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1.
Acta Pharmaceutica Sinica B ; (6): 2462-2478, 2022.
Article in English | WPRIM | ID: wpr-929391

ABSTRACT

Drug optimization, which improves drug potency/specificity by structure‒activity relationship (SAR) and drug-like properties, is rigorously performed to select drug candidates for clinical trials. However, the current drug optimization may overlook the structure‒tissue exposure/selectivity-relationship (STR) in disease-targeted tissues vs. normal tissues, which may mislead the drug candidate selection and impact the balance of clinical efficacy/toxicity. In this study, we investigated the STR in correlation with observed clinical efficacy/toxicity using seven selective estrogen receptor modulators (SERMs) that have similar structures, same molecular target, and similar/different pharmacokinetics. The results showed that drug's plasma exposure was not correlated with drug's exposures in the target tissues (tumor, fat pad, bone, uterus), while tissue exposure/selectivity of SERMs was correlated with clinical efficacy/safety. Slight structure modifications of four SERMs did not change drug's plasma exposure but altered drug's tissue exposure/selectivity. Seven SERMs with high protein binding showed higher accumulation in tumors compared to surrounding normal tissues, which is likely due to tumor EPR effect of protein-bound drugs. These suggest that STR alters drug's tissue exposure/selectivity in disease-targeted tissues vs. normal tissues impacting clinical efficacy/toxicity. Drug optimization needs to balance the SAR and STR in selecting drug candidate for clinical trial to improve success of clinical drug development.

2.
Article in Chinese | WPRIM | ID: wpr-928888

ABSTRACT

The chemical characterization analysis of a medical device often results in chemical substances with unknown toxicities. While identification of each individual toxicity could result in a time-consuming hurdle with tremendous labor and financial burden, quantitative structure-activity relationship (QSAR) is of great significance for toxicity risk assessment of such chemical substances. By establishing quantitative relationship between the molecular structures or active groups of similar chemical compounds with their biological activities, QSAR can be utilized to predict the toxicity of such target compounds with significantly reduced cost and time. In this article, the authors generally summarized the mechanisms of QSAR approaches, current applications of QSAR modeling in the field of medical device, an introduction of the characteristics of publicly and commercially-available QSAR software, and briefly explored future trends of QSAR modeling in medical device toxicological risk assessment. The utilization of QSAR would undoubtedly further advance the toxicological risk assessment of medical devices.


Subject(s)
Quantitative Structure-Activity Relationship , Risk Assessment , Software
3.
Acta Pharmaceutica Sinica ; (12): 605-614, 2022.
Article in Chinese | WPRIM | ID: wpr-922903

ABSTRACT

Proteasome controls the degradation of proteins closely related to life activities and plays a key role in the maintenance of protein homeostasis. Proteasome activities decrease with aging, followed by the overwhelming production of damaged proteins which far exceed the protein consumption. Accumulation of these proteins leads to various diseases including neurodegenerative diseases. Therefore, inducing toxic protein degradation is considered as a promising solution for the treatment of these diseases, while increasing the activity of proteasome is considered as an important strategy. However, the research in this field is still in the preliminary stage, and this review will focus on the discussion of the research progress of various small molecule proteasome activators, including research methods, pharmacological effects, structure-activity relationships and the existing problems.

4.
Acta Pharmaceutica Sinica ; (12): 545-552, 2021.
Article in Chinese | WPRIM | ID: wpr-873778

ABSTRACT

The purpose of this study was to discover novel inhibitors of sirtuin-1 (SIRT1) that could be used in the treatment of acute myeloid leukemia (AML). Eight potential SIRT1 inhibitors were identified from 231 511 natural drug-like molecules by virtual screening-based molecular docking and molecular mechanics-generalized Born surface area (MM-GBSA) calculation of binding free energies. Using existing SIRT1 inhibitor molecules as training and test sets, a series of quantitative structure-activity relationship models were established, and the best quantitative structure-activity relationship (QSAR) model was used to predict the IC50 of these 8 potential inhibitor molecules for SIRT1. Subsequently, molecular dynamics simulations were performed to verify the binding mode and stability of these complexes of potential inhibitors and SIRT1 protein. Finally, the activity of these potential SIRT1 inhibitors was verified by cell proliferation assays of OCI-AML2, OCI-AML3 and MV4-11 cells and SIRT1 enzyme activity assays, and it was found that 5 compounds could inhibit AML cell proliferation. Among them, the most active compound, ZINC000001774455, had an IC50 of 2.29 ± 0.09 μmol·L-1 with OCI-AML2 cells, and at a concentration of 1 μmol·L-1, the inhibitory ratio of this compound on SIRT1 protein activity was 65.33%. ZINC000001774455 can be used as a lead compound for the development of new AML treatments.

