Xiliang Zheng

Pocket-Based Drug Design: Exploring Pocket Space

The identification and application of druggable pockets of targets play a key role in in silico drug design, which is a fundamental step in structure-based drug design. Herein, some recent progresses and developments of the computational analysis of pockets have been covered. Also, the pockets at the protein–protein interfaces (PPI) have been considered to further explore the pocket space for drug discovery. We have presented two case studies targeting the kinetic pockets generated by normal mode analysis and molecular dynamics method, respectively, in which we focus upon incorporating the pocket flexibility into the two-dimensional virtual screening with both affinity and specificity. We applied the specificity and affinity (SPA) score to quantitatively estimate affinity and evaluate specificity using the intrinsic specificity ratio (ISR) as a quantitative criterion. In one of two cases, we also included some applications of pockets located at the dimer interfaces to emphasize the role of PPI in drug discovery. This review will attempt to summarize the current status of this pocket issue and will present some prospective avenues of further inquiry.

A Self-Powered and Reusable Biocomputing Security Keypad Lock System Based on Biofuel Cells

Recently, the combination of unconventional chemical logic gates and logic circuits has been used for developing a keypad lock based on an unconventional chemical system, which is an attractive research direction in the area of unconventional chemical computing and offers a new approach for protecting information. Such unconventional chemical computing devices can distinguish between the sequences of different chemical inputs. Despite the promising future for an unconventional chemical keypad lock, there are only a few reports to date and the reported devices are only designed based on luminescent complexes. In addition to the unconventional chemical keypad lock, the biocomputing keypad lock has been constructed recently. However, the biocomputing keypad locks are relatively rare and no RESET function was reported, which would limit their development, especially for practical applications. Considerable interest has been recently directed towards biofuel cells (BFCs) because of their distinct properties and potential applications, mainly benefiting from the utilization of enzymes and microbes as the biocatalysts and biomass as the biofuel to convert chemical energy into electric energy. For instance, the uses of biocatalysts for catalyzing the oxidation of the biofuels essentially enable the BFCs to work under mild conditions, such as ambient temperature and neutral pH. On the other hand, the uses of biomass, such as glucose, endogenously existing in the biological systems suggests potential applications of the BFCs as a type of implantable power sources for bioelectronics, including micropumps, pacemakers, and neuromorphic circuits. In addition to major research activity relating to long-term operation, miniaturization, and power efficiency of BFCs, some interesting results were recently reported for BFCs with logically controlled power release by biocomputing. Biocomputing is a subarea of unconventional chemical computing and ranges from application of biomolecules (proteins, enzymes, and DNA) to the use of whole biological cells for processing biochemical signals in a digital form according to Boolean logic operations. Due to the highly specific catalytic or recognition reactions designed by nature, biocomputing can easily solve the interference limitation of chemical computing resulting from the incompatibility in most chemical systems. Herein, we report a novel BFC-based biocomputing security system mimicking a keypad lock device, depending on the enzyme-based parameters as the “readin” and the open circuit potential of the BFC as the “readout”, which permits the biocomputing security system to be self-powered and reusable. By combining BFCs with biocomputing security system, their application might significantly enhance the adaptability of the keypad lock to future self-powered security bioelectronic devices. In addition, we performed a global study and found that maximizing the dimensionless ratio of gap versus standard deviation of the open circuit potential spectrum (a funnel in open-circuit potentials) gives the quantitative optimal design criterion. Thus, our construction reported herein may provide a practical example and microscopic structural basis for mimicking the real biomolecular and network systems and bridge the gaps between the theoretical concepts and experiments important for biomolecular systems and synthetic biology. The BFC-based self-powered and reusable biocomputing security system was developed on the basis of a glucose/O2 BFC reported by us recently with a minor modification (see details in the Supporting Information). A bioanode formed by the immobilization of glucose dehydrogenase (GDH; E.C. 1.1.3.4, from Thermoplasma acidophilum, re[a] M. Zhou, X. Zheng, Prof. J. Wang, Prof. S. Dong State Key Laboratory of Electroanalytical Chemistry Changchun Institute of Applied Chemistry Chinese Academy of Sciences Changchun 130022 (P.R. China) Fax: (+86) 431-85262101 E-mail : dongsj@ciac.jl.cn [b] Prof. J. Wang Department of Chemistry and Department of Physics State University of New York at Stony Brook Stony Brook, New York 11794 (USA) Fax: (+1) 631-6327960 E-mail : jin.wang.1@stonybrook.edu Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201000619.

