3D-QSAR, ADMET, and molecular docking studies of aztreonam analogs as E. colis inhibitors.

Background: The development of multidrug resistant strains of extended-spectrum ß-lactamase-producing Escherichia coli has become a global problem; therefore, the discovery of new antibacterial agents is the only available solution. Objective: To improve and propose new compounds with antibacterial activity, the three-dimensional quantitative structure-activity relationship and molecular docking studies were carried out on Aztreonam analogs as E. coli inhibitors in DNA gyrase B. Method: This study's 3D-Quantitative structure-activity relationship model was created using on the Comparative Molecular Field Analysis and the Comparative Molecular Similarity Indices Analysis. Using the Comparative Molecular Field Analysis (Q 2 = 0.73; R 2 = 0.82), excellent predictability was achieved, and the best Comparative Molecular Similarity Indices Analysis model (Q 2 = 0.88; R 2 = 0.9). The generated model's ability to predict outcomes was assessed through external validation using a test set compound and an applicability domain technique. In this study, the steric, electrostatic, and hydrogen bond acceptor fields played a key role in antibacterial activity. Results: The results of the molecular docking revealed that the newly generated compound A6 has the highest binding affinity with DNA gyrase B. It forms 10 hydrogen bonds with amino acid residues of Asn104, Asn274, Asn132, Ser70, Ser237, Thr105, Glu273, and 2 salt bridges with amino acid residues of Ser70 and Glu273 and one pi-pi interacting with Gys271 amino acid residue in the binding site of 5G1, and this result was validated by a new assessment method. We created some novel, highly effective DNA gyrase B inhibitors based on the earlier findings, and the most accurate model predicted their inhibitory actions. The ADMET characteristics and pharmacological similarity of these novel inhibitors were also examined. Conclusion: These findings would be very beneficial in guiding the optimization process for the identification of novel drugs that can address the issue of multiple drug resistance.

Pinpointing prime structural attributes of potential MMP-2 inhibitors comprising alkyl/arylsulfonyl pyrrolidine scaffold: a ligand-based molecular modelling approach validated by molecular dynamics simulation analysis.

MMP-2 overexpression is strongly related to several diseases including cancer. However, none of the MMP-2 inhibitors have been marketed as drug candidates due to various adverse effects. Here, a set of sulphonyl pyrrolidines was subjected to validation of molecular modelling followed by binding mode analysis to explore the crucial structural features required for the discovery of promising MMP-2 inhibitors. This study revealed the importance of hydroxamate as a potential zinc-binding group compared to the esters. Importantly, hydrophobic and sterical substituents were found favourable at the terminal aryl moiety attached to the sulphonyl group. The binding interaction study revealed that the S1' pocket of MMP-2 similar to 'a basketball passing through a hoop' allows the aryl moiety for proper fitting and interaction at the active site to execute potential MMP-2 inhibition. Again, the sulphonyl pyrrolidine moiety can be a good fragment necessary for MMP-2 inhibition. Moreover, some novel MMP-2 inhibitors were also reported. They showed the significance of the 3rd position substitution of the pyrrolidine ring to produce interaction inside S2' pocket. The current study can assist in the design and development of potential MMP-2 inhibitors as effective drug candidates for the management of several diseases including cancers in the future.

3D-QSAR, Scaffold Hopping, Virtual Screening, and Molecular Dynamics Simulations of Pyridin-2-one as mIDH1 Inhibitors.

