Uni-Dock: GPU-Accelerated Docking Enables Ultralarge Virtual Screening.

Molecular docking, a structure-based virtual screening method, is a reliable tool to enrich potential bioactive molecules from molecular databases. With the rapid expansion of compound library sizes, the speed of existing molecular docking programs becomes less than adequate to meet the demand for screening ultralarge libraries containing tens of millions or billions of molecules. Here, we propose Uni-Dock, a GPU-accelerated molecular docking program that supports various scoring functions including vina, vinardo, and ad4. Uni-Dock achieves more than 1000-fold speedup with high accuracy compared with the AutoDock Vina running in single CPU core, outperforming reported GPU-accelerated docking programs including AutoDock-GPU and Vina-GPU based on head-to-head experiments. Uni-Dock docks molecules in batches simultaneously using concurrent threads of each molecule. The data flow between GPU and CPU is optimized to eliminate CPU hotspots and maximize GPU utility. Additionally, Uni-Dock also supports hydrogen bond biased docking for all scoring functions and can be migrated to multiple GPUs of different architectures and manufacturers. We analyzed the improved performance of Uni-Dock on the CASF-2016 and DUD-E datasets and recommend three combinations of hyperparameters corresponding to different docking scenarios. To demonstrate Uni-Dock's capability on routinely screening ultralarge libraries, we performed hierarchical virtual screening experiments with Uni-Dock on the Enamine Diverse REAL druglike set containing 38.2 million molecules to a popular target KRAS G12D in 12 h using 100 NVIDIA V100 GPUs. To the best of our knowledge, Uni-Dock should be the fastest GPU-accelerated docking program to date.

A retro-inverso modified peptide alleviated ovalbumin-induced asthma model by affecting glycerophospholipid and purine metabolism of immune cells.

Allergic asthma is a heterogeneous disease involving a variety of inflammatory cells. Immune imbalance or changes in the immune microenvironment are the essential causes that promote inflammation in allergic asthma. Tetraspanin CD81 can be used as a platform for receptor clustering and signal transmission owing to its special transmembrane structure and is known to participate in the physiological processes of cell proliferation, differentiation, adhesion, and migration. Previous studies have shown that CD81-targeting peptidomimetics exhibit anti-allergic lung inflammation. However, due to the low metabolic stability of peptide drugs, their druggability is limited. Here, we aimed to generate a metabolically stable anti-CD81 peptide, evaluate its anti-inflammatory action and establish its mechanism of action. Based on previous reports, we applied retro-inverse peptide modification to obtain a new compound, PD00 (NH2-D-Gly-D-Ser-D-Thr-D-Tyr-D-Thr-D-Gln-D-Gly-COOH), with high metabolic stability. Enhanced ultraperformance liquid chromatography-tandem mass spectrometry was used to investigate the in vitro and in vivo metabolic stabilities of PD00. The affinities of PD00 and CD81 were studied using molecular docking and surface plasmon resonance techniques. An ovalbumin (OVA)-induced asthma model was used to evaluate the effects of PD00 in vivo. Mice were treated with different concentrations of PD00 (175 and 350 µg/kg) for 10 days. Airway hyperresponsiveness (AHR) to acetyl-ß-methacholine (Mch), inflammatory cell counts in the bronchoalveolar lavage fluid, and serum OVA-specific IgE levels were detected in the mice at the end of the experiment. Lung tissues were collected for haematoxylin and eosin staining, untargeted metabolomic analysis, and single-cell transcriptome sequencing. PD00 has a high affinity for CD81; therefore, administration of PD00 markedly ameliorated AHR and airway inflammation in mice after OVA sensitisation and exposure. Serum OVA-specific IgE levels decreased considerably. In addition, PD00 treatment increased glycerophospholipid and purine metabolism in immune cells. Collectively, PD00 may regulate the glycerophospholipid and purine metabolism pathways to ameliorate the pathophysiological features of asthma. These findings suggest that PD00 is a potential compound for the treatment of asthma.

Chemo- and Site-Selective Lysine Modification of Peptides and Proteins under Native Conditions Using the Water-Soluble Zolinium.

