3D QSAR and docking studies on benzoylsulfonohydrazides as histone acetyltransferase KAT6A inhibitors

Sixty-one analogs of benzoylsulfonohydrazides were subjected to 3D QSAR studies using CoMFA and CoMSIAtechniques followed by docking studies to develop a correlation of the structure with their respective activities. Thegenerated model had shown good predictability and the contour analysis followed by docking study has provided aninsight to develop new inhibitors. The cross-validation values corresponding to CoMFA and COMSIA were observedto be within the acceptable criterion (q2 > 0.5). The docking analysis of the best active compound shown was −41.81kcal/mol. From the obtained analysis results of CoMFA as well as CoMSIA, the data can be useful to develop morepotent histone acetyltransferase inhibitors.

3D-QSAR, molecular docking and dynamics simulation of difluorophenol pyridine derivatives as RSK2 inhibitor

Given the increasing role of P90 Ribosomal S6 Kinase 2 (RSK2) as an anticancer drug target, we performed3D-Quantitative structure–activity relationship, including comparative molecular field analysis (CoMFA) andcomparative molecular similarity indices analysis (CoMSIA) on difluorophenol pyridine derivatives as the inhibitorof RSK2. CoMFA model with q2 of 0.597 and R2 of 0.993, while CoMSIA model with q2 of 0.563 and R2 of 0.993,were obtained. The predictive ability of both models was assured using a test set compound with R2pred values of 0.996each. Using the validated models, novel compound was proposed and its interaction with RSK2 was investigatedemploying molecular docking and molecular dynamics simulation of 50 ns. Furthermore, molecular-mechanicsPoisson–Boltzmann surface area calculation was performed. The result showed that the newly designed compoundhas a comparable binding free energy with the known RSK2 inhibitor, indicating its potential as a new RSK2 inhibitor.

3D-QSAR, molecular docking, and dynamics simulation of quinazoline–phosphoramidate mustard conjugates as EGFR inhibitor

To develop novel and more potent quinazoline–phosphoramidate mustard conjugates as epidermal growth factorreceptor (EGFR) inhibitor, three-dimensional quantitative structure-activity relationship [comparative molecularfield analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA)] combined with moleculardocking were performed. A series of 13 compounds in the training set gave q2 values of 0.577 and 0.537, as well as r2values of 0.926 and 0.921 for CoMFA and CoMSIA models, respectively. The contour maps that were produced by theCoMFA and CoMSIA models revealed that steric, electrostatic, and hydrophobic fields were crucial in the inhibitoryactivity of quinazoline–phosphoramidate derivatives. Based on the CoMFA and CoMSIA models, several novel EGFRinhibitors were designed, which established crucial interactions at the ligand binding domain of EGFR. Nearly, 100ns MD simulation indicated the stability of the designed compounds at 100 ns, while molecular mechanics-PoissonBoltzmann surface area calculation showed that the designed compound had a higher affinity than that of the parentcompound.

3D-QSAR Study for Pyridine Heterocyclic Ring PI3K Inhibitor as Anti-renal Cancer Drug / 中国药房

OBJECTIVE:To study 3D-QSAR of pyridine heterocyclic ring PI3K inhibitor as anti-renal cancer drug,and to provide reference for the design and R&D of new anti-renal cancer inhibitors. METHODS:The data of structure and active value (pIC50) of 30 pyridine heterocyclic ring PI3K inhibitors were collected. After Sybyl-X 1.1 software used for molecular superimposition, CoMFA and CoMSIA model were established to investigate three dimensional field, electrostatic field, hydrophobic field,hydrogen bond donor site and hydrogen bond acceptor field of PI3K inhibitor molecule. Sybyl-X 1.1 software was used for molecular docking,and the mechanism of PI3K inhibitor molecule and receptor target protein were analyzed. PyMOL V1.5 software was used to design new PI3K inhibitor molecules. The activity of inhibitor molecules was predicted with CoMFA and CoMSIA model. RESULTS:The cross validation coefficients of CoMFA and CoMSIA model were 0.617 and 0.601, fitting validation coefficients were 0.969 and 0.974,and external predictive correlation coefficients were 0.656 and 0.670, respectively. In CoMFA model, contributions of three dimensional field and electrostatic field were 56.2% and 43.8%respectively. In CoMSIA model,contributions of three dimensional field,electrostatic field,hydrophobic field,hydrogen bond donor site and hydrogen bond acceptor field were 41.0%,31.3%,21.1%,2.4%,4.2%. After molecular superimposition,small steric hindrance,strong positive and hydrophilic groups introduced nearby R1 group of common skeleton could help to enhance the activity of molecules. The results of molecular docking showed that PI3K inhibitor molecule formed three hydrogen bonds with the key amino acids ALA805,VAL882 and THR887 of receptor target protein,with the length of 1.84,1.99,1.99 ?. According to above information,6 new molecules were designed,among which predicted pIC50 of 2 molecules with higher activity were 3.211,3.247(CoMFA method)and 3.238,3.222(CoMSIA method). CONCLUSIONS:Established new CoMFA and CoMSIA model have good prediction ability and statistical stability. Contribution of three dimensional field is higher than that of electrostatic field,and the influence of hydrophobic field on molecular activity can not be ignored. Pyridine heterocyclic ring PI3K inhibitors have strong hydrogen bonding role with receptor target protein. 3D-QSAR can provide reference for the design,reconstruction and drug R&D of new PI3K inhibitor molecule.