Isocitrate dehydrogenase 1 (IDH1) is a necessary enzyme for cellular respiration in the tricarboxylic acid cycle. Mutant isocitrate dehydrogenase 1 (mIDH1) has been detected overexpressed in a variety of cancers. mIDH1 inhibitor ivosidenib (AG-120) was only approved by the Food and Drug Administration (FDA) for marketing, nevertheless, a range of resistance has been frequently reported. In this study, several mIDH1 inhibitors with the common backbone pyridin-2-one were explored using the three-dimensional structure-activity relationship (3D-QSAR), scaffold hopping, absorption, distribution, metabolism, excretion (ADME) prediction, and molecular dynamics (MD) simulations. Comparative molecular field analysis (CoMFA, R2 = 0.980, Q2 = 0.765) and comparative molecular similarity index analysis (CoMSIA, R2 = 0.997, Q2 = 0.770) were used to build 3D-QSAR models, which yielded notably decent predictive ability. A series of novel structures was designed through scaffold hopping. The predicted pIC50 values of C3, C6, and C9 were higher in the model of 3D-QSAR. Additionally, MD simulations culminated in the identification of potent mIDH1 inhibitors, exhibiting strong binding interactions, while the analyzed parameters were free energy landscape (FEL), radius of gyration (Rg), solvent accessible surface area (SASA), and polar surface area (PSA). Binding free energy demonstrated that C2 exhibited the highest binding free energy with IDH1, which was -93.25 ± 5.20 kcal/mol. This research offers theoretical guidance for the rational design of novel mIDH1 inhibitors.

Novel dihydropyrimidines as promising EGFR & HER2 inhibitors: Insights from experimental and computational studies.

Dihydropyrimidines are widely recognized for their diverse biological properties and are often synthesized by the Biginelli reactions. In this backdrop, a novel series of Biginelli dihydropyrimidines were designed, synthesized, purified, and analyzed by FT-IR, 1H NMR, 13C NMR, and mass spectrometry. Anticancer activity against MCF-7 breast cancer cells was evaluated as part of their cytotoxicity in comparison with the normal Vero cells. The cytotoxicity of dihydropyrimidines ranges from moderate to significant. Among the 38 dihydropyrimidines screened, compounds 16, 21, and 39 exhibited significant cytotoxicity. These 3 compounds were subjected to flow cytometry studies and EGFRwt Kinase inhibition assay using lapatinib as a standard. The study included evaluation for the inhibition of EGFR and HER2 expression at five different concentrations. At a concentration of 1000 nM compound 21 showed 98.51 % and 96.79 % inhibition of EGFR and HER2 expression. Moreover, compounds 16, 21 and 39 significantly inhibited EGFRwt activity with IC50 = 69.83, 37.21 and 76.79 nM, respectively. In addition, 3D-QSAR experiments were conducted to elucidate Structure activity relationships in a 3D grid space by comparing the experimental and predicted cytotoxic activities. Molecular docking studies were performed to validate the results by in silico method. All together, we developed a new series of Biginelli dihydropyrimidines as dual EGFR/HER2 inhibitors.

Hybrid 2D/3D-quantitative structure-activity relationship studies on the bioactivities and molecular mechanism of antibacterial peptides.

Antimicrobial peptide (AMP) is the polypeptide, which protects the organism avoiding attack from pathogenic bacteria. Studies have shown that there were some antimicrobial peptides with molecular action mechanism involved in crossing the cell membrane without inducing severe membrane collapse, then interacting with cytoplasmic target-nucleic acid, and exerting antibacterial activity by interfacing the transmission of genetic information of pathogenic microorganisms. However, the relationship between the antibacterial activities and peptide structures was still unclear. Therefore, in the present work, a series of AMPs with a sequence of 20 amino acids was extracted from DBAASP database, then, quantitative structure-activity relationship (QSAR) methods were conducted on these peptides. In addition, novel antimicrobial peptides with  stronger antimicrobial activities were designed according to the information originated from the constructed models. Hence, the outcome of this study would lay a solid foundation for the in-silico design and exploration of novel antibacterial peptides with improved activity activities.

3D-QSAR Studies on High-affinity Phosphodiestera.

