Current Computer - Aided Drug Design - Volume 11, Issue 1, 2015

Nerve impulses travel along myelinated axons as much as 300-fold faster than they do along unmyelinated axons. Myelination is essential for normal nervous system behavior in vertebrates as illustrated by leukodystrophies, such as amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS), where myelin is degenerated or damaged. The increased conduction velocity that occurs in myelinated axons is dependent on gaps in the myelin called Nodes of Ranvier that are enriched in ion channels. These Nodes are separated by long stretches of myelin insulation where no transmembrane ion conductance occurs. It is believed that the action potential jumps or skips between nodes, conserving its information content, while maintaining its speed. In this study, a model is presented that implicates Nodes of Ranvier as responsible for regenerating the proton hopping that is responsible for nerve impulse conductance in myelinated axons.

Candida albicans is one of the most important causes of life-threating fungal infections. Lanosterol 14α-demethylase (Cytochrome P450DM) is the target enzyme of azole antifungal agents. The study involved selection and modeling of the target enzyme followed by refinement of the model using molecular dynamic simulation. The modeled structure of enzyme was validated using Ramachandran plot and Sequence determination technique. A series of chlorosubstituted imidazole analogues were evaluated for Cytochrome P450 inhibitory activity using molecular docking studies. The imidazole analogues were prepared using Chem sketch and molecular docking was performed using Molergo Virtual Docker program. The docking study indicated that all the imidazole analogues (AN1-AN45) and standard drugs i.e., Ketoconazole, Clotrimazole and Miconazole have interaction with protein residue of 14α-demethylase, Heme cofactor and the water molecules present in the active site.

In view of the serious health problems concerning infectious diseases in heavily populated areas, we followed the strategy of lead compound diversification to evaluate the near-by chemical space for new organic compounds. To this end, twenty derivatives of nitazoxanide (NTZ) were synthesized and tested for activity against Entamoeba histolytica parasites. To ensure drug-likeliness and activity relatedness of the new compounds, the synthetic work was assisted by a quantitative structure-activity relationships study (QSAR). Many of the inherent downsides – well-known to QSAR practitioners – we circumvented thanks to workarounds which we proposed in prior QSAR publication. To gain further mechanistic insight on a molecular level, ligand-enzyme docking simulations were carried out since NTZ is known to inhibit the protozoal pyruvate ferredoxin oxidoreductase (PFOR) enzyme as its biomolecular target.

The protein structure prediction is of three categories: homology modeling, fold recognition and ab initio modeling, and this division into categories depends on whether similar protein structures were previously determined using X-ray crystallography or NMR or not. Protein structure models predicted by the free modeling (ab initio modeling) are considered as low-resolution models. Progress has recently been made in refining low-resolution models (ab initio modeling) closer to the native ones; this can be done by minimizing the energy funnel of physics-based force fields. In this paper, we present a new refinement method based on applying minimum spanning tree to produce a connected graph from the atoms forming the protein. This connected graph represents the minimum van der Waals energy path. The new refinement method causes supplementary execution time (about 55.83486 sec. in the average for a protein sequence of length 166 amino acids) but enhance the predicted model of low resolution. We used a small set of 18 different targets got from CASP10. The results show the improvement in about (83.333%) of the cases. We compare our results with stateof- art algorithms results.

The search for newer cytotoxic agents has taken many paths in the recent years and in fact some of these efforts led to the discovery of some potent cytotoxic agents. Though the vast number of targets of tumor progression has been identified recently, kinases remained key targets in drug design. It is well established that inhibition of JNK1, a serine/threonine protein kinase delays tumor formation. Poly hydroxylated chromenone analog, quescetagetin, inhibits JNK1. As a part of design of coumarin based JNK1 inhibitors, docking studies and 4D QSAR studies were carried out. 3- pyrazolyl substituted coumarin derivatives were chosen for these studies. Docking studies revealed that 3-pyrazolyl substituted coumarins make key interactions with residues at active site of JNK1. In order to investigate the structural features required in these inhibitors, 4D QSAR studies using LQTAgrid module were carried out. The 4D QSAR model built with PLS regression on the matrix of variables specific for interaction energies at each grid point around the molecular dynamics generated conformations of individual compounds shows good predictive abilities. The squared correlation coefficient, R2 for the model is 0.785, R2 cross-validated (Q2) is 0.698, R2 predicted is 0.701. Most of the descriptors contributing to 4D QSAR model are Coulombic potential energy based descriptors which highlight the importance of specific atoms in coumarin derivatives in generating these electrostatic potential at specific grid points with the -NH3 probe. We rationalize that solvent accessible van der Waals surface area around such compounds is good measure of this Coulombic potential energy and can be exploited in designing more active compounds.

