Guimin Wang

Eutypenoids A–C: Novel Pimarane Diterpenoids from the Arctic Fungus Eutypella sp. D-1

Eutypenoids A–C (1–3), pimarane diterpenoid alkaloid and two ring A rearranged pimarane diterpenoids, were isolated from the culture of Eutypella sp. D-1 obtained from high-latitude soil of the Arctic. Their structures, including absolute configurations, were authenticated on the basis of the mass spectroscopy (MS), nuclear magnetic resonance (NMR), X-ray crystallography, and electronic circular dichroism (ECD) analysis. The immunosuppressive effects of eutypenoids A–C (1–3) were studied using a ConA-induced splenocyte proliferation model, which suggested that 2 exhibited potent immunosuppressive activities.

X66, a novel N-terminal heat shock protein 90 inhibitor, exerts antitumor effects without induction of heat shock response

Heat shock protein 90 (HSP90) is essential for cancer cells to assist the function of various oncoproteins, and it has been recognized as a promising target in cancer therapy. Although the HSP90 inhibitors in clinical trials have shown encouraging clinical efficacy, these agents induce heat shock response (HSR), which undermines their therapeutic effects. In this report, we detailed the pharmacologic properties of 4-(2-((1H-indol-3-yl)methylene)hydrazinyl)-N-(4-bromophenyl)-6-(3,5- dimethyl-1H -pyrazol-1-yl)-1,3,5-triazin-2-amine (X66), a novel and potent HSP90 inhibitor. X66 binds to the N-terminal domain in a different manner from the classic HSP90 inhibitors. Cellular study showed that X66 depleted HSP90 client proteins, resulted in cell cycle arrest and apoptosis, and inhibition of proliferation in cancer cell lines. X66 did not activate heat shock factor-1 (HSF-1) or stimulate transcription of HSPs. Moreover, the combination of X66 with HSP90 and proteasome inhibitors yielded synergistic cytotoxicity which was involved in X66-mediated abrogation of HSR through inhibition of HSF-1 activity. The intraperitoneal administration of X66 alone depleted client protein and inhibited tumor growth, and led to enhanced activity when combined with celastrol as compared to either agent alone in BT-474 xenograft model. Collectively, the HSP90 inhibitory action and the potent antitumor activity, with the anti-HSR action, promise X66 a novel HSP90-targeted agent, which merits further research and development.

Molecular docking for drug discovery and development: a widely used approach but far from perfect

It is usually the first step to find active compounds from existing chemicals for a drug discovery and development project. Although many pharmaceutical companies have their own libraries that may have millions of compounds, it is costly to maintain the library and to perform high-throughput screening. Virtual screening provides an alternative approach to fulfill the screening of millions of compounds within a few days [1]. Molecular docking is one of the most applied virtual screening methods, especially, when the 3D structure of target protein is available. This method could predict both the binding affinity between ligand and protein and the structure of protein–ligand complex, which is useful information for lead optimization. Indeed, molecular docking has been applied for more than three decades and a great number of new drugs have been discovered and developed accordingly [2]. Although there is no doubt that it will continue to play important role, molecular docking is still far from full success in terms of success rate. This is also the reason why high-throughput screening is still widely applied nowadays in many pharmaceutical companies. Docking-based virtual screening will never have chance to play an irreplaceable role in drug discovery and development until its success rate is essentially improved.

How Do Distance and Solvent Affect Halogen Bonding Involving Negatively Charged Donors

It was reported that negatively charged donors can form halogen bonding, which is stable, especially, in a polar environment. On the basis of a survey of the Protein Data Bank, we noticed that the distance between the negative charge center and the halogen atom of an organohalogen may vary greatly. Therefore, a series of model systems, composed of 4-halophenyl-conjugated polyene acids and ammonia, were designed to explore the potential effect of distance on halogen bonding in different solvents. Quantum mechanics (QM) calculations demonstrated that the longer the distance, the stronger the bonding. The energy decomposition analysis on all of the model systems demonstrated that electrostatic interaction contributes the most (44-56%) to the overall binding, followed by orbital interaction (42-36%). Natural bond orbital calculations showed that electron transfer takes place from the acceptor to the donor, whereas the halogen atom becomes more positive during the bonding, which is in agreement with the result of neutral halogen bonding. QM/molecular mechanics calculations demonstrated that the polarity of binding pockets makes all of the interactions attractive in a protein system. Hence, the strength of halogen bonding involving negatively charged donors could be adjusted by changing the distance between the negative charge center and halogen atom and the environment in which the bonding exists, which may be applied in material and drug design for tuning their function and activity.

