IV inhibitory activity.     

2-苯氧茚酮类乙酰胆碱酯酶抑制剂的3D-QSAR研究

目的研究2-苯氧茚酮类乙酰胆碱酯酶抑制剂的三维定量构效关系。方法采用比较分子力场分析法(CoMFA)和比较分子相似性指数分析法(CoMSIA)对结构与活性的关系进行研究。结果CoMFA模型表明立体场和静电场对活性的贡献分别为0.805和0.195;CoMSIA模型阐明疏水场和氢键场对活性也有一定的影响。结论两种3D-QSAR模型都显示出相当高的预测能力,CoMFA和CoMSIA的交叉验证值q2分别为0.881和0.918,通过对两种3D-QSAR模型等势图的分析,可为开展进一步的药物设计和结构优化提供理论指导和依据。     

Molecular modeling,quantum polarized ligand docking and structure-based 3D-QSAR analysis of the imidazole series as dual AT~ and ETA receptor antagonists

Aim： Both endothelin ETA receptor antagonists and angiotensin AT1 receptor antagonists lower blood pressure in hypertensive patients. A dual AT1 and ETA receptor antagonist may be more efficacious antihypertensive drug. In this study we identified the mode and mechanism of binding of imidazole series of compounds as dual AT1 and ETA receptor antagonists. Methods： Molecular modeling approach combining quantum-polarized ligand docking （QPLD）, MM/GBSA free-energy calculation and 3D-QSAR analysis was used to evaluate 24 compounds as dual AT1 and ETA receptor antagonists and to reveal their binding modes and structural basis of the inhibitory activity. Pharmacophore-based virtual screening and docking studies were performed to identify more potent dual antagonists. Results： 3D-QSAR models of the imidazole compounds were developed from the conformer generated by QPLD, and the resulting models showed a good correlation between the predicted and experimental activity. The visualization of the 3D-QSAR model in the context of the compounds under study revealed the details of the structure-activity relationship： substitution of methoxymethyl and cyclooctanone might increase the activity against AT~ receptor, while substitution of cyclohexone and trimethylpyrrolidinone was important for the activity against ETA receptor; addition of a trimethylpyrrolidinone to compound 9 significantly reduced its activity against AT~ receptor but significantly increased its activity against ETA receptor, which was likely due to the larger size and higher intensities of the H-bond donor and acceptor regions in the active site of ETA receptor. Pharmacophore-based virtual screening followed by subsequent Glide SP, XP, QPLD and MM/GBSA calculation identified 5 potential lead compounds that might act as dual AT1 and ETA receptor antagonists. Conclusion： This study may provide some insights into the development of novel potent dual ETA and AT1 receptor antagonists. As a result, five compounds are found to be the best dual antagonists against AT1R and ETA receptors.     

Pharmacophore modeling, 3D-QSAR,synthesis, and anti-lung cancer evaluation of novel thieno[2,3-d][1,2,3]triazines targeting EGFR

Two series of thieno[2,3-d][1,2,3]triazine derivatives were designed, synthesized, and biologically evaluated as potential epidermal growth factor receptor (EGFR) inhibitors targeting the non-small-cell lung cancer cell line H1299. Most of the synthesized compounds displayed IC₅₀ values ranging from 25 to 58 nM against H1299, which are superior to that of gefitinib (40 µM). 3-(5,6,7,8-Tetrahydro-7H-cyclohexa[4:5]thieno[2,3-d]-1,2,3-triazin-4-ylamino)benzene-1,3-diamine ( 6b ) achieved the highest cytotoxic activity against H1299 with an IC₅₀ value of 25 nM; it had the ability to decrease the EGFR concentration in H1299 cells from 7.22 to 2.67 pg/ml. In vitro, the IC₅₀ value of compound 6b was 0.33 nM against EGFR, which is superior to that of gefitinib at 1.9 nM and erlotinib at 4 nM. The three-dimensional quantitative structure–activity relationships and molecular modeling studies revealed comparable binding modes of compound 6b , gefitinib, and erlotinib in the EGFR active site. The in silico ADME (absorption, distribution, metabolism, and excretion) prediction parameters of this compound revealed promising pharmacokinetic and physicochemical properties. Moreover, DFT (density functional theory) calculations showed the high reactivity of compound 6b toward the EGFR compared with other compounds. The designed compound 6b might serve as an encouraging lead compound for the discovery of promising anti-lung cancer agents targeting EGFR.     

Validation of Formylchromane Derivatives as Protein Tyrosine Phosphatase 1B Inhibitors by Pharmacophore Modeling,Atom‐Based 3D‐QSAR and Docking Studies

Formylchromane derivatives were reported to possess irreversible and selective inhibition on human protein tyrosine phosphatase 1B (PTP 1B). Inhibition of PTP 1B is a molecular level legitimate approach for the management of type 2 diabetes mellitus (T2DM). 3D‐QSAR studies were performed on a series of formylchromane derivatives using partial least square (PLS) analysis for correlating molecular architecture of the analogs with their PTP 1B inhibitory activity. A five‐point pharmacophore hypothesis with three hydrogen bond acceptors (A) and two aromatic rings (R) as pharmacophoric features was developed using phase module of Schrödinger suite. The hypothesis AAARR.160 was considered as best hypothesis in this study characterized by survival score (3.483), the best cross‐validated r² (Q²) (0.774), regression coefficient (0.960), Pearson‐R (0.891), and F value (100.3). The results of hypothesis AAARR.160 complimented very closely to interactions witnessed in active site of the ligand‐bound complex. The molecular docking simulations into PTP 1B active site also highlighted that biphenyl moiety favorably interacted with amino acid residues lining the lipophilic pocket, and provided hydrophobic interactions with receptor active site. These observations might be useful for further development and optimization of new chemical entities as potential PTP 1B inhibitors prior to its synthesis.     