5.
Acta Pharmaceutica Sinica ; (12): 3401-3413, 2021.
Article in Chinese | WPRIM | ID: wpr-906840

ABSTRACT

Febuxostat, as a xanthine oxidase inhibitor, is a classic anti-gout drug with significant therapeutic effects and good tolerability. The structures of febuxostat and its derivatives can be divided into two parts: a substituted phenyl ring and a five-membered or six-membered heterocyclic ring with a carboxyl substitution. This paper reviewed the research progress of febuxostat derivatives in recent ten years and classified the structure-activity relationships of various febuxostat derivatives. Exploring the action mechanisms and structure-activity relationships of xanthine oxidase inhibitors might be significant for the rational design and development of new anti-gout chemical entities.

6.
Article in Chinese | WPRIM | ID: wpr-904338

ABSTRACT

@#SGP-2 was an acidic polysaccharide with good hypoglycemic activity isolated from Sarcandra glabra (Thunb.) Nakai in the previous study. This study used the laser particle size analysis, transmission electron microscopy (TEM) and atomic force microscopy(AFM) analysis techniques to analyze the advanced structure of SGP-2 in the deionized water and Na2SO4 solution and discuss the structure-activity relationship between the advanced structural characterizations and the α-glucosidase inhibition activities of SGP-2 and its derivative in vitro.Results showed that SGP-2 presented aggregates and spheres in the deionized water.AFM analysis showed that the diameter of SGP-2 was 33 nm and the height was 1.84 nm, whereas compact spherical conformations with high degrees of branching were observed in 0.05 mol/L Na2SO4 solution and SGP-2 had smaller particle size in saline solution compared with that in water.SGP-2 treated by 0.5 mol/L urea and dialysis at the concentration of 1 000 μg/mL showed 98.8% inhibition activity of that from untreated SGP-2. The inhibition rate of short rod conformation with branches reached 83.3% when the temperature rose up to 140 °C, and the α-glucosidase inhibition activity was even higher than that of untreated SGP-2 under the same condition; while SGP-2 with the tangled glycan chains under the condition of carboxyl group reduced had much lower inhibition activity.Therefore, the spherical structure or the short rod conformation with branches played an important role in the activity of SGP-2. This research provides a theoretical basis for further study of structure-function relationship between the advanced structure and activity of polysaccharides.

7.
Article in Chinese | WPRIM | ID: wpr-904324

ABSTRACT

@#In this study, 10 aporphine alkaloids were synthesized with 1, 2-methylenedioxy substituent in ring A and 9, 10, 11-position with different substituents in ring D. Their structures were determined by ESI-MS,13C NMR and 1 H NMR.The potencial antitumor activity of these compounds against B16F10 melanoma cells were evaluated by MTT assay, and their structure-activity relationship was further analyzed.Meanwhile, zebrafish acute toxicity test was conducted to evaluate the safety of the active compounds.The results showed that some compounds had strong inhibitory activity on tumor cells, and could significantly inhibit the proliferation of B16F10 melanoma cells.Compound IVa has the best anti-melanoma activity with wide safety range, and can be used as a lead compound for further study on anti-proliferation of B16F10 melanoma cells.

8.
Acta Pharmaceutica Sinica B ; (6): 2655-2669, 2021.
Article in English | WPRIM | ID: wpr-888878

ABSTRACT

Peptide inhibition of the interactions of the tumor suppressor protein P53 with its negative regulators MDM2 and MDMX activates P53

9.
Acta Pharmaceutica Sinica B ; (6): 2416-2448, 2021.
Article in English | WPRIM | ID: wpr-888868

ABSTRACT

Proteins and peptides (PPs) have gradually become more attractive therapeutic molecules than small molecular drugs due to their high selectivity and efficacy, but fewer side effects. Owing to the poor stability and limited permeability through gastrointestinal (GI) tract and epithelia, the therapeutic PPs are usually administered by parenteral route. Given the big demand for oral administration in clinical use, a variety of researches focused on developing new technologies to overcome GI barriers of PPs, such as enteric coating, enzyme inhibitors, permeation enhancers, nanoparticles, as well as intestinal microdevices. Some new technologies have been developed under clinical trials and even on the market. This review summarizes the history, the physiological barriers and the overcoming approaches, current clinical and preclinical technologies, and future prospects of oral delivery of PPs.