BACKGROUND: Recent studies have found that Phosphodiesterase-4 (PDE4) is closely related to the pathogenesis of depression, cognitive impairment and neurological impairment. OBJECTIVE: Our objective is to develop potent inhibitors of the high-affinity phosphodiesterase 4D isoform (PDE4D) that can serve as radioligands for Positron Emission Tomography (PET) imaging, thereby advancing research in the field of neurological diseases. METHODS: We employed a multi-step approach combining three-dimensional quantitative structure-activity relationship (3D-QSAR) modeling, molecular docking, classification techniques, and CoMSIA analysis to investigate the conformational relationship of highaffinity PDE4D inhibitors as PET ligands. ADMET and Drug-likeness predictions were also conducted. By utilizing these methods, our aim was to identify more potent PDE4D inhibitors. RESULTS: The results showed that the CoMSIA model with the best principal component scores (n=7) had a cross-validated Q2 value of 0.602 and a non-cross-validated R2 value of 0.976. These results affirmed the excellent predictive capability of the established CoMSIA model. Analysis of the generated 3D-QSAR contour plots highlighted specific regions in the molecular structure of the compounds that can be further optimized and modified. Guided by the contour plots, we designed 100 novel PDE4D inhibitors, and molecular docking was performed for the top 4 compounds with high activity. The molecular docking scores were promising, and ADMET and drug similarity predictions yielded satisfactory results. Taking into consideration these factors, compound 51c was determined to be the optimal compound, laying a solid foundation for further research. CONCLUSION: For the continued development of PDE4D PET radioligand, these models and new compounds' developing methodology offer a theoretical foundation and crucial references.

Effects of 1,4-dihydropyridine derivatives on cell injury and mTOR of HepG2 and 3D-QSAR study.

1,4-dihydropyridine derivatives (1,4-DHPs) are a class of drugs used to treat cardiovascular diseases, but these drugs can cause liver injury. To reveal the toxicity characteristics of these compounds, we used a series of assays, including cell viability, enzyme activity detection, and western blotting, to investigate the toxicity of seven kinds of 1,4-DHPs (0-100 µM) on HepG2 cells and establish 3D-QSAR model based on relevant toxicity data. After HepG2 cells were treated with 1,4-DHPs for 24 h, high-dose (100 µM) 1,4-DHPs decreased cell viability to varying degrees, while ROS and MDA contents were significantly increased, and ATP content was reduced. Moreover, with the concentration of 100 µM 1,4-DHPs (Nimodipine, Nitrendipine, Cilnidipine, and Manidipine) were markedly inhibited the phosphorylation levels of mTOR protein. The results of the 3D-QSAR model showed that the non-cross validation coefficient (R2) and cross validation coefficient (Q2) of the model were 0.982 and 0.652, respectively. Combined with external validation and the Williams diagram, the model showed good predictability and application domain. Based on the CoMSIA 3D contour map, the introduction of large volume and hydrogen bond receptor groups on the carbonyl oxygen side chains of the 1,4-DHPs ring 3- and 5- was beneficial for reducing the toxicity of 1,4-DHPs. The results of this study could supplement information on the cytotoxicity of 1,4-DHPs, and could provide theoretical support for predicting the toxicity of 1,4-DHPs.

Integrated computational approaches for designing potent pyrimidine-based CDK9 inhibitors: 3D-QSAR, docking, and molecular dynamics simulations.

CDK9 is an emerging target for the development of anticancer drugs. The development of CDK9 inhibitors with significant potency had consistently posed a formidable challenge. In the current research, a number of computational methodologies, such as, 3D-QSAR, molecular docking, fingerprint analysis, molecular dynamic (MD) simulations followed by MMGB/PBSA and ADMET studies were used systemically to uncover the binding mechanism of pyrimidine derivatives against CDK9. The CoMFA and CoMSIA models having high q2 (0.53, 0.54) and r2 values (0.96, 0.93) respectively indicating that model could accurately predict the bioactivities of CDK9 inhibitors. Using the R-group exploration technique implemented by the Spark™ by Cresset group, the structural requirements revealed by the contour maps of model were utilized strategically to create an in-house library of 100 new CDK9 inhibitors. Additionally, the compounds from the in-house library were mapped into 3D-QSAR model which predicted pIC50 values comparable to the experimental values. A comparison between 3D-QSAR generated contours and molecular docking conformation of ligands was performed to elucidate the essentials of CDK9 inhibitor design. MD simulations (100 ns) were performed on the selected docked complexes A21, A14 and D98 which contributed in validating the binding interactions. According to the findings of binding free energy analysis (MMGB/PBSA), It was observed that residues CYS106 and GLU107 had a considerable tendency to facilitate ligand-protein interactions via H-bond interactions. The aforementioned findings have the potential to enhance researchers comprehension of the mechanism underlying CDK9 inhibition and may be utilized in the development of innovative and efficacious CDK9 inhibitors.

