Current Issue : January - March Volume : 2014 Issue Number : 1 Articles : 5 Articles
Background: Tremendous research from last twenty years has been pursued to cure human life against HIV virus. A\r\nlarge number of HIV protease inhibitors are in clinical trials but still it is an interesting target for researchers due to\r\nthe viral ability to get mutated. Mutated viral strains led the drug ineffective but still used to increase the life span\r\nof HIV patients.\r\nResults: In the present work, 3D-QSAR and docking studies were performed on a series of Danuravir derivatives,\r\nthe most potent HIV- protease inhibitor known so far. Combined study of 3D-QSAR was applied for Danuravir\r\nderivatives using ligand-based and receptor-based protocols and generated models were compared. The results\r\nwere in good agreement with the experimental results. Additionally, docking analysis of most active 32 and least\r\nactive 46 compounds into wild type and mutated protein structures further verified our results. The 3D-QSAR and\r\ndocking results revealed that compound 32 bind efficiently to the wild and mutated protein whereas, sufficient\r\ninteractions were lost in compound 46.\r\nConclusion: The combination of two computational techniques would helped to make a clear decision that\r\ncompound 32 with well inhibitory activity bind more efficiently within the binding pocket even in case of mutant\r\nvirus whereas compound 46 lost its interactions on mutation and marked as least active compound of the series.\r\nThis is all due to the presence or absence of substituents on core structure, evaluated by 3D-QSAR studies. This set\r\nof information could be used to design highly potent drug candidates for both wild and mutated form of viruses....
Histone deacetylase inhibitors (HDAC is) has emerged as effective current cancer therapy drug targets. Molecular\r\ndocking studies of hydroxamates, biphenyl (Part-I knowledge all contains thirty two molecules in conjunction with customary\r\nMS-275 for validation of results) and newly designed indole spinoff and its analogues (Part-II knowledge all contains eighteen\r\ncompounds) by mistreatment HDAC8-human protein and its protein data bank (pdb) id: 1T69 are meted out consecutively to\r\nseek out the foremost vigorous malignant tumor HDACI. Maestro software package has been used for docking studies. The\r\nhighest most lead compound relevant to activity has been known on the premise of sturdy interactions and IC50 price of the\r\nchosen compounds. Six structural analogues have additionally been designed from the lead compound....
Background: Mitogen-activated protein kinase-activated protein kinase 5 (MK5) is\r\ninvolved in one of the major signaling pathways in cells, the mitogen-activated\r\nprotein kinase pathway. MK5 was discovered in 1998 by the groups of Houng Ni\r\nand Ligou New, and was found to be highly conserved throughout the vertebrates.\r\nStudies, both in vivo and in vitro, have shown that it is implicated in tumor\r\nsuppression as well as tumor promotion, embryogenesis, anxiety, locomotion,\r\ncell motility and cell cycle regulation.\r\nMethods: In order to obtain a molecular model of MK5 that can be used as a\r\nworking tool for development of chemical probes, three MK5 models were\r\nconstructed and refined based on three different known crystal structures of the\r\nclosely related MKs; MK2 [PDB: 2OZA and PDB: 3M2W] and MK3 [PDB: 3FHR]. The\r\nmain purpose of the present MK5 molecular modeling study was to identify the best\r\nsuited template for making a MK5 model. The ability of the generated models to\r\neffectively discriminate between known inhibitors and decoys was analyzed using\r\nreceiver operating characteristic (ROC) curves.\r\nResults: According to the ROC curve analyzes, the refined model based on 3FHR\r\nwas most effective in discrimination between known inhibitors and decoys.\r\nConclusions: The 3FHR-based MK5 model may serve as a working tool for\r\ndevelopment of chemical probes using computer aided drug design. The biological\r\nfunction of MK5 still remains elusive, but its role as a possible drug target may be\r\nelucidated in the near future....
Cobalamins are the largest and structurally complex cofactors found in biological systems and have attracted considerable attention\r\ndue to their participation in the metabolic reactions taking place in humans, animals, and microorganisms. Riboflavin (vitamin B2)\r\nis a micronutrient and is the precursor of coenzymes, FMN and FAD, required for a wide variety of cellular processes with a key\r\nrole in energy-based metabolic reactions. As coenzymes of both vitamins are the part of enzyme systems, the possibility of their\r\nmutual interaction in the body cannot be overruled. A molecular docking study was conducted on riboflavin molecule with B12\r\ncoenzymes present in the enzymes glutamate mutase, diol dehydratase, and methionine synthase by using ArgusLab 4.0.1 software\r\nto understand the possible mode of interaction between these vitamins. The results fromArgusLab showed the best binding affinity\r\nof riboflavin with the enzyme glutamate mutase for which the calculated least binding energy has been found to be -7.13 kcal/mol.\r\nThe results indicate a significant inhibitory effect of riboflavin on the catalysis of B12-dependent enzymes. This information can be\r\nutilized to design potent therapeutic drugs having structural similarity to that of riboflavin....
Background: Schizophrenia is a neurodegenerative disorder that occurs worldwide\r\nand can be difficult to diagnose. It is the foremost neurological disorder leading to\r\nsuicide among patients in both developed and underdeveloped countries. D-amino\r\nacid oxidase activator (DAOA), also known as G72, is directly implicated in the\r\nglutamateric hypothesis of schizophrenia. It activates D-amino acid oxidase, which\r\noxidizes D-serine, leading to modulation of the N-methyl-D-aspartate receptor.\r\nMethods: MODELLER (9v10) was utilized to generate three dimensional structures of\r\nthe DAOA candidate gene. The HOPE server was used for mutational analysis. The\r\nMolecular Evolutionary Genetics Analysis (MEGA5) tool was utilized to reconstruct the\r\nevolutionary history of the candidate gene DAOA. AutoDock was used for\r\nprotein-ligand docking and Gramm-X and PatchDock for protein-protein docking.\r\nResults: A suitable template (1ZCA) was selected by employing BLASTp on the basis\r\nof 33% query coverage, 27% identity and E-value 4.9. The Rampage evaluation tool\r\nshowed 91.1% favored region, 4.9% allowed region and 4.1% outlier region in DAOA.\r\nERRAT demonstrated that the predicted model had a 50.909% quality factor.\r\nMutational analysis of DAOA revealed significant effects on hydrogen bonding and\r\ncorrect folding of the DAOA protein, which in turn affect protein conformation.\r\nCiona was inferred as the outgroup. Tetrapods were in their appropriate clusters with\r\nbifurcations. Human amino acid sequences are conserved, with chimpanzee and\r\ngorilla showing more than 80% homology and bootstrap value based on 1000\r\nreplications. Molecular docking analysis was employed to elucidate the binding\r\nmode of the reported ligand complex for DAOA. The docking experiment\r\ndemonstrated that DAOA is involved in major amino acid interactions: the residues\r\nthat interact most strongly with the ligand C28H28N3O5PS2 are polar but uncharged\r\n(Gln36, Asn38, Thr 122) and non-polar hydrophobic (Ile119, Ser171, Ser21, Ala31).\r\nProtein-protein docking simulation demonstrated two ionic bonds and one\r\nhydrogen bond involving DAOA. Lys-7 of the receptor protein interacted with\r\nLys-163 and Asp-2037. Tyr-03 interacted with Arg-286 of the ligand protein and\r\nformed a hydrogen bond....
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