Discovery, synthesis, and optimization of teixobactin, a novel antibiotic without detectable bacterial resistance.

Discovering new antibiotics with novel chemical scaffolds and antibacterial mechanisms presents a challenge for medicinal scientists worldwide as the ever-increasing bacterial resistance poses a serious threat to human health. A new cyclic peptide-based antibiotic termed teixobactin was discovered from a screen of uncultured soil bacteria through iChip technology in 2015. Teixobactin exhibits excellent antibacterial activity against all the tested gram-positive pathogens and Mycobacterium tuberculosis, including drug-resistant strains. Given that teixobactin targets the highly conserved lipid II and lipid III, which induces the simultaneous inhibition of both peptidoglycan and teichoic acid synthesis, the emergence of resistance is considered to be rather difficult. The novel structure, potent antibacterial activity, and highly conservative targets make teixobactin a promising lead compound for further antibiotic development. This review provides a comprehensive treatise on the advances of teixobactin in the areas of discovery processes, antibacterial activity, mechanisms of action, chemical synthesis, and structural optimizations. The synthetic methods for the key building block l-allo-End, natural teixobactin, representative teixobactin analogs, as well as the structure-activity relationship studies will be highlighted and discussed in details. Finally, some insights into new trends for the generation of novel teixobactin analogs and tips for future work and directions will be commented.

Molecular docking and molecular dynamics simulations studies on the protective and pathogenic roles of the amyloid-ß peptide between herpesvirus infection and Alzheimer's disease.

The protective innate immune response of ß-amyloid peptide (Aß) has been indicated as a risk factor for Alzheimer's disease (AD) due to the rapid amyloidosis. In order to obtain molecular-level insights into the protective and pathogenic roles of Aß, the binding modes between Aß1-42 and the envelop glycoprotein D (gD) of Herpes simplex virus-1 (HSV-1)/Aß1-42 were theoretically investigated by using molecular docking, molecular dynamics (MD) simulations and binding free energy decomposition methods in the present study. The Aß1-42 stably binds to the envelop gD via intermolecular hydrogen bonds and van der Waals (vdW) interactions. The Aß1-42 acquires its equilibrium with higher fluctuation amplitude and a better structured C-terminal in the HSV-1 gD-Aß1-42 complex comparing to that in the Aß1-42-Aß1-42 complex. The amino acid residues of Aß1-42 involved in the formation of the Aß1-42 dimer are fully free and accessible in the HSV-1 gD-Aß1-42 complex. It is favorable for the Aß1-42 monomer to interact with the HSV-1 gD-Aß1-42 complex. It may be responsible for the rapid amyloidosis which entraps the herpesvirus as well as causing AD.

Partitioning of evapotranspiration and the influencing factors of evapotranspiration components in a shrub ecosystem dominated by Artemisia ordosica and Hedysarum fruticosum var. mongolicum in the Mu Us Desert, Northwest China.

Evapotranspiration (ET) is an important part of water cycle and energy flow in ecosystem. Accurate estimation of ET and its components is critical for understanding the impacts of ecophysiological processes on ecosystem water balance and plant water use strategy. Using the eddy-covariance technique and the micro-lysimeter, we measured ET, evaporation (E), transpiration (T) of the Artemisia ordosica-Hedysarum fruticosum var. mongolicum shrubland in the Mu Us Desert during May 20 to September 15, 2019, quantified the ET components, and analyzed the seasonal characteristics and influencing factors of ET and its components. The results showed that T was the main component of ET in the growing season, with a T/ET of 53.1%. T/ET increased and E/ET decreased as precipitation decreased. The partitioning of evapotranspiration was regulated by precipi-tation. At the seasonal scale, the value of E was positively correlated with soil water content at 10 cm depth (SWC10) and net radiation (Rn), while SWC10 was the main factor influencing E. The value of T increased with the increases of Rn and leaf area index (LAI), and increased first and then decreased with the increases of soil water content at 30 cm layer (SWC30). T was affected by SWC30, Rn and LAI. Moisture was the main influencing factor of ET. The ET/P in the growing season was 109.2% and was 250.5% in May, indicating that the water consumption of ET in early growing season was partly from the precipitation in non-growing season.