Site-selective lysine modification of peptides and proteins in aqueous solutions or in living cells is still a big challenge today. Here, we report a novel strategy to selectively quinolylate lysine residues of peptides and proteins under native conditions without any catalysts using our newly developed water-soluble zoliniums. The zoliniums could site-selectively quinolylate K350 of bovine serum albumin and inactivate SARS-CoV-2 3CLpro via covalently modifying two highly conserved lysine residues (K5 and K61). In living HepG2 cells, it was demonstrated that the simple zoliniums (5b and 5B) could quinolylate protein lysine residues mainly in the nucleus, cytosol, and cytoplasm, while the zolinium-fluorophore hybrid (8) showed specific lysosome-imaging ability. The specific chemoselectivity of the zoliniums for lysine was validated by a mixture of eight different amino acids, different peptides bearing potential reactive residues, and quantum chemistry calculations. This study offers a new way to design and develop lysine-targeted covalent ligands for specific application.

Simulation and Machine Learning Methods for Ion-Channel Structure Determination, Mechanistic Studies and Drug Design.

Ion channels are expressed in almost all living cells, controlling the in-and-out communications, making them ideal drug targets, especially for central nervous system diseases. However, owing to their dynamic nature and the presence of a membrane environment, ion channels remain difficult targets for the past decades. Recent advancement in cryo-electron microscopy and computational methods has shed light on this issue. An explosion in high-resolution ion channel structures paved way for structure-based rational drug design and the state-of-the-art simulation and machine learning techniques dramatically improved the efficiency and effectiveness of computer-aided drug design. Here we present an overview of how simulation and machine learning-based methods fundamentally changed the ion channel-related drug design at different levels, as well as the emerging trends in the field.

Halogen Bonds Exist between Noncovalent Ligands and Natural Nucleic Acids.

Because of their strong electron-rich properties, nucleic acids (NAs) can theoretically serve as halogen bond (XB) acceptors. From a PDB database survey, Kolár found that no XBs are formed between noncovalent ligands and NAs. Through statistical database analysis, quantum-mechanics/molecular-mechanics (QM/MM) optimizations, and energy calculations, we find that XBs formed between natural NAs and noncovalent ligands are primarily underestimated and that NAs can serve as XB acceptors to interact with noncovalent halogen ligands. Finally, through energy calculations, natural bond orbital analysis, and noncovalent interaction analysis, XBs are confirmed in 13 systems, among which two systems (445D and 4Q9Q) have relatively strong XBs. In addition, on the basis of energy scanning of four model systems, we explore the geometric rule for XB formation in NAs. This work will inspire researchers to utilize XBs in rational drug design targeting NAs.

Site-specific protein modification by 3-n-butylphthalide in primary hepatocytes: Covalent protein adducts diminished by glutathione and N-acetylcysteine.

AIMS: 3-n-Butylphthalide (NBP) is widely used for the treatment of cerebral ischaemic stroke but can causeliver injury in clinical practice. This study aims to elucidate the underlying mechanisms and propose potential preventive strategies. MAIN METHODS: NBP and its four major metabolites, 3-hydroxy-NBP (3-OH-NBP), 10-hydroxy-NBP, 10-keto-NBP and NBP-11-oic acid, were synthesized and evaluated in primary human or rat hepatocytes (PHHs, PRHs). NBP-related substances or amino acid adducts were identified and semi-quantitated by ultra-high performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS). The target proteins and binding sites were identified by shotgun proteomics based on peptide mass fingerprinting coupled with tandem mass spectrometry and verified by molecular docking. KEY FINDINGS: The toxicity of NBP and its four major metabolites were compared in both PHHs and PRHs, and 3-OH-NBP was found to be the most toxic metabolite. 3-OH-NBP induced remarkable cell death and oxidative stresses in hepatocytes, which correlated well with the levels of glutathione and N-acetylcysteine adducts (3-GSH-NBP and 3-NAC-NBP) in cell supernatants. Additionally, 3-OH-NBP covalently conjugated with intracellular Cys, Lys and Ser, with preferable binding to Cys sites at Myh9 Cys1380, Prdx4 Cys53, Vdac2 Cys48 and Vdac3 Cys36. Furthermore, we found that CYP3A4 induction by rifampicin augmented NBP-induced cell toxicity and supplementing with GSH or NAC alleviated the oxidative stresses and reactive metabolites caused by 3-OH-NBP. SIGNIFICANCE: Our work suggests that glutathione depletion, mitochondrial injury and covalent protein modification are the main causes of NBP-induced hepatotoxicity, which may be prevented by exogenous GSH or NAC supplementation and avoiding concomitant use of CYP3A4 inducers.

Discovery of chiral N-2'-aryletheryl-1'-alkoxy-ethyl substituted arylisoquinolones with anti-inflammatory activity from the nucleophilic addition reactions of the thiophenols and oxazolinium.