3D-QSAR studies on thiazole derivatives as potent inhibitors of dihydroorotate dehydrogenase / 药物评价研究

Objective The three-dimensional quantitative structure activity relationship (3D-QSAR) method was applied to study thiazole derivatives as potent inhibitors ofdihydroorotate dehydrogenase,which provided useful guidance for more discovery of potent inhibitors of dihydroorotate dehydrogenase.Methods Molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were applied to systematicly investigate 3D-QSAR of 38 hiazole derivatives as potent inhibitors of dihydroorotate dehydrogenase.Established models of CoMFA and CoMSIA and the predictive ability of models were validated.Three dimensional map was applied to analyzing the relationship between structure and activity of thiazole derivatives.Results The coefficients of cross validation q2 and non-cross validation r2 for CoMFA model were 0.796 and 0.978,and for CoMSIA model were 0.721 and 0.976 respectively.The prediction of activity of compound was close to the actual value of the two models.Effect of compound structure on its activity could be analyzed comprehensively and intuitively by three dimensional map.Conclusion The model reveals the relationship between the structure characteristics and the inhibitory activity,and has good predictive capability and stability to lay a good foundation for further development and research.

Synthesis, QSAR Study and Antitumor Activity of Desmosdumotin-C Analogues / 中国药学杂志

OBJECTIVE: To further design and synthesize Desmosdumotin-C(Des-C) derivatives and investigate their antitumor activities. METHODS: QSAR study using the CoMFA method was performed on a set of reported Des-C derivatives to facilitate the elucidation of their SAR and discovery of new potent Des-C derivatives. Flow cytometry was used to investigate antitumor activity. RESULTS: The established model showed good predictive ability and aid in the design of potent Des-C derivatives. An efficient three-step synthetic strategy toward Des-C derivatives was developed and applied to synthesize 10 new derivatives which showed superior antitumor activities against A549 and HL60 cells in vitro. CONCLUSION: The structural modification of Des-C would significantly increase the antitumor activity. It is preliminarily confirmed that the derivatives are potent antitumor agents with apoptosis-inducing ability, which provides the basis for the further study.

3D-QSAR and molecular docking studies on 23-hydroxybetulinic acid derivatives with antitumor activity / 中国药学杂志

OBJECTIVE: To formulate the three-dimensional quantitative structure-activity relationship (3D-QSAR) model of 23-hydroxybetulinic acid derivatives with promising antitumor activity and study their molecular docking with topoisomerase I (Topo I).

CoMFA -3D QSAR approach in drug design.

Progress in medicinal chemistry and in drug design depends on our ability to understand the interactions of drugs with their biological targets. Classical QSAR studies describe biological activity in terms of physicochemical properties of substituents in certain positions of the drug molecules. The detailed discussion of the present state of the art should enable scientists to further develop and improve these powerful new tools. Comparative Molecular Field Analysis (CoMFA) is a mainstream and down-toearth 3D QSAR technique in the coverage of drug discovery and development. Even though CoMFA is remarkable for high predictive capacity, the intrinsic data-dependent characteristic still makes this methodology certainly be handicapped by noise. It's well known that the default settings in CoMFA can bring about predictive QSAR models, in the meanwhile optimized parameters was proven to provide more predictive results. Accordingly, so far numerous endeavors have been accomplished to ameliorate the CoMFA model’s robustness and predictive accuracy by considering various factors, including molecular conformation and alignment, field descriptors and grid spacing. In the present article we are going to discuss the basic approaches of CoMFA in drug design.