A new coumarin from Murraya alata activates TRPV1 channel.

One new coumarin, muralatin R, was isolated from the leaves of Murraya alata Drake (Rutaceae). Its structure was elucidated by extensive analysis of the NMR and MS data, along with the specific rotation comparison. Muralatin R was found to be capable of activating the transient receptor potential vanilloid 1 (TRPV1) channel through desensitization mechanism. The results supply reference for clarification of the therapeutic basis and mechanism of action of Murraya plants for treating psychogenic pain or somatoform pain disorders.

Highly active rare-earth metal catalysts for heteroselective ring-opening polymerization of racemic lactide.

Rare-earth metal complexes usually exhibit high activities in the ring-opening polymerization (ROP) of lactide, yet only a few scandium complexes have shown satisfactory activity. Herein, we report the synthesis of a series of chiral anilido-oxazoline-supported scandium and yttrium complexes that exhibit high activity in the ROP of racemic lactide (rac-LA). Complexes La-f-Ln(CH2SiMe3)2THF (La-f = 2-(2,6-R2PhN)-phenyl-4-(S)-R'-oxazoline; for 1a-f: L = La-f, Ln = Sc; for 2a-d: L = La-d, Ln = Y) were synthesized via the convenient one-pot reaction of Ln(CH2SiMe3)3(THF)2 (Ln = Sc, Y) with the corresponding proligands. The crystal structures of 1a, 1d, 1e, and 1f were isostructural, adopting a distorted trigonal bipyramidal configuration. Sc complexes 1 showed outstanding activity in the ROP of rac-LA with heteroselectivity. TOFs of up to 720 h-1 and 2910 h-1 were obtained in THF at room temperature and toluene at 60 °C, respectively. To our knowledge, these are the highest activities reported for Sc systems. Y complexes 2 showed higher activity and heteroselectivity than the Sc complexes, with TOFs of up to 1176 h-1 in THF at room temperature. Compared with the ortho-substituent on the anilido moiety, the bulky substituent at the chiral center of the oxazoline ring had a greater effect on controlling the heteroselectivity.

Anilido-oxazoline-ligated rare-earth metal complexes: synthesis, characterization and highly cis-1,4-selective polymerization of isoprene.

Anilido-oxazoline-ligated rare-earth metal dialkyl complexes have been synthesized and structurally characterized. The complexes exhibited strong fluorescence emissions and good catalytic performance on isoprene polymerization with high cis-1,4-selectivity. The treatment of anilido-oxazoline precursors ortho-C6H4[NH(2,6-R12C6H3)][C[double bond, length as m-dash]NC(R2,R3)CH2O] (R1 = R2 = R3 = Me (HL1); R1 = iPr, R2 = R3 = Me (HL2); R1 = R2 = iPr, R3 = H (HL3); and R1 = iPr, R2 = R3 = H (HL4)) with an equimolar amount of Ln(CH2SiMe3)3(THF)2 (Ln = Sc, Y) afforded rare-earth metal complexes L1-4-Ln(CH2SiMe3)2(THF)n (L1-Sc (1), n = 1; L2-Sc (2), n = 0; L1-Y (3), n = 1; L2-Y (4), n = 1; L3-Y (5), n = 1; and L4-Y (6), n = 1) in good yields. The complexes are stable in both the solid state and solution. Single crystal X-ray diffraction study showed that complexes 1, 3 and 4 exhibit a distorted trigonal bipyramidal configuration, while complex 2 is pseudo-tetrahedral without coordinated THF. The luminescence properties of complexes 1-4 were investigated and the emission maxima were found in the range of 465-477 nm. DFT and TD-DFT studies were carried out to explore their characteristic electronic structures and gain insight into their optical properties. Upon activation with organic borates, the reported complexes exhibited high activity and cis-1,4-selectivity for isoprene polymerization. The nature of the central metal and substituent groups in oxazoline have an influence on the cis-1,4-selectivity.

