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Upregulated phosphodiesterase 4D (PDE4D) disrupts the regulation of calcium ion channel in the central nerve system, and hence it is considered as one of the causes of Alzheimer's disease. We employed structure-based drug design techniques and the world's largest traditional Chinese medicine (TCM) database for identifying potential TCM-based PDE4D inhibitors. We then applied multiple linear regression (MLR) and support vector machine (SVM) for quantitative structure–activity relationship model, as well as for molecular dynamics simulation analysis. Screening results suggested that metal cations, Zn2+ and Mg2+, played key roles in mediating stable protein–ligand interactions with the ligand-binding residues, Asp367 and Asp484. In addition, each ligand was shown to interfere with the active residue His326 that suggested inhibitory effects. The MLR and SVM prediction models further implied the PDE4D inhibitory effect of each TCM compound. The molecular simulation further suggested the binding stability of ea...

Human epidermal growth factor receptor type 2 (HER2) overexpression, which has been reported to increase the malignancy of human ovarian cancer cells and the metastatic potential of human breast cancer cells, is an important factor in tumour formation and tumour growth. However, currently available HER2 inhibitors, such as Lapatinib, for cancer therapy cause adverse side effects including diarrhoea, rash and possible liver toxicity. We hoped to find novel agents that cause less adverse side effects by performing virtual screening process on the world's largest traditional Chinese medicine compound database. The results thus obtained were then validated using 3D quantitative structure–activity relationship model. Top three candidates were selected from the docking results. The top three candidates and the control both formed a hydrogen bond with the key residue, Lys724. This showed that the candidates and the control have similar binding effects to HER2. These candidates were investigated using comparative...

In search for novel anti-tumour agents targeting non-homologous end joining pathway, we conducted a virtual screening using traditional Chinese medicine (TCM) on Ku heterodimer which plays an important role on DNA break repair system. Docking results gave glycyrrhizic acid and macedonoside C as potential TCM candidates. Both glycyrrhizic acid and macedonoside C were docked onto the Ku heterodimer with high-predicted binding affinities as evidenced in their Dock Score. These two ligands also interact with key residues which have been previously shown to influence Ku DNA-binding affinity. Both compounds show consistent hydrogen bonding interactions with key residues throughout the 10- ns dynamics simulation run. Furthermore, glycyrrhizic acid and macedonoside C are able to form additional hydrogen bond interactions with positively charged Ku heterodimer surface. Such interactions strengthen the binding interaction of the top two TCM compounds with Ku heterodimer. Glycyrrhizic acid and macedonoside C are pro...

Human XRCC4 protein is a key component of DNA double-strand break (DSB) repair pathway related to the diseases of stroke and cancer. Cancer cells being treated with the drugs that interfere with DSBs repair mechanism have shown increased radiosensitivity to ionising radiation. Therefore, the development of novel radiosensitiser for radiation therapy becomes important for cancer treatment. We screened from the world's largest traditional Chinese medicine (TCM) database and found potential TCM molecules that can dock at XRCC4 functional site. Among the selected potential TCM compounds, we specifically investigated the top-ranked molecules: glycyrrhizic acid and macedonoside C. The molecular docking and molecular dynamics simulations on these compounds show similar location with high predicted binding affinity. Both compounds form continuous interaction with Lys188 and Arg192 of chain C and Lys187 and Lys190 of chain D. All these protein residues are required to form key hydrophobic interactions with other c...

Microsomal prostaglandin E synthase-1 (mPGES-1) has been regarded as an attractive drug for inflammation-related diseases. In search of new mPGES-1 inhibitors, we performed virtual screening using our traditional Chinese medicine and natural products database (http://tcm.cmu.edu.tw/) and constructed comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) using a training set of 30 experimentally tested mPGES-1 inhibitors. The CoMFA and CoMSIA models derived were statistically significant with cross-validated coefficient values of 0.808 for CoMFA and 0.829 for CoMSIA and non-cross-validated coefficient values of 0.829 for CoMFA and 0.980 for CoMSIA. Docking and de novo evolution design gave three top derivatives, 2-O-caffeoyl tartaric acid-Evo_2, glucogallin-Evo_1 and 3-O-feruloylquinic acid-Evo_7 that have higher binding affinities than the control, glutathione. These three derivatives have interactions with Arg70, Arg73, Arg110, Arg126 and Arg38, which ...

The recent H1N1 (swine) influenza pandemic highlighted the urgent need of having effective anti‐viral strategies. In addition to neuraminidase inhibitors, there is another class of anti-viral drug known as M2 inhibitors that were, in the past, effective in treating seasonal influenza. However, due to the emergence of M2 inhibitor‐resistant influenza viruses, this class of drugs was not recommended for clinical usage in the latest influenza pandemic. In order to identify novel M2 inhibitors, we have performed molecular docking using a traditional Chinese medicine database (http://tcm.cmu.edu.tw/index.php). Docking and subsequent de novo designs gave 10 derivatives that have much better docking results than the control. Of these 10 derivatives, the top three, methyl isoferulate_1, genipin_1 and genipin_2, were selected for molecular dynamics simulation. During the simulation run, the top three derivatives all had stable interactions with M2 residues, Ser31 and Ala30. Methyl isoferulate_1 also has stable int...