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As an appealing approach for discovering novel leads, the key advantage of de novo drug design lies in its ability to explore a much broader dimension of chemical space, without being confined to the knowledge of existing compounds. So far, many generative models have been described in the literature, which have completely redefined the concept of de novo drug design. However, many of them lack practical value for real-world drug discovery. In this work, we have developed a graph-based generative model within a reinforcement learning framework, namely, METEOR (Molecular Exploration Through multiplE-Objective Reinforcement). The backend agent of METEOR is based on the well-established GCPN model. To ensure the overall quality of the generated molecular graphs, we implemented a set of rules to identify and exclude undesired substructures. Importantly, METEOR is designed to conduct multi-objective optimization, i.e., simultaneously optimizing binding affinity, drug-likeness, and synthetic accessibility of the generated molecules under the guidance of a special reward function. We demonstrate in a specific test case that without prior knowledge of true binders to the chosen target protein, METEOR generated molecules with superior properties compared to those in the ZINC 250k data set. In conclusion, we have demonstrated the potential of METEOR as a practical tool for generating rational drug-like molecules in the early phase of drug discovery. [ABSTRACT FROM AUTHOR]

The B‐cell lymphoma‐2 (BCL‐2) family of proteins plays a crucial role in the regulation of apoptosis, offering a dual mechanism for its control. Numerous studies have established a strong association between gene disorders of these proteins and the proliferation of diverse cancer cell types. Consequently, the identification and development of drugs targeting BCL‐2 family proteins have emerged as a prominent area in antitumor therapy. Over the last two decades, several small‐molecules have been designed to modulate the protein–protein interactions between anti‐ and proapoptotic BCL‐2 proteins, effectively suppressing tumor growth and metastasis in vivo. The primary focus of research has been on developing BCL‐2 homology 3 (BH3) mimetics to target antiapoptotic BCL‐2 proteins, thereby competitively releasing proapoptotic BCL‐2 proteins and restoring the blocked intrinsic apoptotic program. Additionally, for proapoptotic BCL‐2 proteins, exogenous small molecules have been explored to activate cell apoptosis by directly interacting with executioner proteins such as BCL‐2‐associated X protein (BAX) or BCL‐2 homologous antagonist/killer protein (BAK). In this comprehensive review, we summarize the inhibitors and activators (sensitizers) of BCL‐2 family proteins developed over the past decades, highlighting their discovery, optimization, preclinical and clinical status, and providing an overall landscape of drug development targeting these proteins for therapeutic purposes. [ABSTRACT FROM AUTHOR]

Context: Early diagnosis and early treatment of cornual pregnancy are very important. Conservative treatment before rupture can greatly reduce the patient's trauma. It's very important to choose a treatment method for cornual pregnancy with a high level of effectiveness, few adverse reactions, and no effects on fertility.Objective: The study intended to compare the clinical efficacy of different treatments for unruptured cornual pregnancy to find a safe, effective, minimally invasive treatment for unruptured cornual pregnancy that has few side effects and doesn't affect fertility.Design: The research team retrospectively collected the clinical data of patients to analyze the benefits of treatments for cornual pregnancy.Setting: The study took place in the Department of Obstetrics and Gynecology at the Wuhan Third Hospital in Wuhan, Hubei Province, China.Participants: Participants were 61 patients with an unruptured cornual pregnancy who had been admitted to the hospital between September 2002 and May 2012.Intervention: Participants were divided into four groups according to the treatment they received: (1) 20 patients who had been orally administered mifepristone combined with misoprostol and received uterine curettage were included in the drug abortion + curettage group (D group); (2) 16 patients who had received ultrasound-guided uterine aspiration were included in the uterine aspiration group (U group); (3) 15 patients who had received methotrexate (MTX) chemotherapy were included in the chemotherapy group (C group); and (4) 10 patients who had received ultrasound-guided hysteroscope operation were included in the hysteroscope operation group (H group).Outcome Measures: Adverse reactions and the decrease in participants' blood β-HCG were recorded in detail. The participants were followed up for two months.Results: Of the 61 participants, 12 underwent surgery after failed conservative treatment, one in the D group, four in the U group, three in the C group, and four in the H group. No significant difference existed in the baseline data among the four groups. The decline rates of β-HCG at seven days after treatment and the treatment success rates of participants in the D group were significantly higher than those in the U group, the C group, and the H group (all P < .05). The time at which the β-HCG turned negative and the average hospital stays weren't significantly different among the four groups.Conclusions: The current study found that oral administration of mifepristone, combined with misoprostol, plus uterine curettage was superior to the other three methods in treatment of unruptured cornual pregnancy. The drug abortion + curettage treatment was found to be a safe, effective, minimally invasive treatment for unruptured cornual pregnancy, which has few side effects and doesn't affect fertility. [ABSTRACT FROM AUTHOR]

The cyclizations of two structurally similar 2-oxo-5-hexenyl-type radicals are investigated by ab initio and density functional calculations. The calculations mirror the outcome of simple model reactions and are useful in interpreting the studies of more complex systems.