Inhibition of Hsp70 Suppresses Neuronal Hyperexcitability and Attenuates Epilepsy by Enhancing A-Type Potassium Current.

The heat shock protein 70 (Hsp70) is upregulated in response to stress and has been implicated as a stress marker in temporal lobe epilepsy (TLE). However, whether Hsp70 plays a pathologic or protective role in TLE remains unclear. Here we report a deleterious role of Hsp70 in kainic acid (KA)-induced seizures. Hsp70 expression is upregulated in a KA model of TLE, and silencing or inhibition of Hsp70 suppresses neuronal hyperexcitability and attenuates acute or chronic epilepsy by enhancing A-type potassium current in hippocampal neurons. Hsp70 upregulation leads to proteosomal degradation of Kv4-KChIP4a channel complexes primarily encoding neuronal A-type current. Furthermore, Hsp70 directly binds to the N terminus of auxiliary KChIP4a and targets Kv4-KChIP4a complexes to proteasome. Taken together, our findings reveal a role of Hsp70 in the pathogenesis of epilepsy through degradation of Kv4-KChIP4a complexes, and pharmacological inhibition of Hsp70 may represent therapeutic potential for epilepsy or hyperexcitability-related neurological disorders.

Pharmacological characterization of JWX-A0108 as a novel type I positive allosteric modulator of α7 nAChR that can reverse acoustic gating deficits in a mouse prepulse inhibition model.

The α7 nicotinic acetylcholine receptor (α7 nAChR) is a ligand-gated Ca2+-permeable homopentameric ion channel implicated in cognition and neuropsychiatric disorders. Pharmacological enhancement of α7 nAChR function has been suggested for improvement of cognitive deficits. In the present study, we characterized a thiazolyl heterocyclic derivative, 6-(2-chloro-6-methylphenyl)-2-((3-fluoro-4-methylphenyl)amino)thiazolo[4,5-d]pyrimidin-7(6H)-one (JWX-A0108), as a novel type I α7 nAChR positive allosteric modulator (PAM), and evaluated its ability to reverse auditory gating and spatial working memory deficits in mice. In Xenopus oocytes expressing human nAChR channels, application of JWX-A0108 selectively enhanced α7 nAChR-mediated inward current in the presence of the agonist ACh (EC50 value = 4.35 ± 0.12 µM). In hippocampal slices, co-application of ACh and JWX-A0108 (10 µM for each) markedly increased both the frequency and amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs) recorded in pyramidal neurons, but JWX-A0108 did not affect GABA-induced current in oocytes expressing human GABAA receptor α1ß3γ2 and α5ß3γ2 subtypes. In mice with MK-801-induced deficits in auditory gating, administration of JWX-A0108 (1, 3, and 10 mg/kg, i.p.) dose-dependently attenuates MK-801-induced auditory gating deficits in five prepulse intensities (72, 76, 80, 84, and 88 dB). Furthermore, administration of JWX-A0108 (0.03, 0.1, or 0.3 mg/kg, i.p.) significantly reversed MK-801-induced impaired spatial working memory in mice. Our results demonstrate that JWX-A0108 is a novel type I PAM of α7 nAChR, which may be beneficial for improvement of cognitive deficits commonly found in neuropsychiatric disorders such as schizophrenia and Alzheimer's disease.

Antipruritic Effect of Natural Coumarin Osthole through Selective Inhibition of Thermosensitive TRPV3 Channel in the Skin.

Coumarin osthole is a dominant bioactive ingredient of the natural Cnidium monnieri plant commonly used for traditional Chinese herbal medicines for therapies and treatments including antipruritus and antidermatitis. However, the molecular mechanism underlying the action of osthole remains unclear. In this study, we report that osthole exerts an antipruritic effect through selective inhibition of Ca2+-permeable and thermosensitive transient receptor potential vanilloid 3 (TRPV3) cation channels that are primarily expressed in the keratinocytes of the skin. Coumarin osthole was identified as an inhibitor of TRPV3 channels transiently expressed in HEK293 cells in a calcium fluorescent assay. Inhibition of the TRPV3 current by osthole and its selectivity were further confirmed by whole-cell patch clamp recordings of TRPV3-expressing HEK293 cells and mouse primary cultured keratinocytes. Behavioral evaluation demonstrated that inhibition of TRPV3 by osthole or silencing by knockout of the TRPV3 gene significantly reduced the scratching induced by either acetone-ether-water or histamine in localized rostral neck skin in mice. Taken together, our findings provide a molecular basis for use of natural coumarin osthole from the C. monnieri plant in antipruritic or skin care therapy, thus establishing a significant role of the TRPV3 channel in chronic itch signaling or acute histamine-dependent itch sensation.

