p21-Activated kinase 4 (PAK4) is a serine/threonine protein kinase that plays important roles in a wide variety of human diseases including cancer. Targeting this kinase with specific inhibitors is of great interest in the treatment of cancer. In this study, PAK4 and its interaction with ATP-competitive inhibitors was investigated by a combined ligand- and structure-based approach. First, a ligand-based pharmacophore model was generated, consisting of five chemical features: a positive ionizable center, two hydrophobic groups, a hydrogen bond donor, and a hydrogen bond acceptor, which is consistent with available SAR information. The characteristics of the active site were then described as a topological region and used in docking of nine selected inhibitors. Combination of the pharmacophore model and results from the docking studies allowed us to weigh the various pharmacophore features and to identify the positive ionizable center as a spacer rather than an essential point. This research led to the proposal of an interaction model inside the PAK4 active site and provided guidance for the design of more potent PAK4 inhibitors.

Inosine 5′-monophosphate dehydrogenase (IMPDH) is a key enzyme in the de novo synthesis of guanosine nucleotides. It is considered as an important target in the quest for drugs in the immunosuppressive, antiviral, antibacterial, and anticancer therapeutic areas. Herein, we report the 3D-QSAR analyses using comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis (CoMSIA) and docking on mycophenolic acid derivates for the first time. We obtained cross-validated q² value of 0.805 for CoMFA and 0.620 for CoMSIA, while the non-cross-validated r² values for them were 0.969 and 0.935, respectively. Based on the CoMFA and CoMSIA contour maps and docking analyses, some key structural factors responsible for inhibitory activity were revealed. The results obtained from this study could be used for the rational design of potent inhibitors against IMPDH.

A series of novel (−)-1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline-1-carboxylic acid derivatives were designed and synthesized. All of the prepared compounds were screened for their neuroprotective effects using an in vitro oxygen glucose deprivation (OGD) model of ischemic stroke. Some of the target compounds exhibited moderate to excellent protective potency. In particular, compounds 9d, 9e, 9g, and 9h showed significant protective effects in the SH-SY₅Y cell line at all three concentrations tested.

A series of 4α/4β-imidazolyl podophyllotoxin analogues have been designed and synthesized. All of the compounds were evaluated for their anticancer activity against a panel of three human cancer cell lines. Within the cell lines tested, some of the synthesized compounds showed promising anticancer activity. Compound 12, in particular, exhibited remarkable cytotoxicity, demonstrating effects against all tumor cell lines, including the K562/ADM cell line.

Inosine 5′-monophosphate dehydrogenase (IMPDH) is a key enzyme in the de novo synthesis of guanosine nucleotides. It is considered an important target in the quest for drugs in the immunosuppressive, antiviral, antibacterial and anticancer therapeutic areas. In this study, a chemical feature-based pharmacophore model of IMPDH inhibitors has been firstly developed with the aid of the HypoRefine protocol within Discovery Studio 2.5. The best model for IMPDH inhibitors, Hypo1-1, was characterized by the best correlation coefficient (0.97595) and the lowest RMSD (0.582058). It consisted of one hydrogen-bond donor, one hydrogen-bond acceptor, one aromatic ring and one hydrophobic feature, as well as two excluded volumes. The model was validated using a wide range of test molecules and a cross-validation. Furthermore, the pharmacophore features were confirmed by molecular docking studies. The pharmacophore model could quantitatively predict inhibitor activity and identify highly potent molecules. Therefore, the present results could be valuable for the discovery and development of specific IMPDH inhibitors.

Resistance to chemotherapeutic drugs has long been a considerable barrier to successful treatment of many cancers and over-expression of glutathione S-transferase P1-1 is correlated to carcinogenesis and resistance of cancer cells against chemotherapeutic agents. This study throws light on the role of chalcone derivatives, a new class of glutathione S-transferase P1-1 inhibitors potentially to overcome glutathione S-transferase P1-1-mediated chemotherapy resistance. Nineteen α-substituted chalcone derivatives were synthesized and their in vitro inhibitory effects on glutathione S-transferase P1-1 were determined. We interestingly found that most of these compounds showed inhibitory effect on glutathione S-transferase P1-1 activity. In addition, molecular field-based similarity analysis provides the necessary three-dimensional molecular field properties of α, β-unsaturated carbonyl derivatives to inhibit glutathione S-transferase P1-1 activity. Thus, these compounds have great potential to be developed into novel chemotherapeutic sensitizers.