Herein we disclosed the novel nucleophilic addition reactions of the thiophenols and oxazolinium (DCZ0358) to produce N-2'-aryletheryl-1'-alkoxy-ethyl substituted arylisoquinolones. After evaluating the anti-inflammatory activity in vitro, 2d was found having significant anti-TNFα activity. Through the amplified synthesis of 2d, four monomers (3a-b and 4a-d) were obtained by chiral separation of the product. The reaction mechanism was proposed and explored by the control experiments. However, only the R-stereoisomers 3b and 4b have significant anti-TNFα activity in vitro (IC50 = 56 and 14 nM, respectively). Moreover, 4b exerts potent therapeutic effects on ulcerative colitis in vivo (30 mg/kg bw, qd, i. g.). The subsequent bio-target exploration of compound 4bvia molecular docking and the experimental validation disclosed that 4b has 3-fold selectivity of binding activity on estrogen receptor (ER) beta (ß) (Ki = 760.86 nM) vs. alpha (α) (Ki = 2320.58 nM). Thus, it provides a novel type of non-steroidal leads for developing anti-inflammatory drugs.

Ligand-based approach for predicting drug targets and for virtual screening against COVID-19.

Discovering efficient drugs and identifying target proteins are still an unmet but urgent need for curing coronavirus disease 2019 (COVID-19). Protein structure-based docking is a widely applied approach for discovering active compounds against drug targets and for predicting potential targets of active compounds. However, this approach has its inherent deficiency caused by e.g. various different conformations with largely varied binding pockets adopted by proteins, or the lack of true target proteins in the database. This deficiency may result in false negative results. As a complementary approach to the protein structure-based platform for COVID-19, termed as D3Docking in our previous work, we developed in this study a ligand-based method, named D3Similarity, which is based on the molecular similarity evaluation between the submitted molecule(s) and those in an active compound database. The database is constituted by all the reported bioactive molecules against the coronaviruses, viz., severe acute respiratory syndrome coronavirus (SARS), Middle East respiratory syndrome coronavirus (MERS), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), human betacoronavirus 2c EMC/2012 (HCoV-EMC), human CoV 229E (HCoV-229E) and feline infectious peritonitis virus (FIPV), some of which have target or mechanism information but some do not. Based on the two-dimensional (2D) and three-dimensional (3D) similarity evaluation of molecular structures, virtual screening and target prediction could be performed according to similarity ranking results. With two examples, we demonstrated the reliability and efficiency of D3Similarity by using 2D × 3D value as score for drug discovery and target prediction against COVID-19. The database, which will be updated regularly, is available free of charge at https://www.d3pharma.com/D3Targets-2019-nCoV/D3Similarity/index.php.

Computational Insights into the Conformational Accessibility and Binding Strength of SARS-CoV-2 Spike Protein to Human Angiotensin-Converting Enzyme 2.

The spike protein of SARS-CoV-2 (CoV-2-S) mediates the virus entry into human cells. Experimental studies have shown the stronger binding affinity of the RBD (receptor binding domain) of CoV-2-S to angiotensin-converting enzyme 2 (ACE2) as compared to that of SARS-CoV spike (CoV-S). However, a similar or weaker binding affinity of CoV-2-S compared to that of CoV-S is observed if entire spikes are used in the bioassay. To explore the underlying mechanism, we calculated the binding affinities of the RBDs to ACE2 and simulated the transitions between ACE2-inaccessible and -accessible conformations. We found that the ACE2-accessible angle of CoV-2-S is 52.2° and that the ACE2 binding strength of CoV-2-S RBD is much stronger than that of CoV-S RBD. However, CoV-2-S has much less of an ACE2-accessible conformation and is much more difficult to shift from ACE2-inaccessible to -accessible than CoV-S, making the binding affinity of the entire protein decrease. Further analysis revealed key interactional residues for strong binding and five potential ligand-binding pockets for drug research.

Substitution Effect of the Trifluoromethyl Group on the Bioactivity in Medicinal Chemistry: Statistical Analysis and Energy Calculations.