A pivotal role for the activation of TRPV3 channel in itch sensations induced by the natural skin sensitizer carvacrol.

Itching is an intricate, common symptom of dermatologic and systemic diseases, and both TRPV3 and TRPA1 channels have been suggested to function as downstream effector targets. But the relative contributions of TRPV3 and TRPA1 to itch sensation in vivo remain unclear. To dissect the role of TRPA1 or TRPV3 in the cutaneous sensation of itching, we took the advantage of a natural compound carvacrol from oregano, and examined its effect on the induction of scratching behavior in mice. We showed that the intradermal injection of carvacrol (0.01%, 0.1% and 1%, 50 µL) induced scratching in a concentration-dependent manner. But in TRPV3-knockout mice, the scratching induced by carvacrol (1%, 50 µL) was markedly decreased by approximately 64% (from 275 scratching bouts down to 90) within 60 min. Further analysis revealed that TRPV3-knockout caused a reduction of scratching bouts for approximately 40% in the first 20 min (the initial phase), whereas the scratching bouts were reduced by approximately 90% in the last 40 min (the sustained phase). These results were in consistence with those in our whole-cell recordings in HEK-293T cells expressing either TRPA1 or TRPV3: carvacrol exhibited similar potencies in activating either TRPA1 or TRPV3, but carvacrol-activated TRPA1 current showed a rapid desensitization, which was reduced by approximately 90% within 5 min before a complete washout, whereas carvacrol-induced TRPV3 current showed a slow desensitization that caused less than 30% of current reduction in 10 min and left a significant residual TRPV3 current after washout. Our results demonstrate that carvacrol from plant oregano is a skin sensitizer or allergen; TRPV3 is involved in the initial phase and the sustained phase of pruritus, whereas TRPA1 likely contributes to the initial phase.

Selective Activation of Nociceptor TRPV1 Channel and Reversal of Inflammatory Pain in Mice by a Novel Coumarin Derivative Muralatin L from Murraya alata.

Coumarin and its derivatives are fragrant natural compounds isolated from the genus Murraya that are flowering plants widely distributed in East Asia, Australia, and the Pacific Islands. Murraya plants have been widely used as medicinal herbs for relief of pain, such as headache, rheumatic pain, toothache, and snake bites. However, little is known about their analgesic components and the molecular mechanism underlying pain relief. Here, we report the bioassay-guided fractionation and identification of a novel coumarin derivative, named muralatin L, that can specifically activate the nociceptor transient receptor potential vanilloid 1 (TRPV1) channel and reverse the inflammatory pain in mice through channel desensitization. Muralatin L was identified from the active extract of Murraya alata against TRPV1 transiently expressed in HEK-293T cells in fluorescent calcium FlexStation assay. Activation of TRPV1 current by muralatin L and its selectivity were further confirmed by whole-cell patch clamp recordings of TRPV1-expressing HEK-293T cells and dorsal root ganglion neurons isolated from mice. Furthermore, muralatin L could reverse inflammatory pain induced by formalin and acetic acid in mice but not in TRPV1 knock-out mice. Taken together, our findings show that muralatin L specifically activates TRPV1 and reverses inflammatory pain, thus highlighting the potential of coumarin derivatives from Murraya plants for pharmaceutical and medicinal applications such as pain therapy.

Identification and in vitro pharmacological characterization of a novel and selective α7 nicotinic acetylcholine receptor agonist, Br-IQ17B.

