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JCIM Cover | Observing Noncovalent Interactions in Experimental Electron Density for Macromolecular Systems: A Novel Perspective for Protein–Ligand Interaction Research

We report for the first time the use of experimental electron density (ED) in the Protein Data Bank for modeling of noncovalent interactions (NCIs) for protein–ligand complexes. Our methodology is based on reduced electron density gradient (RDG) theory describing intermolecular NCIs by ED and its first derivative. We established a database named Experimental NCI Database (ExptNCI; http://ncidatabase.stonewise.cn/#/nci) containing ED saddle points, indicating ∼200,000 NCIs from over 12,000 protein–ligand complexes. We also demonstrated the usage of the database in the case of depicting amide−π interactions in protein–ligand binding systems. In summary, the database provides details on experimentally observed NCIs for protein–ligand complexes and can support future studies including studies on rarely documented NCIs and the development of artificial intelligence models for protein–ligand binding prediction.

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Nat Communications | Structure of human NaV1.6 channel reveals Na+ selectivity and pore blockade by 4,9-anhydro-tetrodotoxin

The sodium channel NaV1.6 is widely expressed in neurons of the central and peripheral nervous systems, which plays a critical role in regulating neuronal excitability. Dysfunction of NaV1.6 has been linked to epileptic encephalopathy, intellectual disability and movement disorders. Here we present cryo-EM structures of human NaV1.6/β1/β2 alone and complexed with a guanidinium neurotoxin 4,9-anhydro-tetrodotoxin (4,9-ah-TTX), revealing molecular mechanism of NaV1.6 inhibition by the blocker. The apo-form structure reveals two potential Na+ binding sites within the selectivity filter, suggesting a possible mechanism for Na+ selectivity and conductance. In the 4,9-ah-TTX bound structure, 4,9-ah-TTX binds to a pocket similar to the tetrodotoxin (TTX) binding site, which occupies the Na+ binding sites and completely blocks the channel. Molecular dynamics simulation results show that subtle conformational differences in the selectivity filter affect the affinity of TTX analogues. Taken together, our results provide important insights into NaV1.6 structure, ion conductance, and inhibition.

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Cell | A mechanism for SARS-CoV-2 RNA capping and its inhibition by nucleotide analogue inhibitors

Decoration of cap on viral RNA plays essential roles in SARS-CoV-2 proliferation. Here we report a mechanism for SARS-CoV-2 RNA capping and document structural details at atomic resolution. The NiRAN domain in polymerase catalyzes the covalent link of RNA 5’ end to the first residue of nsp9 (termed as RNAylation), thus being an intermediate to form cap core (GpppA) with GTP catalyzed again by NiRAN. We also reveal that triphosphorylated nucleotide analogue inhibitors can be bonded to nsp9 and fit into a previously unknown ‘Nuc-pocket’ in NiRAN, thus inhibiting nsp9 RNAylation and formation of GpppA. S-loop (residues 50-KTN-52) in NiRAN presents a remarkable conformational shift observed in RTC bound with sofosbuvir monophosphate, reasoning an ‘induce-and-lock’ mechanism to design inhibitors. These findings not only improve the understanding of SARS-CoV-2 RNA capping and the mode of action of NAIs, but also provide a strategy to design antiviral drugs.

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JCIM | Modified Electrostatic Complementary Score Function and Its Application Boundary Exploration in Drug Design

roperties with accuracy comparable to high-level quantum chemistry methods. One such example is the calculation of electrostatic potential (ESP). Different ESP prediction ML models were proposed to generate surface molecular charge distribution. Electrostatic complementarity (EC) can apply ESP data to quantify the complementarity between a ligand and its binding pocket, leading to the potential to increase the efficiency of drug design. However, there is not much research discussing EC score functions and their applicability domain. We propose a new EC score function modified from the one originally developed by Bauer and Mackey, and confirm its effectiveness against the available Pearson's R correlation coefficient. Additionally, the applicability domain of the EC score and two indices used to define the EC score application scope will be discussed.

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Scientific Reports | A pocket-based 3D molecule generative model fueled by experimental electron density

We report for the first time the use of experimental electron density (ED) as training data for the generation of drug-like three-dimensional molecules based on the structure of a target protein pocket. Similar to a structural biologist building molecules based on their ED, our model functions with two main components: a generative adversarial network (GAN) to generate the ligand ED in the input pocket and an ED interpretation module for molecule generation. The model was tested on three targets: a kinase (hematopoietic progenitor kinase 1), protease (SARS-CoV-2 main protease), and nuclear receptor (vitamin D receptor), and evaluated with a reference dataset composed of over 8000 compounds that have their activities reported in the literature. The evaluation considered the chemical validity, chemical space distribution-based diversity, and similarity with reference active compounds concerning the molecular structure and pocket-binding mode. Our model can generate molecules with similar structures to classical active compounds and novel compounds sharing similar binding modes with active compounds, making it a promising tool for library generation supporting high-throughput virtual screening. The ligand ED generated can also be used to support fragment-based drug design. Our model is available as an online service to academic users via https://edmg.stonewise.cn/#/create .

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望石智慧获选《哈佛商业评论》高能创新团队奖

8月18日，致力于建立更快、更好药物研发新范式的望石智慧，凭借其在交叉学科管理体系优化和AI制药底层理论的创新脱颖而出，荣获《哈佛商业评论》“高能创新团队奖”。一同获奖的还有华为、腾讯、默克和拜耳等28家优秀企业， 望石智慧是获得该奖项唯一的AI制药公司。

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Nat Commun. | N-type fast inactivation of a eukaryotic voltage-gated sodium channel

Voltage-gated sodium (NaV) channels initiate action potentials. Fast inactivation of NaV channels, mediated by an Ile-Phe-Met motif, is crucial for preventing hyperexcitability and regulating firing frequency. Here we present cryo-electron microscopy structure of NaVEh from the coccolithophore Emiliania huxleyi, which reveals an unexpected molecular gating mechanism for NaV channel fast inactivation independent of the Ile-Phe-Met motif. An N-terminal helix of NaVEh plugs into the open activation gate and blocks it. The binding pose of the helix is stabilized by multiple electrostatic interactions. Deletion of the helix or mutations blocking the electrostatic interactions completely abolished the fast inactivation. These strong interactions enable rapid inactivation, but also delay recovery from fast inactivation, which is ~160-fold slower than human NaV channels. Together, our results provide mechanistic insights into fast inactivation of NaVEh that fundamentally differs from the conventional local allosteric inhibition, revealing both surprising structural diversity and functional conservation of ion channel inactivation.