Molecular mapping of heterocyclic diazene derivatives for estrogen receptor modulation.

Selective estrogen receptor modulators (SERMs) are effectively used in hormone replacement therapy (HRT) by reducing post-menopausal symptoms, including hormone-responsive breast cancer and osteoporosis. The present study explored the pharmacophore features of diazene derivatives for selective estrogen receptor (ER) modulation using quantitative structure activity relationship (QSAR) and space modeling approaches. The 2D-QSAR models (R2α = 0.907, Q2α = 0.700, R2pred-α = 0.735; R2β = 0.913, Q2β = 0.756, R2pred-β = 0.745) showed the importance of orbital energies, hydrophobicity, refractivity and atomic charges for selective binding affinity to ER. In 3D-QSAR, molecular field (CoMFA, R2α = 0.948, Q2 = 0.720, R2pred-α = 0.708; R2β = 0.994, Q2β = 0.541, R2pred-β = 0.721) and similarity models (CoMSIA, R2α = 0.984, Q2α = 0.793, R2pred-α = 0.738; R2β = 0.996, Q2β = 0.681, R2pred-β = 0.725) indicated that steric and hydrophobic properties were important for binding selectivity. Space modeling study (R2α = 0.885, Q2α = 0.855, R2pred-α = 0.666; R2β = 0.872, Q2β = 0.883, R2pred-β = 0.814) revealed that hydrophobic and aromatic ring features were important for both subtypes, whereas hydrogen bond (HB) acceptor and donor were crucial for β- and α-subtypes, respectively. Interactions observed between ligand and catalytic residues at the active site in docking study substantiated the developed model which may be successfully used in high throughput screening (HTS) to obtain promising lead molecules for selective estrogen therapy.

Cytotoxic Activity and Structure Activity Relationship of Ceramide Analogues in Caki-2 and HL-60 Cells

B13, a ceramide analogue, is a ceramidase inhibitor and induces apoptosis to give potent anticancer activity. A series of thiourea B13 analogues was evaluated for their in vitro cytotoxic activities against human renal cancer Caki-2 and leukemic cancer HL-60 in the MTT assay. Some compounds (12, 15, and 16) showed stronger cytotoxicity than B13 and C6-ceramide against both tumor cell lines, and compound (12) gave the most potent activity with IC50 values of 36 and 9 microM, respectively. Molecular modeling of thiourea B13 analogues was carried out by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). We obtained highly reliable and predictive CoMSIA models with cross-validated q2 values of 0.707 and 0.753 and CoMSIA contour maps to show the structural requirements for potent activity. These data suggest that the amide group of B13 could be replaced by thiourea, that the stereochemistry of 1,3-propandiol may not be essential for activity and that long alkyl chains increase cytotoxicity.

Quantitative Structure Activity Relationship between Diazabicyclo4.2.0octanes Derivatives and Nicotinic Acetylcholine Receptor Agonists

Three dimensional quantitative structure activity relationship between diazabicyclo[4.2.0]octanes and nicotinic acetylcholine receptor (h alpha4beta2 and h alpha3beta4) agonists was studied using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). From 11 CoMFA and CoMSIA models, CoMSIA with steric and electrostatic fields gave the best predictive models (q2=0.926 and 0.945, r2(ncv)=0.983 and 0.988). This study can be used to develop potent h alpha4beta2 receptor agonists with low activity on h alpha3beta4 subtype.

Cytotoxic Activity and Three-Dimensional Quantitative Structure Activity Relationship of 2-Aryl-1,8-naphthyridin-4-ones

A series of substituted 2-arylnaphthyridin-4-one analogues, which were previously synthesized in our laboratory, were evaluated for their in vitro cytotoxic activity against human lung cancer A549 and human renal cancer Caki-2 cells using MTT assay. Some compounds (11, 12, and 13) showed stronger cytotoxicity than colchicine against both tumor cell lines, and compound 13 exhibited the most potent activity with IC50 values of 2.3 and 13.4 micrometer, respectively. Three-dimensional quantitative structure activity relationship (3D-QSAR) studies of comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed. Predictive 3D-QSAR models were obtained with q(2) values of 0.869 and 0.872 and r(2)(ncv) values of 0.983 and 0.993 for CoMFA and CoMSIA, respectively. These results demonstrate that CoMFA and CoMSIA models could be reliably used in the design of novel cytotoxic agents.