QSAR Studies, Synthesis, and Biological Evaluation of New Pyrimido-Isoquinolin-Quinone Derivatives against Methicillin-Resistant Staphylococcus aureus.

According to the WHO, antimicrobial resistance is among the top 10 threats to global health. Due to increased resistance rates, an increase in the mortality and morbidity of patients has been observed, with projections of more than 10 million deaths associated with infections caused by antibacterial resistant microorganisms. Our research group has developed a new family of pyrimido-isoquinolin-quinones showing antibacterial activities against multidrug-resistant Staphylococcus aureus. We have developed 3D-QSAR CoMFA and CoMSIA studies (r2 = 0.938; 0.895), from which 13 new derivatives were designed and synthesized. The compounds were tested in antibacterial assays against methicillin-resistant Staphylococcus aureus and other bacterial pathogens. There were 12 synthesized compounds active against Gram-positive pathogens in concentrations ranging from 2 to 32 µg/mL. The antibacterial activity of the derivatives is explained by the steric, electronic, and hydrogen-bond acceptor properties of the compounds.

Assessing structural insights into in-house arylsulfonyl L-(+) glutamine MMP-2 inhibitors as promising anticancer agents through structure-based computational modelling approaches.

MMP-2 is potentially contributing to several cancer progressions including leukaemias. Therefore, considering MMP-2 as a promising target, novel anticancer compounds may be designed. Here, 32 in-house arylsulfonyl L-(+) glutamines were subjected to various structure-based computational modelling approaches to recognize crucial structural attributes along with the spatial orientation for higher MMP-2 inhibition. Again, the docking-based 2D-QSAR study revealed that the Coulomb energy conferred by Tyr142 and total interaction energy conferred by Ala84 was crucial for MMP-2 inhibition. Importantly, the docking-dependent CoMFA and CoMSIA study revealed the importance of favourable steric, electrostatic, and hydrophobic substituents at the terminal phenyl ring. The MD simulation study revealed a lower fluctuation in the RMSD, RMSF, and Rg values indicating stable binding interactions of MMP-2 and these molecules. Moreover, the residual hydrogen bond and their interaction analysis disclosed crucial amino acid residues responsible for forming potential hydrogen bonding for higher MMP-2 inhibition. The results can effectively aid in the design and discovery of promising small-molecule drug-like MMP-2 inhibitors with greater anticancer potential in the future.

In silico research on new sulfonamide derivatives as BRD4 inhibitors targeting acute myeloid leukemia using various computational techniques including 3D-QSAR, HQSAR, molecular docking, ADME/Tox, and molecular dynamics.

