Yu-Shi Tian

Design and evaluation of antiretroviral peptides corresponding to the C-terminal heptad repeat region (C-HR) of human immunodeficiency virus type 1 envelope glycoprotein gp41

Two alpha-helical heptad repeats, N-HR and C-HR, located in the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein gp41, play an important role in membrane fusion by forming a 6-helix bundle. C34, a peptide mimicking C-HR, inhibits the formation of the 6-helix bundle; thus, it has potential as a novel antiretroviral compound. In order to improve the inhibitory effect of C34 on HIV-1 replication, we designed new C34-derived peptides based on computational analysis of the stable conformation of the 6-helix bundle. Newly designed peptides showed a stronger inhibitory effect on the replication of recombinant viruses containing CRF01_AE, subtype B or subtype C Env than C34 or a fusion inhibitor, T-20. In addition, these peptides inhibited the replication of a T-20-resistant virus. We propose that these peptides could be applied to develop novel antiretroviral compounds to inhibit the replication of various subtypes of HIV-1 as well as of T-20-resistant variants.

Mordred: a molecular descriptor calculator

Molecular descriptors are widely employed to present molecular characteristics in cheminformatics. Various molecular-descriptor-calculation software programs have been developed. However, users of those programs must contend with several issues, including software bugs, insufficient update frequencies, and software licensing constraints. To address these issues, we propose Mordred, a developed descriptor-calculation software application that can calculate more than 1800 two- and three-dimensional descriptors. It is freely available via GitHub. Mordred can be easily installed and used in the command line interface, as a web application, or as a high-flexibility Python package on all major platforms (Windows, Linux, and macOS). Performance benchmark results show that Mordred is at least twice as fast as the well-known PaDEL-Descriptor and it can calculate descriptors for large molecules, which cannot be accomplished by other software. Owing to its good performance, convenience, number of descriptors, and a lax licensing constraint, Mordred is a promising choice of molecular descriptor calculation software that can be utilized for cheminformatics studies, such as those on quantitative structure–property relationships.

Dengue Virus and Its Inhibitors: A Brief Review

The global occurrence of viral infectious diseases poses a significant threat to human health. Dengue virus (DENV) infection is one of the most noteworthy of these infections. According to a WHO survey, approximately 400 million people are infected annually; symptoms deteriorate in approximately one percent of cases. Numerous foundational and clinical investigations on viral epidemiology, structure and function analysis, infection source and route, therapeutic targets, vaccines, and therapeutic drugs have been conducted by both academic and industrial researchers. At present, CYD-TDV or Dengvaxia® is the only approved vaccine, but potent inhibitors are currently under development. In this review, an overview of the viral life circle and the history of DENVs is presented, and the most recently reported antiviral candidates and newly discovered promising targets are focused and summarized. We believe that these successes and failures have enabled progress in anti-DENV drug discovery and hope that our review will stimulate further innovation in this area.

In silico analysis of enantioselective binding of immunomodulatory imide drugs to cereblon.

BackgroundThalidomide and its analogs, lenalidomide and pomalidomide (referred to as immunomodulatory imide drugs or IMiDs) have been known to treat multiple myeloma and other hematologic malignancies as well as to cause teratogenicity. Recently the protein cereblon was identified as the primary target of IMiDs, and crystallographic studies of the cereblon–IMiDs complex showed strong enantioselective binding for the (S)-enantiomer of IMiDs.ResultsUsing the structures of cereblon and IMiDs [both (S)-enantiomers and (R)-enantiomers] we performed docking simulations in order to replicate this enantiomeric selectivity and to identify the region(s) contributing to this selectivity. We confirmed the enantioselective binding of IMiDs to cereblon with high accuracy, and propose that the hairpin connecting the β10–β11 region of cereblon (residues 351–355) contributes to this selectivity and to the increased affinity with IMiDs.ConclusionsOur docking results provide novel insights into the binding mode of IMiD-like molecules and contribute to a deeper understanding of cereblon-related biology.