The substitution of methyl (Me or -CH3) by trifluoromethyl (TFM or -CF3) is frequently used in medicinal chemistry. However, the exact effect of -CH3/-CF3 substitution on bioactivity is still controversial. We compiled a data set containing 28 003 pairs of compounds with the only difference that -CH3 is substituted by -CF3, and the statistical results showed that the replacement of -CH3 with -CF3 does not improve bioactivity on average. Yet, 9.19% substitution of -CH3 by -CF3 could increase the biological activity by at least an order. A PDB survey revealed that -CF3 prefers Phe, Met, Leu, and Tyr, while -CH3 prefers Leu, Met, Cys, and Ile. If we substitute the -CH3 by -CF3 near Phe, His, and Arg, the bioactivity is most probably improved. We performed QM/MM calculations for 39 -CH3/-CF3 pairs of protein-ligand complexes and found that the -CH3/-CF3 substitution does achieve a large energy gain in some systems, although the mean energy difference is subtle, which is consistent with the statistical survey. The -CF3 substitution on the benzene ring could be particularly effective at gaining binding energy. The maximum improvements in energy achieved -4.36 kcal/mol by QM/MM calculation. Moreover, energy decompositions from MM/GBSA calculations showed that the large energy gains for the -CH3/-CF3 substitution are largely driven by the electrostatic energy or the solvation free energy. These findings may shed some light on the biological activity profile for -CH3/-CF3 substitution, which should be useful for further drug discovery and drug design.

Computational study of the substituent effect of halogenated fused-ring heteroaromatics on halogen bonding.

Halogen bonding (XB) has been applied in many fields from crystal engineering to medicinal chemistry. Compared with the well-studied XB of simple halogenated aromatics, little research has been done on the XB of halogenated fused-ring heteroaromatics, a prevalent substructure in organic compounds. With 1H-pyrrolo[3,2-b]pyridines (PPs) as examples of novel fused-ring heteroaromatics with hydrogen bond donor and acceptor and XB donor, the XB formed by the halogenated heteroaromatics was explored in this study. With 4 different substituents, viz., -CH3, -NH2, -F, and -CONH2, at different positions, 339 derivatives of brominated PP (Br-PP) were designed for calculating their electrostatic potential of the σ-hole of the halogen atom (VS,max) and binding energy with ammonia as XB acceptor (Eint) at M06-2X/6-311++G(d,p) level by PCM model in dichloromethane. The calculated VS,max values ranging from -1.3 to 35.1 kcal/mol and the calculated Eint ranging from -0.82 to -2.37 kcal/mol demonstrated that the XB is complicated and highly tunable. Noticeably, the electron-withdrawing substituents, especially at ortho-position, do not always increase the values of VS,max, while the electron-donating substituents do not always decrease VS,max. Similar results were observed from the calculation on 339 iodinated PPs at M06-2X/6-311++G(d,p) level. The complexity of the XB formed by the halogenated fused ring heteroaromatics indicated a great potential of tuning its strength by different substituents at different positions and revealed a necessity of quantum chemistry calculation for predicting the XB.Graphical abstract.

Interaction Nature and Computational Methods for Halogen Bonding: A Perspective.

Halogen bonds are noncovalent interactions that have been widely used in many fields, including drug design, crystal engineering, and material sciences. A clear understanding of the nature of halogen bonding as well as the proper theoretical bonding description, especially the development of efficient and accurate computational chemical methods and their application in complex systems, is of great significance to promote the development of related fields. In this perspective, we reviewed the investigations of the nature of halogen bonding in recent years and discussed the development of quantum mechanical, molecular mechanical, and empirical scoring function methods in properly describing halogen-bonding interactions, as well as their achievements in corresponding areas. An evaluation on the performance of various quantum mechanical and semiempirical quantum mechanical methods in describing halogen bonds was also included, involving the DFT-D4 scheme and the recently reported xTB methods. We hope this perspective may be helpful, from the insights of computational tools and methods, in providing reference and enlightenment for the application of halogen bonds in fields like high-throughput virtual screening and rational drug design.

D3Targets-2019-nCoV: a webserver for predicting drug targets and for multi-target and multi-site based virtual screening against COVID-19.

A highly effective medicine is urgently required to cure coronavirus disease 2019 (COVID-19). For the purpose, we developed a molecular docking based webserver, namely D3Targets-2019-nCoV, with two functions, one is for predicting drug targets for drugs or active compounds observed from clinic or in vitro/in vivo studies, the other is for identifying lead compounds against potential drug targets via docking. This server has its unique features, (1) the potential target proteins and their different conformations involving in the whole process from virus infection to replication and release were included as many as possible; (2) all the potential ligand-binding sites with volume larger than 200 Å3 on a protein structure were identified for docking; (3) correlation information among some conformations or binding sites was annotated; (4) it is easy to be updated, and is accessible freely to public (https://www.d3pharma.com/D3Targets-2019-nCoV/index.php). Currently, the webserver contains 42 proteins [20 severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) encoded proteins and 22 human proteins involved in virus infection, replication and release] with 69 different conformations/structures and 557 potential ligand-binding pockets in total. With 6 examples, we demonstrated that the webserver should be useful to medicinal chemists, pharmacologists and clinicians for efficiently discovering or developing effective drugs against the SARS-CoV-2 to cure COVID-19.

