Molecular docking and 3-D-QSAR studies on the possible antimalarial mechanism of artemisinin analogues

Artemisinin (Qinghaosu) is a natural constituent found in Artemisia annua L, which is an effective drug against chloroquine-resistant Plasmodium falciparum strains and cerebral malaria. The antimalarial activities of artemisinin and its analogues appear to be mediated by the interactions of the drugs with hemin. In order to understand the antimalarial mechanism and the relationship between the physicochemical properties and the antimalarial activities of artemisinin analogues, we performed molecular docking simulations to probe the interactions of these analogues with hemin, and then performed three-dimensional quantitative structure-activity relationship (3-D-QSAR) studies on the basis of the docking models employing comparative molecular force fields analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Molecular docking simulations generated probable 'bioactive' conformations of artemisinin analogues and provided a new insight into the antimalarial mechanism. The subsequent partial least squares (PLS) analysis indicates that the calculate binding energies correlate well with the experimental activity values. The CoMFA and CoMSIA models based on the bioactive conformations proved to have good predictive ability and in turn match well with the docking result, which further testified the reliability of the docking model. Combining these results, that is molecular docking and 3-D-QSAR, together, the binding model and activity of new synthesized artemisinin derivatives were well explained.     

A novel 3D-QSAR comparative molecular field analysis (CoMFA) model of imidazole and quinazolinone functionalized p38 MAP kinase inhibitors

In this study we describe a new comparative molecular field analysis (CoMFA) model of dihydroquinazolinone and tetrasubstituted imidazole compounds with p38 MAPK inhibitory activity. A series of 51 (a training set of 40 and a test set of 11) dihydroquinazolinone [Bioorg. Med. Chem. Lett. 2003, 13, 277.] and tetrasubstituted imidazole [J. Med. Chem. 1999, 42, 2180.] derivatives known as p38 mitogen-activated protein kinase (p38 MAPK) selective inhibitors was studied by quantitative structure-activity relationship (3D-QSAR) analysis using comparative molecular field analysis. The 3D-QSAR models were generated and evaluated by a scheme that combines a genetic algorithm (GA) optimization with partial least squares (PLS) regression and by crossvalidation using the leave-one-out technique. The model was able to efficiently predict the activities of the compounds of the test set, suggesting that it can be used for the planning of new p38 MAPK inhibitor candidates useful to treat chronic inflammatory states.     

Three-dimensional quantitative structure-activity relationship studies on novel series of benzotriazine based compounds acting as Src inhibitors using CoMFA and CoMSIA

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on a series of benzotriazine derivatives, as Src inhibitors. Ligand molecular superimposition on the template structure was performed by database alignment method. The statistically significant model was established of 72 molecules, which were validated by a test set of six compounds. The CoMFA model yielded a q(2)=0.526, non cross-validated R(2) of 0.781, F value of 88.132, bootstrapped R(2) of 0.831, standard error of prediction=0.587, and standard error of estimate=0.351 while the CoMSIA model yielded the best predictive model with a q(2)=0.647, non cross-validated R(2) of 0.895, F value of 115.906, bootstrapped R(2) of 0.953, standard error of prediction=0.519, and standard error of estimate=0.178. The contour maps obtained from 3D-QSAR studies were appraised for activity trends for the molecules analyzed. Results indicate that small steric volumes in the hydrophobic region, electron-withdrawing groups next to the aryl linker region, and atoms close to the solvent accessible region increase the Src inhibitory activity of the compounds. In fact, adding substituents at positions 5, 6, and 8 of the benzotriazine nucleus were generated new compounds having a higher predicted activity. The data generated from the present study will further help to design novel, potent, and selective Src inhibitors as anticancer therapeutic agents.     

A geometry optimization and molecular electrostatic potential mapping study of structure-activity relationship for some anti-Alzheimer agents.