Acute myeloid leukemia, a serious condition affecting stem cells, drives uncontrollable myeloblast proliferation, leading to accumulation. Extensive research seeks rapid, effective chemotherapeutics. A potential option is a BRD4 inhibitor, known for suppressing cell proliferation. Sulfonamide derivatives probed essential structural elements for potent BRD4 inhibitors. To achieve this goal, we employed 3D-QSAR molecular modeling techniques, including CoMFA, CoMSIA, and HQSAR models, along with molecular docking and molecular dynamics simulations. The validation of the 2D/3D QSAR models, both internally and externally, underscores their robustness and reliability. The contour plots derived from CoMFA, CoMSIA, and HQSAR analyses played a pivotal role in shaping the design of effective BRD4 inhibitors. Importantly, our findings highlight the advantageous impact of incorporating bulkier substituents on the pyridinone ring and hydrophobic/electrostatic substituents on the methoxy-substituted phenyl ring, enhancing interactions with the BRD4 target. The interaction mode of the new compounds with the BRD4 receptor (PDB ID: 4BJX) was investigated using molecular docking simulations, revealing favorable binding energies, supported by the formation of hydrogen and hydrophobic bonds with key protein residues. Moreover, these novel inhibitors exhibited good oral bioavailability and demonstrated non-toxic properties based on ADMET analysis. Furthermore, the newly designed compounds along with the most active one from series 58, underwent a molecular dynamics simulation to analyze their behavior. The simulation provided additional evidence to support the molecular docking results, confirming the sustained stability of the analyzed molecules over the trajectory. This outcome could serve as a valuable reference for designing and developing novel and effective BRD4 inhibitors.Communicated by Ramaswamy H. Sarma.

3D-QSAR-based design, synthesis and biological evaluation of 2,4-disubstituted quinoline derivatives as antimalarial agents.

2,4-Disubstituted quinoline derivatives were designed based on a 3D-QSAR study, synthesized and evaluated for antimalarial activity. A large dataset of 178 quinoline derivatives was used to perform a 3D-QSAR study using CoMFA and CoMSIA models. PLS analysis provided statistically validated results for CoMFA (r2ncv = 0.969, q2 = 0.677, r2cv = 0.682) and CoMSIA (r2ncv = 0.962, q2 = 0.741, r2cv = 0.683) models. Two series of a total of 40 2,4-disubstituted quinoline derivatives were designed with amide (quinoline-4-carboxamide) and secondary amine (4-aminoquinoline) linkers at the -C4 position of the quinoline ring. For the purpose of selecting better compounds for synthesis with good pEC50 values, activity prediction was carried out using CoMFA and CoMSIA models. Finally, a total of 10 2,4-disubstituted quinoline derivatives were synthesized, and screened for their antimalarial activity based on the reduction of parasitaemia. Compound #5 with amide linker and compound #19 with secondary amine linkers at the -C4 position of the quinoline ring showed maximum reductions of 64% and 57%, respectively, in the level of parasitaemia. In vivo screening assay confirmed and validated the findings of the 3D-QSAR study for the design of quinoline derivatives.

Tit Structure-activity Relationship Study and Design of Novel 1, 8- Naphthimide Derivatives as Potential DNA-targeting Chemotherapeutic Agents for Osteosarcoma.

BACKGROUND: 1, 8-naphthimide is a novel tumor inhibitor targeting nuclear DNA, which makes it applicable to the design and development of anti-osteosarcoma drugs. OBJECTIVE: The aim of this study is to establish a satisfactory model based on 1, 8-naphthimide derivatives that makes reliable prediction as DNA-targeted chemotherapy agents for osteosarcoma. METHODS: All compounds are constructed using ChemDraw software and subsequently optimized using Sybyl software. COMSIA method is used to construct QSAR model with the optimized compound in Sybyl software package. A series of new 1, 8-naphthalimide derivatives are designed and their IC50 values are predicted using the QSAR model. Finally, the newly designed compounds are screened according to IC50 values, and molecular docking experiments are conducted on the top ten compounds of IC50. RESULTS: The COMSIA model shows that q2 is 0.529 and the optimum number of components is 6. The model has a high r2 value of 0.993 and a low SEE of 0.033, with the F value and the r2 predicted to be 495.841 and 0.996 respectively. The statistical results and verification results of the model are satisfactory. In addition, analyzing the contour maps is conducive to finding the structural requirements. CONCLUSION: The results of this study can provide guidance for medical chemists and other related workers to develop targeted chemotherapy drugs for osteosarcoma.

Molecular modeling of pyrrolo-pyrimidine based analogs as potential FGFR1 inhibitors: a scientific approach for therapeutic drugs.