10.
Acta Pharmaceutica Sinica B ; (6): 2396-2415, 2021.
Article in English | WPRIM | ID: wpr-888867

ABSTRACT

The need for long-term treatments of chronic diseases has motivated the widespread development of long-acting parenteral formulations (LAPFs) with the aim of improving drug pharmacokinetics and therapeutic efficacy. LAPFs have been proven to extend the half-life of therapeutics, as well as to improve patient adherence; consequently, this enhances the outcome of therapy positively. Over past decades, considerable progress has been made in designing effective LAPFs in both preclinical and clinical settings. Here we review the latest advances of LAPFs in preclinical and clinical stages, focusing on the strategies and underlying mechanisms for achieving long acting. Existing strategies are classified into manipulation of

11.
Acta Pharmaceutica Sinica B ; (6): 1947-1964, 2021.
Article in English | WPRIM | ID: wpr-888844

ABSTRACT

Anoctamin 1 (ANO1) is a kind of calcium-activated chloride channel involved in nerve depolarization. ANO1 inhibitors display significant analgesic activity by the local peripheral and intrathecal administration. In this study, several thiophenecarboxylic acid and benzoic acid derivatives were identified as novel ANO1 inhibitors through the shape-based virtual screening, among which the 4-arylthiophene-3-carboxylic acid analogues with the best ANO1 inhibitory activity were designed, synthesized and compound

12.
Acta Pharmaceutica Sinica B ; (6): 1446-1468, 2021.
Article in English | WPRIM | ID: wpr-888814

ABSTRACT

The 90-kiloDalton (kD) heat shock protein (Hsp90) is a ubiquitous, ATP-dependent molecular chaperone whose primary function is to ensure the proper folding of several hundred client protein substrates. Because many of these clients are overexpressed or become mutated during cancer progression, Hsp90 inhibition has been pursued as a potential strategy for cancer as one can target multiple oncoproteins and signaling pathways simultaneously. The first discovered Hsp90 inhibitors, geldanamycin and radicicol, function by competitively binding to Hsp90's N-terminal binding site and inhibiting its ATPase activity. However, most of these N-terminal inhibitors exhibited detrimental activities during clinical evaluation due to induction of the pro-survival heat shock response as well as poor selectivity amongst the four isoforms. Consequently, alternative approaches to Hsp90 inhibition have been pursued and include C-terminal inhibition, isoform-selective inhibition, and the disruption of Hsp90 protein-protein interactions. Since the Hsp90 protein folding cycle requires the assembly of Hsp90 into a large heteroprotein complex, along with various co-chaperones and immunophilins, the development of small molecules that prevent assembly of the complex offers an alternative method of Hsp90 inhibition.

13.
Article in English | WPRIM | ID: wpr-888794

ABSTRACT

Ocotillol (OT)-type ginsenosides, one subtype of ginsenosides, consist of a dammarane skeleton and a tetrahydrofuran ring. Most naturally-occurring OT-type ginsenosides exist in Panax species, particularly in Panax quinquefolius, which may be attributed to the warm and humid climate of its native areas. Till now, merely 28 types of naturally-occurring OT-type ginsenosides have been isolated. In contrast, semi-synthesized OT-type ginsenosides are attracted considerable attentions. These ginsenosides can be obtained through oxidation and cyclization of side chains of dammarane-type ginsenosides, and other methods, which may change their physical and chemical properties and further improve their bioavailabilities. It is also notable that the pharmacological activities of ginsenosides are closely related to the stereoisomers caused by the configuration at C-20. Semi-synthesis of OT-type ginsenosides can facilitate our understanding of the biosynthesis, transformation and metabolism of OT-type ginsenosides in the body. This review will systematically summarize the research progress on naturally-occurring and semi-synthetic OT-type ginsenosides, which provides a theoretical basis for their bioactivity-guided research.

14.
Acta Pharmaceutica Sinica ; (12): 1265-1278, 2021.
Article in Chinese | WPRIM | ID: wpr-887065

ABSTRACT

Indoleamine 2,3-dioxygenase 1 (IDO1) and tryptophan 2,3-dioxygenase (TDO) catalyze the initial and rate limiting step in the catabolism of tryptophan, which is related to tumor immune tolerance and poor prognosis in patients. In this regard, two enzymes have become important therapeutic targets for tumor immunotherapy. So far, nine IDO1 inhibitors and three IDO1/TDO dual inhibitors have entered clinical trials. This review summarizes the research progress of IDO1 inhibitors, TDO inhibitors and IDO1/TDO dual inhibitors from the perspective of medicinal chemistry.