Influence of the deposition time of barrier layers on optical and structural properties of high-efficiency green-light-emitting InGaN∕GaN multiple quantum wells

We reported the effect of the deposition time of barrier layers on optical and structural properties of high-efficiency green-light-emitting InGaN∕GaN multiple quantum wells (MQWs) by photoluminescence (PL) and high-resolution x-ray diffraction techniques. The MQW samples on (0001)-plane sapphire substrates were prepared with a ramping method by metalorganic chemical deposition. It was found that the structural or interface quality of the MQW system improved as the deposition time of barrier layers increased from 10 to 14min, but lattice relaxation was still observed. The relaxation degree decreases from 33% to 6% as the deposition time increases. Temperature-dependent PL measurements from 12 to 300K indicated that the integrated PL intensities start to decay rapidly as temperature rises above 50K for the sample with the shorter deposition time, and above 100K for the sample with the longer deposition time. The luminescence thermal quenching of the two samples suggests the two nonradiative recombination c...

Affinity and Specificity of Levamlodipine-Human Serum Albumin Interactions: Insights into Its Carrier Function

The affinity and specificity of drugs with human serum albumin (HSA) are crucial factors influencing the bioactivity of drugs. To gain insight into the carrier function of HSA, the binding of levamlodipine with HSA has been investigated as a model system by a combined experimental and theoretical/computational approach. The fluorescence properties of HSA and the binding parameters of levamlodipine indicate that the binding is characterized by one binding site with static quenching mechanism, which is related to the energy transfer. As indicated by the thermodynamic analysis, hydrophobic interaction is the predominant force in levamlodipine-HSA complex, which is in agreement with the computational results. And the hydrogen bonds can be confirmed by computational approach between levamlodipine and HSA. Compared to predicted binding energies and binding energy spectra at seven sites on HSA, levamlodipine binding HSA at site I has a high affinity regime and the highest specificity characterized by the largest intrinsic specificity ratio (ISR). The binding characteristics at site I guarantee that drugs can be carried and released from HSA to carry out their specific bioactivity. Our concept and quantification of specificity is general and can be applied to other drug-target binding as well as molecular recognition of peptide-protein, protein-protein, and protein-DNA interactions.

A comparison of various optimization algorithms of protein–ligand docking programs by fitness accuracy

In protein–ligand docking, an optimization algorithm is used to find the best binding pose of a ligand against a protein target. This algorithm plays a vital role in determining the docking accuracy. To evaluate the relative performance of different optimization algorithms and provide guidance for real applications, we performed a comparative study on six efficient optimization algorithms, containing two evolutionary algorithm (EA)-based optimizers (LGA, DockDE) and four particle swarm optimization (PSO)-based optimizers (SODock, varCPSO, varCPSO-ls, FIPSDock), which were implemented into the protein–ligand docking program AutoDock. We unified the objective functions by applying the same scoring function, and built a new fitness accuracy as the evaluation criterion that incorporates optimization accuracy, robustness, and efficiency. The varCPSO and varCPSO-ls algorithms show high efficiency with fast convergence speed. However, their accuracy is not optimal, as they cannot reach very low energies. SODock has the highest accuracy and robustness. In addition, SODock shows good performance in efficiency when optimizing drug-like ligands with less than ten rotatable bonds. FIPSDock shows excellent robustness and is close to SODock in accuracy and efficiency. In general, the four PSO-based algorithms show superior performance than the two EA-based algorithms, especially for highly flexible ligands. Our method can be regarded as a reference for the validation of new optimization algorithms in protein–ligand docking.

A Potent Lead Induces Apoptosis in Pancreatic Cancer Cells

Pancreatic cancer is considered a lethal and treatment-refractory disease. To obtain a potent anticancer drug, the cytotoxic effect of 2-(benzo[d]oxazol-3(2H)-ylmethyl)- 5-((cyclohexylamino)methyl)benzene-1,4-diol, dihydrochloride (NSC48693) on human pancreatic cancer cells CFPAC-1, MiaPaCa-2, and BxPC-3 was assessed in vitro. The proliferation of CFPAC-1, MiaPaCa-2, and BxPC-3 is inhibited with IC50 value of 12.9±0.2, 20.6±0.3, and 6.2±0.6 µM at 48 h, respectively. This discovery is followed with additional analysis to demonstrate that NSC48693 inhibition is due to induction of apoptosis, including Annexin V staining, chromatins staining, and colony forming assays. It is further revealed that NSC48693 induces the release of cytochrome c, reduces mitochondrial membrane potential, generates reactive oxygen species, and activates caspase. These results collectively indicate that NSC48693 mainly induces apoptosis of CFPAC-1, MiaPaCa-2, and BxPC-3 cells by the mitochondrial-mediated apoptotic pathway. Excitingly, the study highlights an encouraging inhibition effect that human embryonic kidney (HEK-293) and liver (HL-7702) cells are more resistant to the antigrowth effect of NSC48693 compared to the three cancer cell lines. From this perspective, NSC48693 should help to open up a new opportunity for the treatment of patients with pancreatic cancer.