Molecular geometries of some substituted (pyrroloamino)pyridines which possess anti-Alzheimer activity were optimized and potential-derived CHelpG point charges were computed using ab initio SCF molecular orbital approach employing the 3-21G basis set. AM1 molecular orbital calculations were performed using these optimized geometries and thus optimized Hybridization. Displacement Charges (HDC) combined with L?wdin charges continuously distributed in three dimension were obtained. Molecular electrostatic potential (MEP) maps of the molecules were obtained in two ways: (i) using the HDC-based model with the help of which MEP minima near the molecules were located, and (ii) using the CHelpG point charges, MEP values on the van der Waals surfaces of the molecules were computed. The MEP maps computed using both the methods have negative MEP regions near the pyridine nitrogen atom which appears to be the main binding site of the molecules with the appropriate receptor. Both electrostatic interaction and lipophilic association between these molecules and the receptor appear to contribute to biological activity.     

Conformational and stereoelectronic investigation of tryptamine. An AIM/NBO study

Due to the free radical scavenger properties of Tryptamine (TRA), as well as of others indole derivatives, it is in our interest to explore deeply the stereoelectronic aspects that would be relevant in their stabilization and antioxidant activity. In this work the conformational space of TRA was scanned using molecular dynamics complemented with functional density calculations at B3LYP/6-31 + G** level. Twenty one conformers of lowest energy were obtained, their electronic distributions were analyzed at a higher calculation level, thus improving the basis set (B3LYP/6-311++G**). A topological study based on Bader's theory (AIM: atoms in molecules) and natural bond orbital (NBO) framework was performed. The study was enriched by a deep analysis of maps of molecular electrostatic potential (MEP) through a coordinated NBO/AIM analysis. The conformational preferences were explained by hyperconjugative interactions, which were revealed by NBO data. Because radical scavenging by indolic compounds is strongly modulated by their functional residues our study was related to similar analysis done previously on Indole and 1H-indole-3-acetic acid (IAA). Therefore, the conformational space of TRA was studied from a new perspective focusing on a deep analysis of the geometric and electronic properties of TRA conformers. The changes of the electronic distribution introduced by the substituent and the conformational flexibility of the side chain were addressed. The results reported contribute to the understanding of the structure, stability and reactivity of TRA and others indole derivatives.     

2,6-Bis(3,4,5-trihydroxybenzylydene) derivatives of cyclohexanone: novel potent HIV-1 integrase inhibitors that prevent HIV-1 multiplication in cell-based assays

A number of 2,6-bisbenzylidenecyclohexane-1-one derivatives have been synthesized and tested as HIV-1 integrase (IN) inhibitors with the aim of obtaining compounds capable to elicit antiviral activity at non-cytotoxic concentrations in cell-based assays. 3,5-Bis(3,4,5-trihydroxybenzylidene)-4-oxocyclohexaneacetic acid (20d) resulted one of the most potent and selective derivatives in acutely infected MT-4 cells (EC(50) and CC(50) values of 2 and 40 microM, respectively). In enzyme assays with recombinant HIV-1 integrase (rIN), this compound proved able to inhibit both 3'-processing and disintegration with IC(50) values of 0.2 and 0.5 microM, respectively. In order to develop a model capable to predict the anti HIV-IN activity and useful to design novel derivatives, we performed a comparative molecular field analysis (CoMFA) like 3-D-QSAR. In our model the ligands were described quantitatively in the GRID program, and the model was optimized by selecting only the most informative variables in the GOLPE program. We found the predictive ability of the model to increase significantly when the number of variables was reduced from 20,925 to 1327. A Q(2) of 0.73 was obtained with the final model, confirming the predictive ability of the model. By studying the PLS coefficients in informative 3-D contour plots, ideas for the synthesis of new compounds could be generated.     