AIM: Alpha7-nicotinic acetylcholine receptor (α7 nAChR) is a ligand-gated Ca(2+)-permeable ion channel implicated in cognition and neuropsychiatric disorders. Activation of α7 nAChR improves learning, memory, and sensory gating in animal models. To identify novel α7 nAChR agonists, we synthesized a series of small molecules and characterized a representative compound, Br-IQ17B, N-[(3R)-1-azabicyclo[2,2,2]oct-3-yl]-5-bromoindolizine-2-carboxamide, which specifically activates α7 nAChR. METHODS: Two-electrode voltage clamp (TEVC) recordings were primarily used for screening in Xenopus oocytes expressing human α7 nAChR. Assays, including radioisotope ligand binding, Western blots, whole-cell recordings of hippocampal culture neurons, and spontaneous IPSC recordings of brain slices, were also utilized to evaluate and confirm the specific activation of α7 nAChR by Br-IQ17B. RESULTS: Br-IQ17B potently activates α7 nAChR with an EC50 of 1.8±0.2 µmol/L. Br-IQ17B is selective over other subtypes such as α4ß2 and α3ß4, but it blocks 5-HT3A receptors. Br-IQ17B displaced binding of the α7 blocker [(3)H]-MLA to hippocampal crude membranes with a Ki of 14.9±3.2 nmol/L. In hippocampal neurons, Br-IQ17B evoked α7-like currents that were inhibited by MLA and enhanced in the presence of the α7 PAM PNU-120596. In brain slice recordings, Br-IQ17B enhanced GABAergic synaptic transmission in CA1 neurons. Mechanistically, Br-IQ17B increased ERK1/2 phosphorylation that was MLA-sensitive. CONCLUSION: We identified the novel, potent, and selective α7 agonist Br-IQ17B, which enhances synaptic transmission. Br-IQ17B may be a helpful tool to understand new aspects of α7 nAChR function, and it also has potential for being developed as therapy for schizophrenia and cognitive deficits.

Application of the 4D fingerprint method with a robust scoring function for scaffold-hopping and drug repurposing strategies.

Two factors contribute to the inefficiency associated with screening pharmaceutical library collections as a means of identifying new drugs: [1] the limited success of virtual screening (VS) methods in identifying new scaffolds; [2] the limited accuracy of computational methods in predicting off-target effects. We recently introduced a 3D shape-based similarity algorithm of the SABRE program, which encodes a consensus molecular shape pattern of a set of active ligands into a 4D fingerprint descriptor. Here, we report a mathematical model for shape similarity comparisons and ligand database filtering using this 4D fingerprint method and benchmarked the scoring function HWK (Hamza-Wei-Korotkov), using the 81 targets of the DEKOIS database. Subsequently, we applied our combined 4D fingerprint and HWK scoring function VS approach in scaffold-hopping and drug repurposing using the National Cancer Institute (NCI) and Food and Drug Administration (FDA) databases, and we identified new inhibitors with different scaffolds of MycP1 protease from the mycobacterial ESX-1 secretion system. Experimental evaluation of nine compounds from the NCI database and three from the FDA database displayed IC50 values ranging from 70 to 100 µM against MycP1 and possessed high structural diversity, which provides departure points for further structure-activity relationship (SAR) optimization. In addition, this study demonstrates that the combination of our 4D fingerprint algorithm and the HWK scoring function may provide a means for identifying repurposed drugs for the treatment of infectious diseases and may be used in the drug-target profile strategy.

Structural insight into the binding complex: ß-arrestin/CCR5 complex.