Alopecines A-E, five chloro-containing matrine-type alkaloids with immunosuppressive activities from the seeds of Sophora alopecuroides.

Alopecines A-E (1-5), five unusual matrine-type alkaloids featuring with an additional dichlorocyclopropane (1-3) or a di/tri-chloromethyl (4/5) attached on the D ring, were isolated from the seeds of Sophora alopecuroides. Their structures and absolute configurations were elucidated by extensive spectroscopic techniques, and X-ray diffraction analyses or time-dependent density functional theory-based electronic circular dichroism (TDDFT-ECD) calculations. Alkaloid 4 exhibited potent inhibitory effects on the proliferation of ConA-induced T lymphocytes or LPS-induced B cells with IC50 value of 3.98 or 3.74 µM, respectively.

SAMPL6 host-guest binding affinities and binding poses from spherical-coordinates-biased simulations.

Host-guest binding is a challenging problem in computer simulation. The prediction of binding affinities between hosts and guests is an important part of the statistical assessment of the modeling of proteins and ligands (SAMPL) challenges. In this work, the volume-based variant of well-tempered metadynamics is employed to calculate the binding affinities of the host-guest systems in the SAMPL6 challenge. By biasing the spherical coordinates describing the relative position of the host and the guest, the initial-configuration-induced bias vanishes and all possible binding poses are explored. The agreement between the predictions and the experimental results and the observation of new binding poses indicate that the volume-based technique serves as a nice candidate for the calculation of binding free energies and the search of the binding poses.

Pnictogen, chalcogen, and halogen bonds in catalytic systems: theoretical study and detailed comparison.

Although halogen bond (XB), a typical σ-hole noncovalent interaction, has been widely exploited in organocatalysis within the last two decades, only very recently has its sister σ-hole interactions, such as chalcogen bond (ChB) and pnictogen bond (PnB), begun to be explored for potential applications in catalysis. Herein, a detailed comparison investigation of PnB, ChB, and XB interactions in catalytic systems was performed from a theoretical point of view. Owing to the excellent properties of the pentafluorophenyl moiety (C6F5) in catalysis, the complexes of (C6F5)3Pn, (C6F5)2Ch, and C6F5X with chloride ion were firstly studied. Then, we successively substituted C6F5 by phenyl groups, to examine the influence of substituents on the characteristics of such interactions. In addition, several halogen-bonded complexes between the donor 1,3,5-trifluoro-2,4,6-triiodobenzene (C6F3I3) and heavier Pn and Ch species as acceptors were also investigated. Our calculations showed that the interactions become gradually stronger upon going from row 3 to 5 and from main group VII to V, which correlates well with the experimental observations. As the strength of the interactions enhances, the contribution of electrostatics to the attraction increases, while the orbital term contribution becomes smaller. Particularly, the significant differences between the three types of σ-hole interactions found in catalysis and anion transport were clarified.

2Ch-2N square and hexagon interactions: a combined crystallographic data analysis and computational study.

In recent years, chalcogen bonding (ChB), a typical σ-hole interaction, has shown great potential as a bottom-up design approach for specific applications. According to our survey of the Cambridge Structural Database (CSD), a large number of crystal structures containing 2Ch-2N square and hexagon interaction motifs were extracted. On the basis of the CSD search results, the 2Ch-2N square interactions in the dimers of 2,1,3-benzochalcogenadiazole 1 and 2,1,3-pyridochalcogenadiazole 2, together with 2Ch-2N hexagon interactions in the dimers of chalcogenazolo-pyridine 3 and triazolo-chalcogenadiazole 4, were firstly studied. Then, substituent effects on these peculiar interactions were thoroughly examined by introducing a diversity of small, non-aromatic substituents at the 4,7-positions of the 1S scaffold and various aryl substituents at the 2-position of the 3Te scaffold. Our calculations showed that the major contribution to the attraction of such bidentate ChB interactions is electrostatics, while the orbital term also plays an important role. Some strong electron-withdrawing substituents, such as NO2, CN, and CF3, tend to enhance square ChB interactions, while C6F5 and CF3 substituents with a strong electron-withdrawing ability strengthen hexagon ChB interactions. Particularly, a good linear correlation has been established between the binding energies of the dimers under study and both the surface electrostatic potential (ESP) maxima for the Ch σ-holes and the minimum surface ESP of the N atoms, which provides reasonable models to evaluate these interactions. The results reported in this work will provide design guidance for the applications of 2Ch-2N cyclic motifs in materials science and biochemistry.

