Mapping the binding site of a large set of quinazoline type EGF-R inhibitors using molecular field analyses and molecular docking studies

In the current work, three-dimensional QSAR studies for one large set of quinazoline type epidermal growth factor receptor (EGF-R) inhibitors were conducted using two types of molecular field analysis techniques: comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). These compounds belonging to six different structural classes were randomly divided into a training set of 122 compounds and a test set of 13 compounds. The statistical results showed that the 3D-QSAR models derived from CoMFA were superior to those generated from CoMSIA. The most optimal CoMFA model after region focusing bears significant cross-validated r(2)(cv) of 0.60 and conventional r(2) of 0.92. The predictive power of the best CoMFA model was further validated by the accurate estimation to these compounds in the external test set, and the mean agreement of experimental and predicted log(IC(50)) values of the inhibitors is 0.6 log unit. Separate CoMFA models were conducted to evaluate the influence of different partial charges (Gasteiger-Marsili, Gasteiger-Hückel, MMFF94, ESP-AM1, and MPA-AM1) on the statistical quality of the models. The resulting CoMFA field map provides information on the geometry of the binding site cavity and the relative weights of various properties in different site pockets for each of the substrates considered. Moreover, in the current work, we applied MD simulations combined with MM/PBSA (Molecular mechanics/Possion-Boltzmann Surface Area) to determine the correct binding mode of the best inhibitor for which no ligand-protein crystal structure was present. To proceed, we define the following procedure: three hundred picosecond molecular dynamics simulations were first performed for the four binding modes suggested by DOCK 4.0 and manual docking, and then MM/PBSA was carried out for the collected snapshots. The most favorable binding mode identified by MM/PBSA has a binding free energy about 10 kcal/mol more favorable than the second best one. The most favorable binding mode identified by MM/PBSA can give satisfactory explanation of the SAR data of the studied molecules and is in good agreement with the contour maps of CoMFA. The most favorable binding mode suggests that with the quinazoline-based inhibitor, the N3 atom is hydrogen-bonded to a water molecule which, in turn, interacts with Thr 766, not Thr 830 as proposed by Wissner et al. (J. Med. Chem. 2000, 43, 3244). The predicted complex structure of quinazoline type inhibitor with EGF-R as well as the pharmacophore mapping from CoMFA can interpret the structure activities of the inhibitors well and afford us important information for structure-based drug design.     

MM3(96) parameterization for camptothecin analogs: An ab initio and molecular mechanics study

Torsional parameters for MM3(96) were derived for the missing atom types present in thenatural product camptothecin (CPT). Potential energy curves were calculated via ab initiocalculations on representative compounds for dihedral angles containing these missingparameters. Gaussian 92 at the restricted Hartree–Fock level of theory using thestandard 6-31G** and 4-31G** basis sets, was used for all the quantum-mechanicscalculations. Missing MM3 torsional terms were obtained by optimizing the V1, V2 and V3parameters such that MM3 could reproduce the ab initio torsional profile. MM3 calculatedmolecular structures that compare well with the ab initio results. Using the newly developedparameters, conformational analyses and QSAR studies of camptothecin analogs wereundertaken. MM3 predicts two distinct boatlike conformations for the -hydroxy lactonemoiety. The low-energy lactone conformation predicted by MM3 is in general agreement withreported X-ray crystal structures of CPT iodoacetate and 7-ethyl-10-(4-piperidino)piperidinylcarbonyloxy CPT HCl as well as the ab initio structure of a CPT-like-hydroxy lactone.     

A structure-based 3D-QSAR study of anthrapyrazole analogues of the anticancer agents losoxantrone and piroxantrone

A series of 13 anthrapyrazole compounds that are analogues of piroxantrone and losoxantrone were synthesized, and their cell growth inhibitory effects, DNA binding, topoisomerase IIalpha mediated (EC 5.99.1.3) cleavage of DNA, and inhibition of DNA topoisomerase IIalpha decatenation catalytic activities were determined. Cell growth inhibitory activity was well-correlated with DNA binding, suggesting that these compounds may act by targeting DNA. However, cell growth inhibition was not well-correlated with the inhibition of topoisomerase IIalpha catalytic activity, suggesting that these anthrapyrazoles did not act solely by inhibiting the catalytic activity of topoisomerase II. Most of the analogues were able to induce DNA cleavage, and thus, it was concluded that they acted, at least in part, as topoisomerase II poisons. Structure-based three-dimensional quantitative structure-activity analyses (3D-QSAR) were carried out on the aligned structures of the anthrapyrazoles docked into DNA using comparative molecular field analysis (CoMFA) and comparative molecular similarity index (CoMSIA) analyses in order to determine the structural features responsible for their activity. Both CoMFA and CoMSIA yielded statistically significant models upon partial least-squares analyses. The 3D-QSAR analyses showed that hydrogen-bond donor interactions and electrostatic interactions with the protonated amino side chains of the anthrapyrazoles led to high cell growth inhibitory activity.     

A comparative molecular field analysis (CoMFA) study using semiempirical, density functional, ab initio methods and pharmacophore derivation using DISCOtech on sigma 1 ligands

The Comparative Molecular Field Analysis (CoMFA) was developed to investigate a three-dimensional quantitative structure activity relationship (3D-QSAR) model of ligands for the sigma 1 receptor. The starting geometry of sigma-1 receptor ligands was obtained from the Tripos force field minimizations and conformations were decided from DISCOtech using the SYBYL 6.8. program. The structures of 48 molecules were fully optimized at the ab initio HF/3-21G* and semiempirical AM1 calculations using GAUSSIAN 98. The electrostatic charges were calculated using several methods such as semiempirical AM1, density functional B3LYP/3-21G*, and ab initio HF/3-21G*, MP2/3-21G* calculations within GAUSSIAN 98. Using the optimized geometries, the CoMFA results derived from the HF/3-21G method were better than those from AM1. The best CoMFA was obtained from HF/3-21G* optimized geometry and charges (R2 = 0.977). Using the optimized geometries, the CoMFA results derived from the HF/3-21G methods were better than those from AM1 calculations. The training set of 43 molecules gave higher R2 (0.989-0.977) from HF/3-21G* optimized geometries than R2 (0.966-0.911) values from AM1 optimized geometries. The test set of five molecules also suggested that HF/3-21G* optimized geometries produced good CoMFA models to predict bioactivity of sigma 1 receptor ligands but AM1 optimized geometries failed to predict reasonable bioactivity of sigma 1 receptor ligands using different calculations for atomic charges.     