15.
Acta Pharmaceutica Sinica ; (12): 1880-1892, 2021.
Article in Chinese | WPRIM | ID: wpr-887015

ABSTRACT

As a key signal transduction molecule involved in the innate immune response, stimulator of interferon genes (STING) is triggered by cytosolic DNA from pathogen and host origins, and plays an important role in inducing the secretion of type I interferons and proinflammatory cytokines, thereby defending against viral and intracellular bacterial infections and regulating the production of spontaneous antitumor immune responses in vivo. Thus, STING agonists have shown useful therapeutic effects for pathogen infection and cancer. In the past decade research on STING and its agonists has progressed rapidly. Here, we summarize recent advances in the structure and activation of STING and the mechanism of the cGAS-STING pathway. In particular, we review research advances of STING agonists, analyze the crystal structure of STING in complex with its agonists and the structure-activity relationship of STING agonists, and summarize the strong challenges of developing STING agonists.

16.
Acta Pharmaceutica Sinica B ; (6): 1300-1314, 2021.
Article in English | WPRIM | ID: wpr-881200

ABSTRACT

HMG-CoA reductase (HMGCR) protein is usually upregulated after statin (HMGCR inhibitor) treatment, which inevitably diminishes its therapeutic efficacy, provoking the need for higher doses associated with adverse effects. The proteolysis targeting chimera (PROTAC) technology has recently emerged as a powerful approach for inducing protein degradation. Nonetheless, due to their bifunctional nature, developing orally bioavailable PROTACs remains a great challenge. Herein, we identified a powerful HMGCR-targeted PROTAC (

17.
Acta Pharmaceutica Sinica B ; (6): 810-822, 2021.
Article in English | WPRIM | ID: wpr-881170

ABSTRACT

Of all known small molecules targeting human immunodeficiency virus (HIV) capsid protein (CA), PF74 represents by far the best characterized chemotype, due to its ability to confer antiviral phenotypes in both early and late phases of viral replication. However, the prohibitively low metabolic stability renders PF74 a poor antiviral lead. We report herein our medicinal chemistry efforts toward identifying novel and metabolically stable small molecules targeting the PF74 binding site. Specifically, we replaced the inter-domain-interacting, electron-rich indole ring of PF74 with less electron-rich isosteres, including imidazolidine-2,4-dione, pyrimidine-2,4-dione, and benzamide, and identified four potent antiviral compounds (

18.
Acta Pharmaceutica Sinica B ; (6): 781-794, 2021.
Article in English | WPRIM | ID: wpr-881169

ABSTRACT

Fibroblast growth factor receptors (FGFRs) have emerged as promising targets for anticancer therapy. In this study, we synthesized and evaluated the biological activity of 66 pyrazolo[3,4-

19.
Acta Pharmaceutica Sinica B ; (6): 488-504, 2021.
Article in English | WPRIM | ID: wpr-881149

ABSTRACT

Medulloblastoma (MB) is a common yet highly heterogeneous childhood malignant brain tumor, however, clinically effective molecular targeted therapy is lacking. Modulation of hedgehog (HH) signaling by epigenetically targeting the transcriptional factors GLI through bromodomain-containing protein 4 (BRD4) has recently spurred new interest as potential treatment of HH-driven MB. Through screening of current clinical BRD4 inhibitors for their inhibitory potency against glioma-associated oncogene homolog (GLI) protein, the BRD4 inhibitor

20.
Acta Pharmaceutica Sinica B ; (6): 373-393, 2021.
Article in English | WPRIM | ID: wpr-881142

ABSTRACT

The 18 kDa translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor, is predominately localized to the outer mitochondrial membrane in steroidogenic cells. Brain TSPO expression is relatively low under physiological conditions, but is upregulated in response to glial cell activation. As the primary index of neuroinflammation, TSPO is implicated in the pathogenesis and progression of numerous neuropsychiatric disorders and neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), multiple sclerosis (MS), major depressive disorder (MDD) and obsessive compulsive disorder (OCD). In this context, numerous TSPO-targeted positron emission tomography (PET) tracers have been developed. Among them, several radioligands have advanced to clinical research studies. In this review, we will overview the recent development of TSPO PET tracers, focusing on the radioligand design, radioisotope labeling, pharmacokinetics, and PET imaging evaluation. Additionally, we will consider current limitations, as well as translational potential for future application of TSPO radiopharmaceuticals. This review aims to not only present the challenges in current TSPO PET imaging, but to also provide a new perspective on TSPO targeted PET tracer discovery efforts. Addressing these challenges will facilitate the translation of TSPO in clinical studies of neuroinflammation associated with central nervous system diseases.

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