Computational Studies of the Active and Inactive Regulatory Domains of Response Regulator PhoP Using Molecular Dynamics Simulations.

The response regulator PhoP is part of the PhoP/PhoQ two-component system, which is responsible for regulating the expression of multiple genes involved in controlling virulence, biofilm formation, and resistance to antimicrobial peptides. Therefore, modulating the transcriptional function of the PhoP protein is a promising strategy for developing new antimicrobial agents. There is evidence suggesting that phosphorylation-mediated dimerization in the regulatory domain of PhoP is essential for its transcriptional function. Disruption or stabilization of protein-protein interactions at the dimerization interface may inhibit or enhance the expression of PhoP-dependent genes. In this study, we performed molecular dynamics simulations on the active and inactive dimers and monomers of the PhoP regulatory domains, followed by pocket-detecting screenings and a quantitative hot-spot analysis in order to assess the druggability of the protein. Consistent with prior hypothesis, the calculation of the binding free energy shows that phosphorylation enhances dimerization of PhoP. Furthermore, we have identified two different putative binding sites at the dimerization active site (the α4-ß5-α5 face) with energetic "hot-spot" areas, which could be used to search for modulators of protein-protein interactions. This study delivers insight into the dynamics and druggability of the dimerization interface of the PhoP regulatory domain, and may serve as a basis for the rational identification of new antimicrobial drugs.

Retrieving novel C5aR antagonists using a hybrid ligand-based virtual screening protocol based on SVM classification and pharmacophore models.

C5aR antagonists have been thought as potential immune mediators in various inflammatory and autoimmune diseases, and discovery of C5aR antagonists has attracted much attention in recent years. The discovery of C5aR antagonists was usually achieved through high-throughput screening, which usually suffered a high cost and a low success rate. Currently, the fast developing computer-aided virtual screening (VS) methods provide economic and rapid approaches to the lead discovery. In this account, we proposed a hybrid ligand-based VS protocol that is based on support vector machine (SVM) classification and pharmacophore models for retrieving novel C5aR antagonists. Performance evaluation of this hybrid VS protocol in virtual screening against a large independent test set, T-CHEM, showed that the hybrid VS approach significantly increased the hit rate and enrichment factor compared with the individual SVM classification model-based VS and pharmacophore model-based VS, as well as molecular docking-based VS in that the receptor structure was created by homology modeling. The hybrid VS approach was then used to screen several large chemical libraries including PubChem, Specs, and Enamine. Finally, a total of 20 compounds were selected from the top ranking hits, and shifted to the subsequent in vitro and in vivo studies, which results will be reported in the near future.

Synthesis and biological evaluation of novel N-methyl-picolinamide-4-thiol derivatives as potential antitumor agents.

A novel series of N-methylpicolinamide-4-thiol derivatives were synthesized and evaluated on human cancer cell lines. Among them, compound 6p displayed potent and broad-spectrum anti-proliferative activities in vitro on some human cancer cell lines, even better than sorafenib. The advanced kinase inhibitory assays showed that compound 6p could selectively inhibit Aurora-B kinase. The biological results were rationalized by the molecular docking study, which indicated the stable interactions of 6p with the Aurora-B kinase.

6-Chloro-3-nitro-N-(propan-2-yl)pyridin-2-amine.

There are two mol-ecules in the asymmetric unit mol-ecule of the title compound, C(8)H(10)ClN(3)O(2). Intra-molecular N-H⋯O hydrogen bonds stabilize the mol-ecular structure. There are no classical inter-molecular hydrogen bonds in the crystal structure.

4-{[4-(3,5-Dimeth-oxy-benzamido)-phen-yl]sulfan-yl}-N-methyl-pyridine-2-carboxamide.

There are two independent mol-ecules in the asymmetric unit of the title compound, C(22)H(21)N(3)O(4)S. The central benzene ring makes dihedral angles of 74.28 (6) and 68.84 (6)° with the pyridine and 3,5-dimeth-oxy-phenyl rings, respectively, in one molecule [86.66 (6) and 81.14 (6)° respectively, in the other]. Each of the mol-ecules forms a centrosymmetric dimer with another mol-ecule via pairs of inter-molecular N-H⋯O hydrogen bonds. These hydrogen bonds connect the N-H groups and the O atoms of the carbonyl groups next to the 3,5-dimeth-oxy-phenyl rings. Additional inter-molecular N-H⋯O inter-actions link the dimers in the crystal structure.