The chemokine receptor 5 (CCR5) belongs to the superfamily of serpentine G protein-coupled receptors (GPCRs). The DRY motif (Asp, Arg, Tyr) of the intracellular loop 2 (ICL2), which is highly conserved in the GPCRs has been shown to be essential for the stability of folding of CCR5 and the interaction with ß-arrestin. But the molecular mechanism by which it recognizes and interacts with ß-arrestin has not been elucidated. In the present study, we described the active state of the ß-arrestin structure using normal mode analysis and characterized the binding cleft of CCR5-ICL2 with ß-arrestin using SABRE© docking tool and molecular dynamics simulation. Based on our computational results, we proposed a mode of binding between the ICL2 loop of CCR5 and ß-arrestin structure, and modeled the energetically stable ß-arrestin/CCR5 complex. In view of CCR5's importance as a therapeutic target for the treatment of HIV, this observation provides novel insight into the ß-arrestin/CCR5 pathway. As a result, the current computational study of the detailed ß-arrestin/CCR5 binding complex could provide the rationale for the development of next generation of HIV peptide inhibitors as therapeutic agents.

SABRE: ligand/structure-based virtual screening approach using consensus molecular-shape pattern recognition.

We present an efficient and rational ligand/structure shape-based virtual screening approach combining our previous ligand shape-based similarity SABRE (shape-approach-based routines enhanced) and the 3D shape of the receptor binding site. Our approach exploits the pharmacological preferences of a number of known active ligands to take advantage of the structural diversities and chemical similarities, using a linear combination of weighted molecular shape density. Furthermore, the algorithm generates a consensus molecular-shape pattern recognition that is used to filter and place the candidate structure into the binding pocket. The descriptor pool used to construct the consensus molecular-shape pattern consists of four dimensional (4D) fingerprints generated from the distribution of conformer states available to a molecule and the 3D shapes of a set of active ligands computed using SABRE software. The virtual screening efficiency of SABRE was validated using the Database of Useful Decoys (DUD) and the filtered version (WOMBAT) of 10 DUD targets. The ligand/structure shape-based similarity SABRE algorithm outperforms several other widely used virtual screening methods which uses the data fusion of multiscreening tools (2D and 3D fingerprints) and demonstrates a superior early retrieval rate of active compounds (EF(0.1%) = 69.0% and EF(1%) = 98.7%) from a large size of ligand database (∼95,000 structures). Therefore, our developed similarity approach can be of particular use for identifying active compounds that are similar to reference molecules and predicting activity against other targets (chemogenomics). An academic license of the SABRE program is available on request.

Structural insight into a novel human CCR5-V130I variant associated with resistance to HIV-1 infection.

We report the identification of a novel CC chemokine receptor 5 (CCR5) variant that seems associated with resistance to HIV-1 infection. The V130I mutation of the CCR5 receptor is located in the intracellular loop ICL2 known as DRY box and described in the literature as a nonsynonymous mutation present in nonhuman primates group. Extensive molecular modeling and dynamics simulations were performed to elucidate the mechanism by which the V130I mutation may induce conformational change of the CCR5 folding protein and prevent the interaction with the ß-arrestin protein. Our study provides new mechanistic insight into how a specific mutation in the regulatory domain of CCR5 might alter the structural folding of the DRY box and the possible ICL2 loop binding with the ß-arrestin protein, as described in our previous computational study. The results from our large-scale simulations complement recent experimental results and clinical features and offer useful insights into the mechanism behind CCR5 protein folding and signal transduction. In order for HIV, the entry of the virus to the cells must fuse with the CCR5 receptor that sits on the surface of T-helper immune cells. The described V130I mutation in the gene encoding the CCR5 protein may results in a defective CCR5-Arrestin binding complex that blocks entry of the virus.

Microscopic Modes and Free Energies for Topoisomerase I-DNA Covalent Complex Binding with Non-campothecin Inhibitors by Molecular Docking and Dynamics Simulations.

Topoisomerase I (Topo1) has been identified as an attractive target for anticancer drug development due to its central role in facilitating the nuclear process of the DNA. It is essential for rational design of novel Topo1 inhibitors to reliably predict the binding structures of the Topo1 inhibitors interacting with the Topo1-DNA complex. The detailed binding structures and binding free energies for the Topo1-DNA complex interacting with typical non-camptothecin (CPT) Topo1 inhibitors have been examined by performing molecular docking, molecular dynamic (MD) simulations, and binding free energy calculations. The computational results provide valuable insights into the binding modes of the inhibitors binding with the Topo1-DNA complex and the key factors affecting the binding affinity. It has been demonstrated that the - stacking interaction with the DNA base pairs and the hydrogen bonding with Topo1 have the pivotal contributions to the binding structures and binding free energies, although the van der Waals and electrostatic interactions also significantly contribute to the stabilization of the binding structures. The calculated binding free energies are in good agreement with the available experiment activity data. The detailed binding modes and the crucial factors affecting the binding free energies obtained from the present computational studies may provide valuable insights for future rational design of novel, more potent Topo1 inhibitors.