Comparative molecular field analysis of artemisinin derivatives: Ab initio versus semiempirical optimized structures

Based on the belief that structural optimization methods, producing structures more closely to the experimental ones, should give better, i.e. more relevant, steric fields and hence more predictive CoMFA models, comparative molecular field analyses of artemisinin derivatives were performed based on semiempirical AM1 and HF/3-21G optimized geometries. Using these optimized geometries, the CoMFA results derived from the HF/3-21G method are found to be usually but not drastically better than those from AM1. Additional calculations were performed to investigate the electrostatic field difference using the Gasteiger and Marsili charges, the electrostatic potential fit charges at the AM1 level, and the natural population analysis charges at the HF/3-21G level of theory. For the HF/3-21G optimized structures no difference in predictability was observed, whereas for AM1 optimized structures such differences were found. Interestingly, if ionic compounds are omitted, differences between the various HF/3-21G optimized structure models using these electrostatic fields were found.     

Combined 3D-QSAR, molecular docking, and molecular dynamics study on piperazinyl-glutamate-pyridines/pyrimidines as potent P2Y12 antagonists for inhibition of platelet aggregation

An unusually large data set of 397 piperazinyl-glutamate-pyridines/pyrimidines as potent orally bioavailable P2Y(12) antagonists for inhibition of platelet aggregation was studied for the first time based on the combination of three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking, and molecular dynamics (MD) methods. The comparative molecular field analysis (CoMFA) and comparative molecular similarity index analysis (CoMSIA) studies have been performed with a training set of 317 compounds, estimating three superimposition methods. The best CoMFA and CoMSIA models, derived from superimposition I, shows leave-one-out cross-validation correlation coefficients (Q(2)) of 0.571 and 0.592 as well as the conventional correlation coefficients (R(2)(ncv)) of 0.814 and 0.834, respectively. In addition, the satisfactory results, based on the bootstrapping analysis and 10-fold cross-validation, further indicate the highly statistical significance of the optimal models. The external predictive abilities of these models were evaluated using a prediction set of 80 compounds, producing the predicted correlation coefficients (R(2)(pred)) of 0.664 and 0.668, respectively. The key amino acid residues were identified by molecular docking, and the stability and rationality of the derived molecular conformations were also validated by MD simulation. The good concordance between the docking results and CoMFA/CoMSIA contour maps provides helpful clues about the rational modification of molecules in order to design more potent P2Y(12) antagonists. We hope the developed models could provide some instructions for further synthesis of highly potent P2Y(12) antagonists.     

Synthesis of 7‐Triazole‐substituted Camptothecin via Click Chemistry and Evaluation of in vitro Antitumor Activity

Camptothecin (CPT) is a natural topoisomerase I inhibitor with powerful antineoplastic activity against colorectal, breast, lung and ovarian cancers. To discover more potent antitumor agents, a series of new CPT derivatives were synthesized utilizing click chemistry. All compounds were assessed for cytotoxicity against A549, HCT‐116, HT‐29, LoVo, MDA‐MB‐231 cell lines, and some compounds exhibited good in vitro potency. Furthermore, all compounds kept or enhanced Topo I inhibition.     

Comparative molecular field analysis and energy interaction studies of thrombin-inhibitor complexes

A Comparative Molecular Field Analysis (CoMFA) and an interaction energy-based method were applied on a database holding the 3D structures of 29 thrombin-inhibitor complexes. Several parameters were optimized in both methods in order to obtain the best correlation between theoretical and experimentally determined binding (Ki) data. CoMFA, which only uses the information of the inhibitors, performed best (r = 0.99, q2 = 0.46, N = 29) when HF 6-31G charges were used in combination with a pharmacophore-based alignment. Inclusion of hydrophobic fields did not lead to improvements. The interaction energy-based approach uses the information of the whole thrombin-inhibitor complex. A statistically significant correlation (r = 0.74, N = 14) could only be obtained for a subset of the database containing the high resolution structures. Geometry optimization of the ligand only in combination with downscaled electrostatics performed best.     

QSAR and 3D-QSAR studies of the diacyl-hydrazine derivatives containing furan rings based on the density functional theory

QSAR studies of 27 diacyl-hydrazine derivatives containing furan rings were conducted and compared with the DFT method and AM1-MOPAC method. q ² values of 0.61 and 0.40 validated the predictability and reliability of eq. (5) from the DFT method were higher than those of eq. (6) from the AM1-MOPAC method. The DFT-optimized conformations and ESP-fitting charges of the target compounds were also used for 3D-QSAR analysis, including CoMFA and CoMSIA. The leave-one-out cross-validation correlation coefficient and the good correlation between the predicted and experimental activities of excluded test compounds revealed that CoMFA and CoMSIA models were robust. The QSAR results were consistent with the 3D-QSAR results, indicating that the electrostatic and hydrophobic properties of the target compounds were significant to the biological activity. These models are useful tools for predicting the larvicidal activities of new compounds and designing new specific insect growth regulators.