Halogen bonding in differently charged complexes: basic profile, essential interaction terms and intrinsic σ-hole.

Studies on halogen bonds (XB) between organohalogens and their acceptors in crystal structures revealed that the XB donor and acceptor could be differently charged, making it difficult to understand the nature of the interaction, especially the negatively charged donor's electrophilicity and positively charged acceptor's nucleophilicity. In this paper, 9 XB systems mimicking all possibly charged halogen bonding interactions were designed and explored computationally. The results revealed that all XBs could be stable, with binding energies after removing background interaction as strong as -1.2, -3.4, and -8.3 kcal mol-1 for Cl, Br, and I involved XBs respectively. Orbital and dispersion interactions are found to be always attractive while unidirectional intermolecular electron transfer from a XB acceptor to a XB donor occurs in all XB complexes. These observations could be attributed to the intrinsic σ-hole of the XB donor and the intrinsic electronic properties of the XB acceptor regardless of their charge states. Intramolecular charge redistribution inside both the donor and the acceptor is found to be system-dependent but always leads to a more stable XB. Accordingly, this study demonstrates that the orbital-based origin of halogen bonds could successfully interpret the complicated behaviour of differently charged XB complexes, while electrostatic interaction may dramatically change the overall bonding strength. The results should further promote the application of halogens in all related areas.

Description of noncovalent interactions involving π-system with high precision: An assessment of RPA, MP2, and DFT-D methods.

Efficient approaches with high precision are essential for understanding the formation and stability of noncovalent interaction complexes. Here, 21 noncovalent interaction complexes involving π-system are selected and grouped in three subsets according to ETS-NOCV method: dispersion-dominated, electrostatic-dominated, and mixed. We mainly focus on examining the performance of random-phase approximation (RPA) on these π systems. The tested RPA-based method includes standard RPA and its variants including the related single excitations (SEs), renormalized single excitations (rSEs), second-order screened exchange (SOSEX), and the renormalized second-order perturbation theory (rPT2). The routine second-order Møller-Plesset perturbation theory (MP2) and three popular DFT-D functionals (M06-2X-D3, ωB97XD, and PBE-D3(BJ)) are also assessed for comparison. In this work, besides the calculation of interaction energies at Dunning-type aug-cc-pVDZ and aug-cc-pVTZ basis set, we also present a larger database of interaction energies calculated using MP2 and RPA methods with Dunning-type aug-cc-pVQZ basis set. An accurate CCSD(T)/CBS scheme is used to provide benchmark database. In addition to the high-level results, we also provide potential energy surfaces (PES) of different interaction type. Among all the tested methods, MP2 has a satisfactory performance on electrostatic-dominated and mixed-type systems, except for dispersion-dominated systems. DFT-D functionals, especially ωB97XD functional, has a balanced performance across all the tested systems. Importantly, for RPA-based methods, the calculation accuracy can be dramatically improved by taking into account SE or exchange effects, especially in the mixed complexes. We conclude that rPT2 among all the test RPA-based methods gives an overall satisfactory performance across different interaction types. © 2019 Wiley Periodicals, Inc.

Coxsackievirus A10 atomic structure facilitating the discovery of a broad-spectrum inhibitor against human enteroviruses.

Coxsackievirus A10 (CV-A10) belongs to the Enterovirus species A and is a causative agent of hand, foot, and mouth disease. Here we present cryo-EM structures of CV-A10 mature virion and native empty particle (NEP) at 2.84 and 3.12 Å, respectively. Our CV-A10 mature virion structure reveals a density corresponding to a lipidic pocket factor of 18 carbon atoms in the hydrophobic pocket formed within viral protein 1. By structure-guided high-throughput drug screening and subsequent verification in cell-based infection-inhibition assays, we identified four compounds that inhibited CV-A10 infection in vitro. These compounds represent a new class of anti-enteroviral drug leads. Notably, one of the compounds, ICA135, also exerted broad-spectrum inhibitory effects on a number of representative viruses from all four species (A-D) of human enteroviruses. Our findings should facilitate the development of broadly effective drugs and vaccines for enterovirus infections.