Design, synthesis, pharmacological evaluation, and computational study of benzo[d] isothiazol-based small molecule inhibitors targeting PD-1/PD-l1 interaction.

Blockade of the programmed cell death-1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway is an attractive strategy for immunotherapy, but the clinical application of small molecule PD-1/PD-L1 inhibitors remains unclear. In this work, based on BMS-202 and our previous work YLW-106, a series of compounds with benzo[d]isothiazol structure as scaffold were designed and synthesized. Their inhibitory activity against PD-1/PD-L1 interaction was evaluated by a homogeneous time-resolved fluorescence (HTRF) assay. Among them, LLW-018 (27c) exhibited the most potent inhibitory activity with an IC50 value of 2.61 nM. The cellular level assays demonstrated that LLW-018 exhibited low cytotoxicity against Jurkat T and MDA-MB-231. Further cell-based PD-1/PD-L1 blockade bioassays based on PD-1 NFAT-Luc Jurkat cells and PD-L1 TCR Activator CHO cells indicated that LLW-018 could interrupt PD-1/PD-L1 interaction with an IC50 value of 0.88 µM. Multi-computational methods, including molecular docking, molecular dynamics, MM/GBSA, MM/PBSA, Metadynamics, and QM/MM MD were utilized on PD-L1 dimer complexes, which revealed the binding modes and dissociation process of LLW-018 and C2-symmetric small molecule inhibitor LCH1307. These results suggested that LLW-018 exhibited promising potency as a PD-1/PD-L1 inhibitor for further investigation.

Application of molecular dynamics-based pharmacophore and machine learning approaches to identify novel Mcl1 inhibitors through drug repurposing and mechanics research.

Myeloid cell leukemia 1 (Mcl1), a critical protein that regulates apoptosis, has been considered as a promising target for antitumor drugs. The conventional pharmacophore screening approach has limitations in conformation sampling and data mining. Here, we offered an innovative solution to identify Mcl1 inhibitors with molecular dynamics-refined pharmacophore and machine learning methods. Considering the safety and druggability of FDA-approved drugs, virtual screening of the database was performed to discover Mcl1 inhibitors, and the hit was subsequently validated via TR-FRET, cytotoxicity, and flow cytometry assays. To reveal the binding characteristics shared by the hit and a typical Mcl1 selective inhibitor, we employed quantum mechanics and molecular mechanics (QM/MM) calculations, umbrella sampling, and metadynamics in this work. The combined studies suggested that fluvastatin had promising cell inhibitory potency and was suitable for further investigation. We believe that this research will shed light on the discovery of novel Mcl1 inhibitors that can be used as a supplemental treatment against leukemia and provide a possible method to improve the accuracy of drug repurposing with limited computational resources while balancing the costs of experimentation well.

[The development and Assessment on the general quality of life intrument for Chinese people].

OBJECTIVE: To develop a general quality of life (QOL) instrument for Chinese in accordance with the Chinese culture and to assess its reliability, validity and sensitivity. METHODS: A 35-item QOL questionnaire(QOL-35) was developed with reference to the World Health Organization QOL questionnaire(WHO-100) and the 36-item medical outcomes study on short-form health status(SF-36). Thirty five items were divided into six domains (general, physical, independent, psychological, social, environment) and one item on QOL transition. The reliability of QOL-35 was assessed by a test-retest survey among 127 adults with an interval of 24-72 hours. The internal consistency and validity were evaluated by a survey on 135 adults from outpatients or general population, using QOL-35, WHO-100 and SF-36. The adaptability was assessed by application to 1356 community-based samples in Beijing. RESULTS: (1)Test-retest reliability of QOL-35: weighted Kappa indexes for items were from 0.86 to 1.00. Intraclass correlation coefficients were from 0.68 to 0.94 for domains, and 0.94 for total score. (2) On internal consistency: Cronbach's Alphas were 0.93, 0.97 and 0.89 for QO1-35, WHO-100 and SF-36. (3)On construct validity. The accumulated proportions of variances of the preceding seven factors were 66.5%, 50.3% and 65.3% for QOL-35, WHO-100 and SF-36. (4) On criterion validity. Spearman correlation coefficients of total QOL score of QOL-35 with those of WHO-100 and SF-36 were 0.805 and 0.745. (5)The rates of chronic diseases were 53.1%, 33.1%, 26.4% and 25.1% from first to fourth quantile of the total QOL scores of QOL-35(P<0.05). (6)Cronbach's Alpha was from 0.68 to 0.93 in 135 subjects, and from 0.71 to 0.91 in 1356 individuals of natural population. CONCLUSION: The QOL-35 instrument satisfied test-retest reliability and was highly correlated with WHO-100 and SF-36, having fewer items but better construction validity, better internal consistency, and better discrimination ability. We suggested that QOL-35 be used as a replicable tool to assess quality of life in the Chinese general population.