Rational Drug Design: The Search for Ras Protein Hydrolysis Intermediate Conformation Inhibitors with Both Affinity and Specificity

Computer-aided drug design (CADD) plays significant roles in all stages of todays drug discovery. Many CADD technologies and methods were employed in finding promising hits against different targets during the past several decades. In this review, the most common molecular modeling methods applied to computer-aided drug design are discussed. However, how to effectively integrate these computational methods and then combine them with experiments to improve the hit rate is still a challenge. In addition, the present study reviews the ISR (intrinsic specificity ratio) as a novel concept and quantitative criterion for binding specificity to be applied as a complement in addition to binding affinity for finding new leads. Using Ras protein as a case study, Molecular modeling calculations and the subsequent biological testings for the hits are performed, the specificity of these hits is also studies against the normal and cancer cells aiming at discovering the novel chemical compounds with minimal side effects. Herein, the case study also includes the evaluations for tumor-specific cytotoxicity on different cell lines. The current results suggest that ISR is useful for quantitative assessment of specificity of small molecules.

Selective Induction of Apoptosis: Promising Therapy in Pancreatic Cancer

Pancreatic cancer is one of lethal and poor prognostic malignancies. Due to the absence of effective detecting methods, quite a number of efforts have been made to improve a survival advantage for treatment in patients with pancreatic cancer. Over the past decade, single-agent gemcitabine and gemcitabine-containing combinations were considered standard first-line therapies for advanced pancreatic cancer. Although these routine uses of chemotherapy failed to significantly improve survival benefit for most therapies, these trials provided insights into the molecular mechanisms involved in the development of pancreatic cancer and therefore opened up new therapeutic avenues. Apoptotic inducer as a therapeutic concept has been widely proposed and experimentally identified in some works. Some reviews have revealed that apoptosis-inducing was a promising therapy in cancers with the least side effects and more effectiveness. Apoptosis is a highly controlled physiological mechanism and proceeds through two major pathways for apoptosis-inducing. Some anticancer drugs kill cancer cells by inducing apoptosis via death receptor pathway; however, other chemotherapeutic drugs trigger apoptosis via mitochondrial pathway. In this review, we summarize briefly current chemotherapy in pancreatic cancer, describe the apoptotic mechanisms, and provide a novel therapeutic strategy by targeting Ras intermediate.

Spiclomazine Induces Apoptosis Associated with the Suppression of Cell Viability, Migration and Invasion in Pancreatic Carcinoma Cells

The effective treatment for pancreatic carcinoma remains critically needed. Herein, this current study showed that spiclomazine treatment caused a reduction in viability in pancreatic carcinoma cell lines CFPAC-1 and MIA PaCa-2 in vitro. It was notable in this regard that, compared with pancreatic carcinoma cells, normal human embryonic kidney (HEK-293) and liver (HL-7702) cells were more resistant to the antigrowth effect of spiclomazine. Biochemically, spiclomazine treatment regulated the expression of protein levels in the apoptosis related pathways. Consistent with this effect, spiclomazine reduced the mitochondria membrane potential, elevated reactive oxygen species, and activated caspase-3/9. In addition, a key finding from this study was that spiclomazine suppressed migration and invasion of cancer cells through down-regulation of MMP-2/9. Collectively, the proposed studies did shed light on the antiproliferation effect of spiclomazine on pancreatic carcinoma cell lines, and further clarified the mechanisms that spiclomazine induced apoptosis associated with the suppression of migration and invasion.

A small-molecule induces apoptosis and suppresses metastasis in pancreatic cancer cells

Pancreatic cancer is one of the most malignant tumor diseases with the characters of aggressive growth and metastasis. With the inefficiency of the current therapeutics, new potential targets and new therapeutic agents for healing of pancreatic cancer are critically needed. We have previously found a small molecule, named 4-tert-butyl-2-[(cyclohexylamino) methyl]-6-methylphenol (TBMMP, NSC number: 48160), which can freeze the intermediate of Ras-GTP hydrolysis in the open non-signaling conformation with high affinity and high specificity in silico. In this work, we studied the effect and mechanism of TBMMP on two pancreatic cancer cell lines, CFPAC-1 and BxPC-3. The results showed that TBMMP could restrain the growth of the pancreatic cancer cells with IC(50) value 84.3 μM for CPFAC-1 and 94.5 μM for BxPC-3, respectively. Additionally, TBMMP increased cytochrome c release, reduced mitochondrial membrane potential, activated caspase-3, -9, elevated ROS and increased expression of the Bax in the pancreatic cancer cell lines. The results indicated that TBMMP induced the apoptosis of pancreatic cancer cells through the mitochondrial pathway. Further, we also found that TBMMP could suppress the metastasis of both pancreatic cancer cells in vitro. Taken together, we proposed that TBMMP might be a therapeutic potential lead for treating patients with pancreatic cancer.