Physiological behaviors of Acer mono under drought and low light

The seedlings of Acer mono Maxim. were exposed to two watering regimes (well watered (100% of field capacity) and drought (30% of field capacity)) and two light levels (high light (100% of full sunlight) and low light (15% of full sunlight)) in a greenhouse to assess growth, photosynthesis, and foliar nutrient traits of woody plants under drought and low light. Drought significantly reduced growth and gas exchange characteristics of A. mono, including net photosynthetic rate (PN), stomatal conductance (gs), intercellular CO2 concentration (Ci), and photosynthetic nitrogen use efficiency (PNUE). Also, drought reduced relative water content (RWC) and foliar C and N concentrations, but increased the C/N ratio. PN and C concentration were lower under drought and low light than in any other treatment, indicating that deep shade might seriously decrease C assimilation. However, the negative effect induced by drought was alleviated by improving RWC and maintaining C balance, and therefore low-light seedlings accumulated more biomass than those under high light when they were exposed to drought. Our results showed that trade-off and facilitation effects of drought and low light might be complementary and alter in different species.

Structural insights into HIV-1 protease flap opening processes and key intermediates

HIV-1 protease (PR) is an effective drug target for antiviral inhibitors. The conformational dynamics in the flaps of HIV-1 PR plays a crucial role in the mechanism of substrate binding. Here, the structural properties of the functionally important intermediate states of the flap opening transition of HIV-1 PR have been characterized by enhanced sampling molecular dynamics simulation as well as long-time conventional non-enhanced simulations at atomic level. Not only crystallographically measured “closed” and “semi-open” structures but also a novel “curled” structure of HIV-1 PR is captured by both kinds of simulations qualitatively and quantitatively. The observation of the “curled” intermediate state helps to connect all other functionally important states to provide an integrated view of the transition pathway of the flap opening of HIV-1 PR (closed → curled → semi-open → fully open). The key residue–residue interactions which are broken or formed in the transition are analyzed to reveal the inherent driving force for the protein conformational transition.

Combined Virtual Screening and Substructure Search for Discovery of Novel FABP4 Inhibitors

Fatty acid-binding protein 4 (FABP4, AFABP) is a potential drug target for diabetes and atherosclerosis. In this study, a series of novel FABP4 inhibitors were discovered through combining virtual screening and substructure search. Seventeen compounds exhibited FABP4 inhibitory activities with IC50 < 10 μM, among which 11 compounds showed high selectivity against FABP3. The best compound 36b displayed an IC50 value of 1.5 μM. Molecular docking and point mutation studies revealed that Gln95, Arg126, and Tyr128 play key roles for these compounds binding with FABP4. Interestingly, Gln95 seems to be essential for conformation stability of FABP4. The new scaffolds of these compounds and their interaction mechanisms binding with FABP4 should provide an important clue for the further development of novel FABP4 inhibitors.

Docking-based structural splicing and reassembly strategy to develop novel deazapurine derivatives as potent B-Raf V600E inhibitors

The mutation of B-RafV600E is widespread in a variety of human cancers. Its inhibitors vemurafenib and dabrafenib have been launched as drugs for treating unresectable melanoma, demonstrating that B-RafV600E is an ideal drug target. This study focused on developing novel B-RafV600E inhibitors as drug leads against various cancers with B-RafV600E mutation. Using molecular modeling approaches, 200 blockbuster drugs were spliced to generate 283 fragments followed by molecular docking to identify potent fragments. Molecular structures of potential inhibitors of B-RafV600E were then obtained by fragment reassembly followed by docking to predict the bioactivity of the reassembled molecules. The structures with high predicted bioactivity were synthesized, followed by in vitro study to identify potent B-RafV600E inhibitors. A highly potent fragment binding to the hinge area of B-RafV600E was identified via a docking-based structural splicing approach. Using the fragment, 14 novel structures were designed by structural reassembly, two of which were predicted to be as strong as marketed B-RafV600E inhibitors. Biological evaluation revealed that compound 1m is a potent B-RafV600E inhibitor with an IC50 value of 0.05 μmol/L, which was lower than that of vemurafenib (0.13 μmol/L). Moreover, the selectivity of 1m against B-RafWT was enhanced compared with vemurafenib. In addition, 1m exhibits desirable solubility, bioavailability and metabolic stability in in vitro assays. Thus, a highly potent and selective B-RafV600E inhibitor was designed via a docking-based structural splicing and reassembly strategy and was validated by medicinal synthesis and biological evaluation.