Comparative molecular field analysis and molecular docking studies on novel aryl chalcone derivatives against an important drug target cysteine protease in Plasmodium falciparum.

The computational studies namely molecular docking simulations and Comparative Molecular Field Analysis (CoMFA) are executed on series of 52 novel aryl chalcones derivatives using Plasmodium falciparum cysteine proteases (falcipain - 2) as vital target. In the present study, the correlation between different molecular field effects namely steric and electrostatic interactions and chemical structures to the inhibitory activities of novel aryl chalcone derivatives is inferred to perceive the major structural prerequisites for the rational design and development of potent and novel lead anti-malarial compound. The apparent binding conformations of all the compounds at the active site of falcipain - 2 and the hydrogen-bond interactions which could be used to modify the inhibitory activities are identified by using Surflex-dock study. Statistically significant CoMFA model has been developed with the cross-validated correlation coefficient (q(2)) of 0.912 and the non-cross-validated correlation coefficient (r(2)) of 0.901. Standard error of estimation (SEE) of 0.210, with the optimum number of components is ten. The predictability of the derived model is examined with a test set consists of sixteen compounds and the predicted r(2) value is found to be 0.924. The docking and QSAR study results confer crucial suggestions for the optimization of novel 1,3-diphenyl-2-propen-1-one derivatives and synthesis of effective anti- malarial compounds.

Molecular docking and dynamics studies on novel benzene sulfonamide substituted pyrazole-pyrazoline analogues as potent inhibitors of Plasmodium falciparum Histo aspartic protease.

Malaria is the major health issue in African, Asian and Mediterranean regions of the world. Due to the emerging resistance by the parasites and mosquitoes for the current medications and insecticides, respectively, the malaria free human world can be attained only by the novel design and development of new anti-malarial drugs. Hence, we attempted to carry out in silico screening of benzene sulfonamide substituted pyrazole-pyrazoline series against Histo aspartic protease. Our results reveal that the 65% of the data set with the free binding energy in the range of -11.58 to -11.21 kcal/mol, which is categorized as 'high scoring'. Ligands are docked with the catalytic residues Asp 215, Ser 75, Thr 33 and Ala 217, respectively. Molecular dynamic simulation study of free enzyme and the enzyme complex with 4-(5-(4-methoxyphenyl)-1'phenyl-3'-(p-tolyl)-3,4-1'H,2H-[3,4'-bipyrazol]-2-yl)benezenesulfonamide indicated structural stability. The trajectory analysis of complex reveals that the HAP-ligand complex is more stable than the free HAP. We are of the opinion that our results will be useful for designing potential anti-malarial compounds. AbbreviationsADTauto dock toolsBSPPbenzene sulfonamide substituted pyrazole-pyrazolineCQchloroquineHAPhisto aspartic proteaseKKelvinMDmolecular dockingMM/PBSAmolecular mechanics/Poisson Boltzmann surface areaNVTnormal volume and temperatureNPTnormal pressure and temperatureNsnanosecondsPDBprotein data bank.pdbprogram data base formatP. falciparumPlasmodium falciparumPspicosecondsPMsplasmepsinsP. vivaxPlasmodium vivaxRgradius of gyrationRMSDroot mean square deviationRMSFroot mean square fluctuationWHOWorld Health OrganizationCommunicated by Ramaswamy H. Sarma.

Insights on inhibition of Plasmodium falciparum plasmepsin I by novel epoxyazadiradione derivatives - molecular docking and comparative molecular field analysis.

In the present study, we have explored the anti-malarial potential of epoxyazadiradione, the natural entity extracted from the neem seed oil and its chemical derivatives, against Plasmodium falciparum. The Surflex dock analysis of 41 compounds against an indispensable target, plasmepsin I (PM-I) revealed that around 70% of the compounds are found to have good binding capacity with the consensus score (C-score) of 5 to 4 with few hydrogen bonds. To elucidate the major structural requirements, vital for binding with the plasmepsin enzyme and to develop the predictive models, three-dimentional quantitative structural activity relationship (3D-QSAR) - comparative molecular field analysis (CoMFA) was carried out using Sybyl X.0. Robust and predictive models were obtained with cross-validated correlation coefficient (q2) value of 0.967 and the non-cross-validated correlation coefficient (r2) value of 0.825, which were validated by an external test set with the predictive correlation coefficient r2(pred) values of 0.773. Three zones were identified for substitution with bulky groups and one zone for substitution with non-bulky groups. Three positions favouring the electronegative group substitution and one for the electropositive group substitution were identified. The physicochemical properties of ligands with the highest C-score were studied. Communicated by Ramaswamy H. Sarma.

In-Silico molecular docking and simulation studies on novel chalcone and flavone hybrid derivatives with 1, 2, 3-triazole linkage as vital inhibitors of Plasmodium falciparum dihydroorotate dehydrogenase.

The structural motifs of chalcones, flavones, and triazoles with varied substitutions have been studied for the antimalarial activity. In this study, 25 novel derivatives of chalcone and flavone hybrid derivatives with 1, 2, 3-triazole linkage are docked with Plasmodium falciparum dihydroorotate dehydrogenase to establish their inhibitory activity against Plasmodium falciparum. The best binding conformation of the ligands at the catalytic site of dihydroorotate dehydrogenase are selected to characterize the best bound ligand using the best consensus score and the number of hydrogen bond interactions. The ligand namely (2E)-3-(4-{[1-(3-chloro-4-fluorophenyl)-1H-1, 2, 3-triazol-4-yl]methoxy}-3-methoxyphenyl-1-(2-hydroxy-4,6-dimethoxyphenyl)prop-2-en-1-one, is one the among the five best docked ligands, which interacts with the protein through nine hydrogen bonds and with a consensus score of five. To refine and confirm the docking study results, the stability of complexes is verified using Molecular Dynamics Simulations, Molecular Mechanics /Poisson-Boltzmann Surface Area free binding energy analysis, and per residue contribution for the binding energy. The study implies that the best docked Plasmodium falciparum dihydroorotate dehydrogenase-ligand complex is having high negative binding energy, most stable, compact, and rigid with nine hydrogen bonds. The study provides insight for the optimization of chalcone and flavone hybrids with 1, 2, 3-triazole linkage as potent inhibitors.

In silico analysis reveals the anti-malarial potential of quinolinyl chalcone derivatives.

In this study, the correlation between chemical structures and various parameters such as steric effects and electrostatic interactions to the inhibitory activities of quinolinyl chalcone derivatives is derived to identify the key structural elements required in the rational design of potent and novel anti-malarial compounds. The molecular docking simulations and Comparative Molecular Field Analysis (CoMFA) are carried out on 38 chalcones derivatives using Plasmodium falciparum lactate dehydrogenase (PfLDH) as potential target. Surflex-dock is used to determine the probable binding conformations of all the compounds at the active site of pfLDH and to identify the hydrogen bonding interactions which could be used to alter the inhibitory activities. The CoMFA model has provided statistically significant results with the cross-validated correlation coefficient (q(2)) of .850 and the non-cross-validated correlation coefficient (r(2)) of .912. Standard error of estimation (SEE) is .280 and the optimum number of component is five. The predictive ability of the resultant model is evaluated using a test set comprising of 13 molecules and the predicted r(2) value is .885. The results provide valuable insight for optimization of quinolinyl chalcone derivatives for better anti-malarial therapy.