Homology Modeling,Docking Studies and Molecular Dynamic Simulations Using Graphical Processing Unit Architecture to Probe the Type‐11 Phosphodiesterase Catalytic Site: A Computational Approach for the Rational Design of Selective Inhibitors

Phosphodiesterase 11 (PDE11) is the latest isoform of the PDEs family to be identified, acting on both cyclic adenosine monophosphate and cyclic guanosine monophosphate. The initial reports of PDE11 found evidence for PDE11 expression in skeletal muscle, prostate, testis, and salivary glands; however, the tissue distribution of PDE11 still remains a topic of active study and some controversy. Given the sequence similarity between PDE11 and PDE5, several PDE5 inhibitors have been shown to cross‐react with PDE11. Accordingly, many non‐selective inhibitors, such as IBMX, zaprinast, sildenafil, and dipyridamole, have been documented to inhibit PDE11. Only recently, a series of dihydrothieno[3,2‐d]pyrimidin‐4(3H)‐one derivatives proved to be selective toward the PDE11 isoform. In the absence of experimental data about PDE11 X‐ray structures, we found interesting to gain a better understanding of the enzyme–inhibitor interactions using in silico simulations. In this work, we describe a computational approach based on homology modeling, docking, and molecular dynamics simulation to derive a predictive 3D model of PDE11. Using a Graphical Processing Unit architecture, it is possible to perform long simulations, find stable interactions involved in the complex, and finally to suggest guideline for the identification and synthesis of potent and selective inhibitors.     

Molecular Docking and QSAR Studies on Substituted Acyl(thio)urea and Thiadiazolo [2,3-α] Pyrimidine Derivatives as Potent Inhibitors of Influenza Virus Neuraminidase

Surflex–Dock was employed to dock 36 thiourea and thiadiazolo [2,3-α] pyrimidine derivatives into neuraminidase 1a4g. Molecular docking results showed that hydrogen bonding, electrostatic, and hydrophobic features were important factors affecting inhibitory activities of these neuraminidase inhibitors. Moreover, there was a significant correlation between the predicted binding affinity (total scores) and experimental pIC₅₀ values with correlation coefficient r = 0.846 and p < 0.0001. Hologram quantitative structure–activity relationship, comparative molecular field analysis, and comparative molecular similarity indices analysis were used to develop quantitative structure–activity relationship models. Squared multiple correlation coefficients (r ²) of hologram quantitative structure–activity relationship, comparative molecular field analysis, and comparative molecular similarity indices analysis models were 0.899, 0.878, and 0.865, respectively. Squared cross-validated correlation coefficient (q ²) of hologram quantitative structure–activity relationship, comparative molecular field analysis, and comparative molecular similarity indices analysis models was in turn 0.628, 0.656, and 0.509. In addition, squared multiple correlation coefficients for test set (r ²_test) of hologram quantitative structure–activity relationship, comparative molecular field analysis, and comparative molecular similarity indices analysis models were 0.558, 0.667, and 0.566, respectively. The most active sample ID 2 was taken as a template molecule to design new molecules. Based on the comparative molecular field analysis model, new compounds were designed by LeapFrog. Seven new compounds with improved binding energy and predicted activities were finally obtained.     

Molecular modeling,quantum polarized ligand docking and structure-based 3D-QSAR analysis of the imidazole series as dual AT1 and ETA receptor antagonists

Aim:

Both endothelin ET_A receptor antagonists and angiotensin AT₁ receptor antagonists lower blood pressure in hypertensive patients. A dual AT₁ and ET_A receptor antagonist may be more efficacious antihypertensive drug. In this study we identified the mode and mechanism of binding of imidazole series of compounds as dual AT₁ and ET_A receptor antagonists.

Methods:

Molecular modeling approach combining quantum-polarized ligand docking (QPLD), MM/GBSA free-energy calculation and 3D-QSAR analysis was used to evaluate 24 compounds as dual AT₁ and ET_A receptor antagonists and to reveal their binding modes and structural basis of the inhibitory activity. Pharmacophore-based virtual screening and docking studies were performed to identify more potent dual antagonists.

Results:

3D-QSAR models of the imidazole compounds were developed from the conformer generated by QPLD, and the resulting models showed a good correlation between the predicted and experimental activity. The visualization of the 3D-QSAR model in the context of the compounds under study revealed the details of the structure-activity relationship: substitution of methoxymethyl and cyclooctanone might increase the activity against AT₁ receptor, while substitution of cyclohexone and trimethylpyrrolidinone was important for the activity against ET_A receptor; addition of a trimethylpyrrolidinone to compound 9 significantly reduced its activity against AT₁ receptor but significantly increased its activity against ET_A receptor, which was likely due to the larger size and higher intensities of the H-bond donor and acceptor regions in the active site of ET_A receptor. Pharmacophore-based virtual screening followed by subsequent Glide SP, XP, QPLD and MM/GBSA calculation identified 5 potential lead compounds that might act as dual AT₁ and ET_A receptor antagonists.

Conclusion:

This study may provide some insights into the development of novel potent dual ET_A and AT₁ receptor antagonists. As a result, five compounds are found to be the best dual antagonists against AT₁R and ET_A receptors.