Fibroblast growth factor receptors 1 (FGFR1) is an emerging target for the development of anticancer drugs. Uncontrolled expression of FGFR1 is strongly associated with a number of different types of cancers. Apart from a few FGFR inhibitors, the FGFR family members have not been thoroughly studied to produce clinically effective anticancer drugs. The application of proper computational techniques may aid in understanding the mechanism of protein-ligand complex formation, which may provide a better notion for developing potent FGFR1 inhibitors. In this study, a variety of computational techniques, including 3D-QSAR, flexible docking and MD simulation followed by MMGB/PBSA, H-bonds and distance analysis, have been performed to systematically explore the binding mechanism of pyrrolo-pyrimidine derivatives against FGFR1. The 3D-QSAR model was generated to deduce the structural determinants of FGFR1 inhibition. The high q2 and r2 values for the CoMFA and CoMSIA models indicated that the created 3D-QSAR models could reliably predict the bioactivities of FGFR1 inhibitors. The computed binding free energies (MMGB/PBSA) for the selected compounds were consistent with the ranking of their experimental binding affinities against FGFR1. Furthermore, per-residue energy decomposition analysis revealed that the residues Lys514 in catalytic region, Asn568, Glu571 in solvent accessible portion and Asp641 in DFG motif exhibited a strong tendency to mediate ligand-protein interactions through the hydrogen bonding and Van Der Waals interactions. These findings may benefit researchers in gaining better knowledge of FGFR1 inhibition and may serve as a guideline for the development of novel and highly effective FGFR1 inhibitors.Communicated by Ramaswamy H. Sarma.

Structural Insights on Hyp-Gly-Containing Peptides as Antiplatelet Compounds through Topomer CoMFA and CoMSIA Analysis.

Increasing evidence has shown collagen hydrolysate involves a variety of bioactivities. In our previous study, multiple antiplatelet peptides containing Hyp/Pro-Gly were identified in collagen hydrolysates from Salmo salar and silver carp skin and exhibited anti-thrombosis activity without bleeding risks in vivo. However, the relationship between structure and activity remains unknown. We performed 3D-QSAR studies on 23 Hyp/Pro-Gly-containing peptides in which 13 peptides were reported before. CoMFA, Topomer CoMFA and CoMSIA analyses were used to generate the QSAR models. Topomer CoMFA analysis showed a q2 value of 0.710, an r2 value of 0.826, an r2pred value of 0.930, and the results showed that Hyp instead of Pro was more important for improving the antiplatelet activity. CoMSIA analysis showed a q2 value of 0.461, an r2 value of 0.999, and an r2pred value of 0.999. Compared with the electrostatic field and hydrogen bond donor field, the steric field, hydrophobic field and hydrogen bond receptor field have great influence on the activity of antiplatelet peptides. The predicted peptide EOGE exhibited antiplatelet activity induced by ADP, and inhibited thrombus formation (300 µmol/kg bw) without bleeding risks. Combined results of these studies indicate that OG-containing peptides had a potential to be developed into an effective specific medical food in the prevention of thrombotic diseases.

3D-QSAR modeling and molecular docking studies on a series of 2, 4, 5-trisubstituted imidazole derivatives as CK2 inhibitors.

Protein case in kinase II alpha subunit (CK2) plays an imperative function in treating cancer disease. Herein, we have performed a three-dimensional quantitative structure activity relationship (3D-QSAR), and molecular docking analysis on a novel series of 2, 4, 5-trisubstituted imidazole derivatives in order to design potent kinase II alpha subunit (CK2) inhibitors. The 3D-QSAR methods such as comparative molecular similarity indexes analysis (COMSIA), and the comparative molecular field analysis (COMFA) were investigate using twenty-four molecules of 2, 4, 5-trisubstituted imidazole derivatives as anticancer agent. The best COMFA and COMSIA models exhibit excellent Q2 values of 0.66 and 0.75 and R2 values of 0.98 and 0.99 respectively. To check the validity of the selected COMFA and COMSIA models, a variety of validation tests were utilized: Internal validation analyses, and externally validation beside Y-randomization according to the principles of the Organization for Economic Co-operation and Development (OECD), and the Golbraikh and Tropsha's criteria for the validation of 3D-QSAR models. The proposed models for COMFA and COMSIA analysis have been successful. The developed models, indicating that they were reliable for activity prediction. Based on the preceding results, we designed several new potent molecules. Such outcome can proffer helpful theoretical references for future experimental studies.Communicated by Ramaswamy H. Sarma.