Pharmacophore models of G protein-coupled receptor40 (GPR40) agonists were developed using Discovery Studio V2.1. One hydrogen bond acceptor and three hydrophobic features, Hypo 1 which was the best hypothesis, had a correlation co-efficient of 0.971, cost difference of 73.041, and RMSD 0.680. This model was validated by test set, Fischer randomization test and decoy set. Subsequently, Hypo 1 was employed as a 3D query to identify potent molecules from chembridge database. 21 compounds were identified with estimated EC50 less than 500 nM. Seven top-scored hit compounds were chosen for further evaluation in FLIPR assay and two compounds were discovered as potent GPR40 agonists.

Diabetes accounts for high mortality rate worldwide affecting million of lives annually. Global prevalence of diabetes and its rising frequency makes it a key area of research in drug discovery programs. The research article describes the development of quantitative structure activity relationship model against PPARγ, a promising drug target for diabetes. Multiple linear regression approach was adopted for statistical model development and the QSAR relationship suggested the regression coefficient (r2) of 0.84 and the cross validation coefficient (rCV2) of 0.77. Further, the study suggested that chemical descriptors viz., dipole moment, electron affinity, dielectric energy, secondary amine group count and LogP correlated well with the activity. The docking studies showed that most active gymnemic acid analogues viz., gymnemasin D and gymnemic acid VII possess higher binding affinity to PPARγ. QSAR and ADMET studies based other predicted active gymnemc acid analogues were gymnemic acid I, gymnemic acid II, gymnemic acid III, gymnemic acid VIII, gymnemic acid X, gymnemic acid XII, gymnemic acid XIV, gymnemic acid XVIII and gymnemoside W2. Predicted activity results of three query compounds were found comparable to experimental in vivo data. Oral bioavailability of these active analogues is still a limiting factor and therefore further lead optimization required. Also, such study would be of great help in active pharmacophore discovery and lead optimization, and offering new insights into therapeutics for diabetes mellitus.

Induction of apoptosis by the activation of caspase 3 makes it a promising target for designing anticancer drugs hence an investigation for the essential structural features mandatory for caspase 3 activation has been carried out using a dataset comprising of caspase 3 activator candidate drug Azixa in phase II clinical trial and its analogs using DS2.0. A training set of 40 compounds was selected for the purpose of model generation from 76 molecules with an activity range spanning from 0.002μM to 6.9μM. Among the generated pharmacophore models, the best model Hypo1 constituted by two hydrophobic aliphatic (Hal), two hydrophobic aromatic (Har), and one hydrogen bond acceptor (HBA) features with a correlation coefficient of 0.85, and a cost difference (null cost – total cost) of 46 bits well predicted the test set of 36 compounds (Rpred = 0.8). The key mechanism conferring caspase 3 activation is due to binding of Azixa at β-tubulin site that is located close to or at same site as colchicine. In the absence of co-crystal structure we have proposed a binding mode of Azixa at the tubulin site by performing docking studies and performed molecular dynamics simulation to ascertain the temporal changes of the protein-ligand complex.

Dengue virus (DENV) is the member of Flaviviridae and causative agent of Dengue Haemorrhagic Fever and Dengue Shock Syndrome. Every year, around 70% of the world population is at risk, due to epidemic episodes orchestrated by one or more of its serotypes. So, a tetravalent DENV vaccine is needed which may induce the immune response against all four DENV serotypes. In this study, B-cell and T-cell epitopes have been predicted from the DENV envelope glycoprotein (Eg) using a consensus based approach in complement with the physico-chemical property (PCP) conservancy analysis. Through DENV-Eg analysis, a total of 7 PCP conserved, water soluble, in vitro and in vivo stable epitopes were predicted which may induce the B-cell and T-cell mediated anti-viral immune response.