CoMFA and CoMSIA 3D-QSAR analysis of DMDP derivatives as anti-cancer agents

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) based on three dimensional quantitative structure-activity relationship (3D-QSAR) studies were conducted on a series (78 compounds) of 2, 4-diamino-5-methyl-5-deazapteridine (DMDP) derivatives as potent anticancer agents. The best prediction were obtained with a CoMFA standard model (q(2) = 0.530, r(2) = 0.903) and with CoMSIA combined steric, electrostatic, hydrophobic and hydrogen bond donor fields (q(2) = 0.548, r(2) = 0.909). Both models were validated by a test set of ten compounds producing very good predictive r(2) values of 0.935 and 0.842, respectively. CoMFA and CoMSIA contour maps were then used to analyze the structural features of ligands to account for the activity in terms of positively contributing physiochemical properties such as steric, electrostatic, hydrophobic and hydrogen bond donor fields. The resulting contour maps produced by the best CoMFA and CoMSIA models were used to identify the structural features relevant to the biological activity in this series of analogs. This study suggests that the highly electropositive substituents with low steric tolerance are required at 5 position of the pteridine ring and bulky electronegatve substituents are required at the meta-position of the phenyl ring. The information obtained from CoMFA and CoMSIA 3-D contour maps can be used for the design of deazapteridine-based analogs as anticancer agents.     

Molecular modeling and evaluation of binding mode and affinity of artemisinin-quinine hybrid and its congeners with Fe-protoporphyrin-IX as a putative receptor

A recent rational approach to anti-malarial drug design is characterized as "covalent biotherapy" involves linking of two molecules with individual intrinsic activity into a single agent, thus packaging dual activity into a single hybrid molecule. In view of this background and reported anti malaria synergism between artemisinin and quinine; we describe the computer-assisted docking to predict molecular interaction and binding affinity of Artemisinin-Quinine hybrid and its derivatives with the intraparasitic haeme group of human haemoglobin. Starting from a crystallographic structure of Fe-protoporphyrin-IX, binding modes, orientation of peroxide bridge (Fe-O distance), docking score and interaction energy are predicted using the docking molecular mechanics based on generalized Born/surface area (MM-GBSA) solvation model. Seven new ligands were identified with a favourable glide score (XP score) and binding free energy (ΔG) with reference to the experimental structure from a data set of thirty four hybrid derivatives. The result shows the conformational property of the drug-receptor interaction and may lead to rational design and synthesis of improved potent artemisinin based hybrid antimalarial that target haemozoin formation.     

Novel ferrocenic artemisinin derivatives: synthesis, in vitro antimalarial activity and affinity of binding with ferroprotoporphyrin IX

Following our search for novel compounds with high antimalarial activity, a series of artemisinin (QHS) derivatives containing a ferrocenic nucleus was prepared and tested in vitro against Plasmodium falciparum strains. Two new metallocenic derivatives (1 and 3) were found as potent as QHS. All compounds showed a capacity to bind with ferroprotoporphyrin IX. A decrease in the Soret band absorbance of ferroprotoporphyrin IX, resulting from the addition of different drugs concentrations, was shown. The association stoichiometry of compounds to ferroprotoporphyrin IX appears to be 1:2 at equilibrium, with an intermediate 1:1 complexation. These results appear to strengthen the role of adducts between artemisinin derivatives and heme in generation of artemisinin radicals. Such interaction of artemisinin ferrocenyl derivatives with ferroprotoporphyrin IX and its biological significance could form a basis in future drug development.     

Synthesis, in vitro evaluation, and SAR studies of a potential antichagasic 1H-pyrazolo[3,4-b]pyridine series

The development of new drugs against Trypanosoma cruzi is still required since the only two drugs currently used cause severe side effects. In this work we described the synthesis, the in vitro biological evaluation, and the SAR results of 1H-pyrazolo[3,4-b]pyridine derivatives, a new antichagasic agent series. The presence of fluorine, hydroxyl or nitro group at Y position resulted in at least one or two promising compounds in each set of derivatives (6f, 6g, 6i, 6l, and 6m). The SAR study showed that trypanocidal activity observed depends on both geometric and stereoelectronic parameters (MEP and frontier molecular orbitals HOMO and LUMO). We also used the Osiris program for calculating and comparing the fragment based druglikeness of the most active derivative (6g) (IC(50)=1.9microg/mL), the inactive compound (6o), and the current toxic antichagasic drugs (nifurtimox and benznidazole). Interestingly 6g presented a potential druglikeness higher than nifurtimox and benznidazole while 6o presented the lowest value among them.     