A comparative quantitative structural assessment of benzothiazine-derived HDAC8 inhibitors by predictive ligand-based drug designing approaches.

Histone deacetylase 8 (HDAC8) is a verified biomolecular target associated with diverse diseases including cancer. Though several HDAC inhibitors emerged effective against such diseases, no selective HDAC8 inhibitor is approved to date. Therefore, the development of potent HDAC8-selective inhibitors is inevitable to combat such diseases. Here, some benzothiazine-derived HDAC8 inhibitors were considered for a comparative QSAR analysis which may elucidate the prime structural components responsible for modulating their efficacy. Several outcomes from these diverse modelling techniques justified one another and thus validated each other. The ligand-based pharmacophore modelling study identified ring aromatic, positive ionizable, and hydrophobic features as essential structural attributes for HDAC8 inhibition. Besides, MLR, HQSAR and field-based 3D-QSAR studies signified the utility of the positive ionizable and hydrophobic features for potent HDAC8 inhibition. Again, the field-based 3D-QSAR study provided useful insight regarding the substitution in the fused phenyl ring. Moreover, the current observations also validated the previously reported molecular docking observations. Based on the outcomes, some new molecules were designed and predicted. Therefore, this comparative structural analysis of these HDAC8 inhibitors will surely assist in the development of potent HDAC8 inhibitors as promising anticancer therapeutics in the future.

Structure-Activity Relationship Studies Based on 3D-QSAR CoMFA/CoMSIA for Thieno-Pyrimidine Derivatives as Triple Negative Breast Cancer Inhibitors.

Triple-negative breast cancer (TNBC) is defined as a kind of breast cancer that lacks estrogen receptors (ER), progesterone receptors (PR), and human epidermal growth factor receptors (HER2). This cancer accounts for 10-15% of all breast cancers and has the features of high invasiveness and metastatic potential. The treatment regimens are still lacking and need to develop novel inhibitors for therapeutic strategies. Three-dimensional quantitative structure-activity relationship (3D-QSAR) analyses, based on a series of forty-seven thieno-pyrimidine derivatives, were performed to identify the key structural features for the inhibitory biological activities. The established comparative molecular field analysis (CoMFA) presented a leave-one-out cross-validated correlation coefficient q2 of 0.818 and a determination coefficient r2 of 0.917. In comparative molecular similarity indices analysis (CoMSIA), a q2 of 0.801 and an r2 of 0.897 were exhibited. The predictive capability of these models was confirmed by using external validation and was further validated by the progressive scrambling stability test. From these results of validation, the models were determined to be statistically reliable and robust. This study could provide valuable information for further optimization and design of novel inhibitors against metastatic breast cancer.

In silico multiscale drug design to discover key structural features of potential JAK2 inhibitors.

Background: JAK2 inhibitors have been proposed as a new therapeutic option for thalassemia therapy. The objective of this study was to discover the key structural features for improving 2-aminopyrimidine derivatives as potential JAK2 inhibitors. Materials & methods: Quantitative structure-activity relationship (QSAR) approaches (hologram QSAR and comparative molecular similarity indices analysis), molecular dynamics simulations, binding energy calculations and pharmacokinetic predictions were employed. Results: Reliable QSAR models, binding mode and binding interactions of JAK2 inhibitors were obtained and these obtained results were used as the key information for rational design of highly potent JAK2 inhibitors. Conclusion: The concept of new potential JAK2 inhibitors integrated from the obtained results was proved, producing two newly designed compounds, D01 and D02, with potential for use as JAK2 inhibitors.