Structural insights into the interaction of three Y-shaped ligands with PI3Kα.

Class IA phosphoinositide 3-kinase alpha (PI3Kα) is an important drug target because it is one of the most frequently mutated proteins in human cancers. However, small molecule inhibitors currently on the market or under development have safety concerns due to a lack of selectivity. Therefore, other chemical scaffolds or unique mechanisms of catalytic kinase inhibition are needed. Here, we report the cryo-electron microscopy structures of wild-type PI3Kα, the dimer of p110α and p85α, in complex with three Y-shaped ligands [cpd16 (compound 16), cpd17 (compound 17), and cpd18 (compound 18)] of different affinities and no inhibitory effect on the kinase activity. Unlike ATP-competitive inhibitors, cpd17 adopts a Y-shaped conformation with one arm inserted into a binding pocket formed by R770 and W780 and the other arm lodged in the ATP-binding pocket at an angle that is different from that of the ATP phosphate tail. Such a special interaction induces a conformation of PI3Kα resembling that of the unliganded protein. These observations were confirmed with two isomers (cpd16 and cpd18). Further analysis of these Y-shaped ligands revealed the structural basis of differential binding affinities caused by stereo- or regiochemical modifications. Our results may offer a different direction toward the design of therapeutic agents against PI3Kα.

Identification of a Non-Nucleoside Reverse Transcriptase Inhibitor against Human Immunodeficiency Virus-1.

The HIV-1 infection epidemic remains a global health problem. Current antiretroviral treatments are effective in controlling the progression of a severe infection. However, the emergence of drug resistance requires an urgent identification of new treatment regimes. HIV-1 reverse transcriptase (RTs) has been a successful therapeutic target owing to its high specificity and potent antiviral properties; therefore, it has become an essential component of current HIV-1 standard treatments. This study identified a new HIV-1 RTs inhibitor (Compound #8) that is structurally unique and greatly effective against HIV-1 through chemical library screening and a medicinal chemistry program by analyzing the structure-activity relationship (SAR). Further analysis of molecular docking and mechanisms of action demonstrated that Compound #8 is a novel type of HIV-1 non-nucleoside reverse transcriptase inhibitor (NNRTI) with a flexible binding mode. Therefore, it exhibits great therapeutic potential when combined with other existing HIV-1 drugs. Our current studies suggest that Compound #8 is a promising novel scaffold for the development of new HIV-1 treatments.

Recent Advancements in the Development of Anti-Breast Cancer Synthetic Small Molecules.

Among all cancer types, breast cancer (BC) still stands as one of the most serious diseases responsible for a large number of cancer-associated deaths among women worldwide, and diagnosed cases are increasing year by year worldwide. For a very long time, hormonal therapy, surgery, chemotherapy, and radiotherapy were used for breast cancer treatment. However, these treatment approaches are becoming progressively futile because of multidrug resistance and serious side effects. Consequently, there is a pressing demand to develop more efficient and safer agents that can fight breast cancer belligerence and inhibit cancer cell proliferation, invasion and metastasis. Currently, there is an avalanche of newly designed and synthesized molecular entities targeting multiple types of breast cancer. This review highlights several important synthesized compounds with promising anti-BC activity that are categorized according to their chemical structures.

2-furyl(phenyl)methanol isolated from Atractilis gummifera rhizome exhibits anti-leishmanial activity.

We report for the first time the isolation of 2-furyl(phenyl)methanol (5) from the chloroform extracts of the Atractylis gummifera roots. A. gummifera is a thistle belonging to the Asteraceae family that produces the ent-kaurane diterpenoid glycoside atractyloside (ATR). ATR (1) was isolated and chemically modified to obtain its aglycone atractyligenin (2) and the methylated derivatives ATR-OMe (3) and genine-OMe (4). The compounds 1-5 were structurally characterised and evaluated against the intracellular amastigote, cultured within macrophages, and the extracellular promastigote of Leishmania donovani, the protozoan parasite responsible for the highly infective disease visceral leishmaniasis, which is fatal if untreated. The 2-furyl(phenyl)methanol 5 exhibited notable activity against the promastigote.

Quantitative Structure-Activity Relationship Study for HIV-1 LEDGF/p75 Inhibitors.

BACKGROUND: HIV-1 Integrase (IN) is an important target for the development of the new anti-AIDS drugs. HIV-1 LEDGF/p75 inhibitors, which block the integrase and LEDGF/p75 interaction, have been validated for reduction in HIV-1 viral replicative capacity. METHODS: In this work, computational Quantitative Structure-Activity Relationship (QSAR) models were developed for predicting the bioactivity of HIV-1 integrase LEDGF/p75 inhibitors. We collected 190 inhibitors and their bioactivities in this study and divided the inhibitors into nine scaffolds by the method of T-distributed Stochastic Neighbor Embedding (TSNE). These 190 inhibitors were split into a training set and a test set according to the result of a Kohonen's self-organizing map (SOM) or randomly. Multiple Linear Regression (MLR) models, support vector machine (SVM) models and two consensus models were built based on the training sets by 20 selected CORINA Symphony descriptors. RESULTS: All the models showed a good prediction of pIC50. The correlation coefficients of all the models were more than 0.7 on the test set. For the training set of consensus Model C1, which performed better than other models, the correlation coefficient(r) achieved 0.909 on the training set, and 0.804 on the test set. CONCLUSION: The selected molecular descriptors show that hydrogen bond acceptor, atom charges and electronegativities (especially π atom) were important in predicting the activity of HIV-1 integrase LEDGF/p75-IN inhibitors.

Synthesis of 2-Oxo-1, 2-Dihydroquinoline Chemotype with Multiple Attachment Points as Novel Screening Compounds for Drug Discovery.

The 2-oxo-1, 2-dihydroquinoline Chemotype is well represented among screening compound collection. However, the chemical space of 2-oxo-1, 2-dihydroquinoline has not been thoroughly investigated. In this work we report the synthesis of a small but novel 2-oxo-1, 2-dihydroquinoline compound array for screening purposes, especially in drug discovery, possessing three convenient point of diversity.

Recently disclosed chemical entities as potential candidates for management of tuberculosis.

Tuberculosis (TB) is one of the deadliest infectious diseases worldwide. The drug discovery process of novel, safe and effective agents to combat TB involves identification of new molecular targets and novel chemical scaffolds. The current anti-TB drug pipeline includes several small molecules with more to follow as new candidates are disclosed. This review highlights the most significant findings described in 78 international, European and US patents for chemically diverse compounds as prospective anti-TB medications. Main points of emphasis include chemical classification, in vitro and in vivo activity, ADME/Tox profile and mycobacterial target as described in each patent. The collective mass of compounds disclosed in the reviewed patents introduces new candidates as potential therapeutic agents for TB infections.