A Practical Estimation Method for Analyzing Adverse Drug Reactions Using Data Mining

This study aimed to determine the potentially severe chemical properties of drugs that can cause adverse drug reactions (ADRs) such as erythema multiforme (EM), Stevens–Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) by using a data mining method. The study data were extracted from the Adverse Event Reporting System database of the FDA. EM was considered a mild reaction, and SJS and TEN were considered severe reactions. In this study, a new concept termed the “risk of aggravation” (ROA) was defined as whether a certain drug is more likely to cause severe adverse reactions than mild ones. Partial least squares and logistic regression analysis were applied using binary response variable ROAs. These analyses correctly predicted 50 of the 72 drugs associated with SJS and/or TEN and 28 of the 38 drugs associated with EM using binary chemical descriptors that are the same as those using the metric chemical descriptors.

Novel Concepts for Drug Hypersensitivity Based on the Use of Long-Time Scale Molecular Dynamic Simulation

The discovery that several drug hypersensitivity reactions (DHRs) are associated with specific human leukocyte antigen (HLA) alleles has attracted increasing research interest. However, the underlying mechanisms of these HLA-induced DHRs remain unclear, especially for drug-induced immediate activation of T-cell clones (TCCs). Recently, a novel hypothesis involving partial detachment between self-peptide(s) and the HLA molecule (altered peptide-HLA (pHLA) model) has been proposed to explain these phenomena. In order to clarify this hypothesis, we performed long-timescale molecular dynamics (MD) simulations. We focused on HLA-B⁎57:01-restricted abacavir hypersensitivity reactions (AHRs), one of the most famous DHRs. One of the simulation results showed that this altered-pHLA model might be driven by an increase in the distance not only between HLA and self-peptides but also between the α 1 and α 2 helices of HLA. Our findings provide novel insights into abacavir-induced immediate activation of TCCs and these findings might also be applied to other DHRs, such as HLA-B⁎58:01-restricted allopurinol hypersensitivity reactions.

Search for Low Molecular Weight Compounds that Inhibit Human Immunodeficiency Virus Type 1 Replication

Highly active antiretroviral (ARV) therapy has successfully reduced viral transmission, morbidity, and mortality associated with human immunodeficiency virus type 1 (HIV-1) disease; however, the emergence of drug-resistant viruses is a major obstacle associated with ARV therapy. Therefore, the development of a new class of ARV drugs is urgently required. Cyclophilin A (CypA) is a host factor required for HIV-1 replication, and plays a role in viral replication by interacting with the HIV-1 capsid protein (CA). As such, it represents a potential target for novel ARV drugs. We here searched for low molecular weight compounds that inhibited HIV-1 replication by interfering with binding between CypA and HIV-1 CA. A total of 106 compounds were screened in an in silico docking study as candidates that were predicted to interact with the HIV-1 CA binding pocket of CypA. Biological tests were then conducted to evaluate the anti-HIV-1 activities as well as cytotoxicities of these test compounds, and 4 compounds that efficiently inhibited viral replication without exhibiting strong cytotoxicity were subsequently selected. The molecular mechanisms underlying the inhibition of HIV-1 replication by the 4 selected compounds have not been elucidated in the present study; however, we consider that these compounds will become the lead compounds for developing novel ARV drugs once more detailed studies are performed on the molecular mechanisms responsible for their anti-HIV-1 activities.

Pharmacophore Modeling and Molecular Docking Studies of potential inhibitors to E6 PBM–PDZ from Human Papilloma Virus (HPV)

High-risk human papillomaviruses (HPVs) are known to cause cervical cancer. Vaccines are now available to prevent HPV infection. However, a clinically approved drug is yet not available to treat HPV. The PDZ(PSD−95/Dlg/ZO−1)−binding motif (PBM) in the E6 protein of HPVs targets the PDZ domain (known to be associated with oncogenesis) for degradation. Therefore, it is of interest to study PBM–PDZ interaction towards its possible inhibition with a potential inhibitor. Thus, four pharmocophore models of PBM−PDZ complex were developed. In order to obtain potent small molecules for its inhibition, a commercial compound database was screened using both these pharmacophore models and molecule docking method. These efforts identified four potential compounds (1−4) towards its inhibition with the docking scores range -18.2 to -15.0.