3D-QSAR studies of farnesyltransferase inhibitors: a comparative molecular field analysis approach

3D-QSAR analysis has been performed on a series of previously synthesized benzonitrile derivatives, which were screened as farnesyltransferase inhibitors, using comparative molecular field analysis (CoMFA) with partial least-square fit to predict the steric and electrostatic molecular field interactions for the activity. The CoMFA study was carried out using a training set of 34 compounds. The predictive ability of the model developed was assessed using a test set of eight compounds (r(pred)(2) as high as 0.770). The analyzed 3D-QSAR CoMFA model has demonstrated a good fit, having r(2) value of 0.991 and cross-validated coefficient q(2) value as 0.619. The analysis of CoMFA contour maps provided insight into the possible modification of the molecules for better activity.     

Structure-Activity Relationship for Some 2′,3′-Dideoxynucleoside Anti-HIV Drugs Using Molecular Electrostatic Potential Mapping

Molecular electrostatic potential(MEP) maps of azido thymidine (AZT), some of its analogs and derivatives and certain other 2′,3′-dideoxy nucleosides having different anti-HIV activities have been studied. The optimised hybridization displacement charges (HDC) combined with MNDO Löwdin charges, continuosly distributed in three dimension spherically symmetrically as a Slater cloud at each site were used to compute the MEP maps. The negative MEP region near the O5′ sites of these molecules appears to be of primary importance from the point of view of their anti-HIV activity. The roles of the azido group in AZT and fluorine atoms substituted at different positions in the sugar moiety have been evaluated. The azido group in AZT behaves as a strongly electronegative group.     

Design of novel quinazolinone derivatives as inhibitors for 5HT7 receptor

To study the pharmacophore properties of quinazolinone derivatives as 5HT(7) inhibitors, 3D QSAR methodologies, namely Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) were applied, partial least square (PLS) analysis was performed and QSAR models were generated. The derived model showed good statistical reliability in terms of predicting the 5HT(7) inhibitory activity of the quinazolione derivative, based on molecular property fields like steric, electrostatic, hydrophobic, hydrogen bond donor and hydrogen bond acceptor fields. This is evident from statistical parameters like q(2) (cross validated correlation coefficient) of 0.642, 0.602 and r(2) (conventional correlation coefficient) of 0.937, 0.908 for CoMFA and CoMSIA respectively. The predictive ability of the models to determine 5HT(7) antagonistic activity is validated using a test set of 26 molecules that were not included in the training set and the predictive r(2) obtained for the test set was 0.512 & 0.541. Further, the results of the derived model are illustrated by means of contour maps, which give an insight into the interaction of the drug with the receptor. The molecular fields so obtained served as the basis for the design of twenty new ligands. In addition, ADME (Adsorption, Distribution, Metabolism and Elimination) have been calculated in order to predict the relevant pharmaceutical properties, and the results are in conformity with required drug like properties.     

In vitro schizontocidal activity of standard antimalarial drugs on chloroquine-sensitive and chloroquine-resistant isolates of Plasmodium falciparum

The expanding foci of multiple drug resistant malaria and emergence of different strains requires the reassessment of antimalarial activity with various drugs. In vitro response of a chloroquine sensitive and a chloroquine resistant isolate of P. falciparum to a group of 6 quinine derived and 3 artemisinin derived standard drugs has been screened, to evaluate schizontocidal activity of the drugs. In a conventional test system the IC50s were derived from the log dose response curves and evaluated by a rigorous statistical interpretation. Analysis by Tukey's test was significant for the quinine related drugs (Q < or = 0.01) and excludes the statistical significance of artemisinin related drugs in these isolates. The dose-responses of these two isolates vary with quinine derivatives, with some overlap at lower doses for the sensitive isolate than for the resistant one which manifests at higher doses.