In the present study, 3D QSAR pharmacophore models were undertaken from a set of 16 colchicine binding site inhibitors (CSIs). The best pharmacophore model possessing two chemical features (hydrogen-bond acceptor and hydrophobic) showed an excellent correlation coefficient for the training (\(r_{\text{training}} = 0.96\)) and a fair correlation coefficient for the test set (\(r_{\text{test}} = 0.88\)) molecules. Considering the statistically significant results of the best pharmacophore model, the hypothesis was selected as a 3D structural query to screen the Maybridge and MiniMaybridge database. Ultimately, three of the hit molecules satisfied all of these conditions, which were then submitted to molecular docking studies to evaluate their optimal orientations and their interactions with the critical residues of tubulin. The molecules showed strong hydrogen-bond interactions as well as hydrophobic contacts with critical residues such as β:Tyr376, β:Ile378, Tyr48, and Ser178. As indicated above, the hit three molecules can be good candidates for the CSIs. And the developed pharmacophore model can be used to determine the essential structural requirements, thus as a valuable tool to select the novel compounds based on virtual screening approach.

Two kinds of core–shell structured multifunctional nanocarriers of gold nanoclusters (Au NCs) as core and folate (FA)-conjugated amphiphilic hyperbranched block copolymer as shell based on poly(l-lactide) (PLA) inner arm and FA-conjugated sulfated polysaccharide (GPPS–FA) outer arm (Au NCs-PLA-GPPS-FA) were synthesized for targeted anticancer drug delivery. The structure and properties of Au NCs-PLA-GPPS-FA copolymers were characterized and determined by 1H NMR spectrum, FT-IR spectra, dynamic light scattering (DLS), fluorescence spectroscopy, and transmission electron microscopic (TEM) analyses. The anticancer drug, camptothecin (CPT) was used as a hydrophobic model anticancer drug. In vitro, two kinds of the nanocarriers presented a relatively rapid release in the first stage (up to 1 h) followed by a sustained release period (up to 15 h), and then reached a plateau at pH 5.3, 7.4, and 9.6. The release results indicated that CPT release from two kinds of the nanocarriers at pH 9.6 was much greater than that at both pH 5.3 and 7.4. The cytotoxicity studies showed that the CPT-loaded nanocarriers provided high anticancer activity against Hela cells. Furthermore, nanocarriers gained specificity to target some cancer cells because of the enhanced cell uptake mediated by FA moiety. The fluorescent images studies showed that the nanocarriers could track at the cellular level for advance therapy. The results indicated that the Au NCs-PLA-GPPS-FA copolymers not only had great potential as tumor-targeted drug delivery carrier, but also had an assistant role in the treatment of cancer.Keywords: Au NCs; cytotoxicity; drug delivery; nanocarriers;

A series of eight novel podophyllotoxin derivatives were designed, synthesized and evaluated for biological activities. The antiproliferative activities were tested against a panel of human cancer cell lines (K562, SGC, Hela and HepG) and the inhibition of tubulin polymerization was also evaluated. Compound 8e displayed significant antiproliferative activities for all four cell lines and strong levels of tubulin polymerization inhibition effect. Combined with cell apoptosis and cell cycle analysis, it demonstrated that compound 3e that effectively interfere with tubulin dynamics prevent mitosis in cancer cells, leading to cell cycle arrest and, eventually dose dependent apoptosis. All experimental measurements were also supported by molecular docking simulations of colchicine binding site, which revealed the governing forces for the binding behavior and a good relationship with anti-tubulin activity and antiproliferative activities. The synthesis and biological studies provided an interesting new class of antitubulin agents for development of lead compounds and also a direction for further structure modification to obtain more potent anti-cancer drugs.

•Novel peptide mimetics that bind and activate c-Mpl receptor were identified, synthesized and tested for biological activities.•TPO receptor was modeled and an atomic-level look at the protein-peptide dynamics was conducive to understand key molecular mechanisms and structural features responsible for peptide binding.•Hydrophobic interaction was the driven positive forces for the interaction and the larger distances between the centroids of the P-Helix and P'-Helix, togather with the bigger surface area and volume of peptides generally did great favor to the binding behavior.Thrombopoietin (TPO) acts in promoting the proliferation of hematopoietic stem cells and by initiating specific maturation events in megakaryocytes. Now, TPO-mimetic peptides with amino acid sequences unrelated to TPO are of considerable pharmaceutical interest. In the present paper, four new TPO mimetic peptides that bind and activate c-Mpl receptor have been identified, synthesized and tested by Dual-Luciferase reporter gene assay for biological activities. The molecular modeling research was also approached to understand key molecular mechanisms and structural features responsible for peptide binding with c-Mpl receptor. The results presented that three of four mimetic peptides showed significant activities. In addition, the molecular modeling approaches proved hydrophobic interactions were the driven positive forces for binding behavior between peptides and c-Mpl receptor. TPO peptide residues in P7, P13 and P7′ positions were identified by the analysis of hydrogen bonds and energy decompositions as the key ones for benefiting better biological activities. Our data suggested the synthesized peptides have considerable potential for the future development of stable and highly active TPO mimetic peptides.