Protein flexibility and conformational states of Leishmania antigen eIF-4A: identification of a novel plausible protein adjuvant using comparative genomics and molecular modeling.

Recent homology modeling studies have identified specific residues (epitope) of the Leishmania RNA helicase protein (LmeIF) that stimulates production of IL-12 cytokine. However, question remains concerning how LmeIF's N-terminal moiety initiates adjuvant effects. Extensive molecular modeling combining the normal mode analysis (NMA) and molecular dynamics simulations, in the present study, has demonstrated that the LmeIF structure may exist in two different forms corresponding to the extended and collapsed (closed) states of the entire structure. The computational results showed that the two domains of the LmeIF structure tend to undergo large fluctuations in a concerted fashion and have strong effect on the solvent accessible surface of the epitope situated on the N-terminal structure. The conformational freedom of the C-terminal domains may explain why the entire LmeIF protein is not as active as the N-terminal moiety. Thereafter, a comparative genome analysis with subsequent homology modeling and molecular electrostatic potential (MEP) techniques allowed us to predict a novel and plausible RNA helicase (LI-helicase) from the Listeria source with adjuvant property as observed for the Leishmania eIF-4A protein. The structural folding and MEP maps revealed similar topologies of the epitope of both LmeIF and LI-helicase proteins and striking identity in the local disposition of the charged groups. An animated Interactive 3D Complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:7.

A novel and efficient ligand-based virtual screening approach using the HWZ scoring function and an enhanced shape-density model.

In this work, we extend our previous ligand shape-based virtual screening approach by using the scoring function Hamza-Wei-Zhan (HWZ) score and an enhanced molecular shape-density model for the ligands. The performance of the method has been tested against the 40 targets in the Database of Useful Decoys and compared with the performance of our previous HWZ score method. The virtual screening results using the novel ligand shape-based approach demonstrated a favorable improvement (area under the receiver operator characteristics curve AUC = .89 ± .02) and effectiveness (hit rate HR(1%) = 53.0% ± 6.3 and HR(10%) = 71.1% ± 4.9). The comparison of the overall performance of our ligand shape-based method with the highest ligand shape-based virtual screening approach using the data fusion of multi queries showed that our strategy takes into account deeper the chemical information of the set of active ligands. Furthermore, the results indicated that our method are suitable for virtual screening and yields superior prediction accuracy than the other study derived from the data fusion using five queries. Therefore, our novel ligand shape-based screening method constitutes a robust and efficient approach to the 3D similarity screening of small compounds and open the door to a whole new approach to drug design by implementing the method in the structure-based virtual screening.

Ligand-based virtual screening approach using a new scoring function.

In this study, we aimed to develop a new ligand-based virtual screening approach using an effective shape-overlapping procedure and a more robust scoring function (denoted by the HWZ score for convenience). The HWZ score-based virtual screening approach was tested against the compounds for 40 protein targets available in the Database of Useful Decoys (DUD; dud.docking.org/jahn/ ), and the virtual screening performance was evaluated in terms of the area under the receiver operator characteristic (ROC) curve (AUC), enrichment factor (EF), and hit rate (HR), demonstrating an improved overall performance compared to other popularly used approaches examined. In particular, the HWZ score-based virtual screening led to an average AUC value of 0.84 ± 0.02 (95% confidence interval) for the 40 targets. The average HR values at the top 1% and 10% of the active compounds for the 40 targets were 46.3% ± 6.7% and 59.2% ± 4.7%, respectively. In addition, the performance of the HWZ score-based virtual screening approach is less sensitive to the choice of the target.