Plant-based therapies date back centuries. Cannabis sativa is one such plant that was used medicinally up until the early part of the 20th century. Although rich in diverse and interesting phytochemicals, cannabis was largely ignored by the modern scientific community due to its designation as a schedule 1 narcotic and restrictions on access for research purposes. There was renewed interest in the early 1990s when the endocannabinoid system (ECS) was discovered, a complex network of signaling pathways responsible for physiological homeostasis. Two key components of the ECS, cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2), were identified as the molecular targets of the phytocannabinoid Δ9-tetrahydrocannabinol (Δ9-THC). Restrictions on access to cannabis have eased worldwide, leading to a resurgence in interest in the therapeutic potential of cannabis. Much of the focus has been on the two major constituents, Δ9-THC and cannabidiol (CBD). Cannabis contains over 140 phytocannabinoids, although only a handful have been tested for pharmacological activity. Many of these minor cannabinoids potently modulate receptors, ionotropic channels, and enzymes associated with the ECS and show therapeutic potential individually or synergistically with other phytocannabinoids. The following review will focus on the pharmacological developments of the next generation of phytocannabinoid therapeutics.Retinoid X receptor (RXR) heterodimers such as PPAR/RXR, LXR/RXR, and FXR/RXR can be activated by RXR agonists alone and are therefore designated as permissive. Similarly, existing RXR antagonists show allosteric antagonism toward partner receptor agonists in these permissive RXR heterodimers. Here, we show 1-(3-(2-ethoxyethoxy)-5,5,8,8-tetramethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-2-(trifluoromethyl)-1H-benzo[d]imidazole-5-carboxylic acid (14, CBTF-EE) as the first RXR antagonist that does not show allosteric inhibition in permissive RXR heterodimers. This compound was designed based on the hypothesis that RXR antagonists that do not induce conformational changes of RXR would not exhibit such allosteric inhibition. CD spectra and X-ray co-crystallography of the complex of 14 and the RXR ligand binding domain (LBD) confirmed that 14 does not change the conformation of hRXR-LBD. The X-ray structure analysis revealed that 14 binds at the entrance of the ligand binding pocket (LBP), blocking access to the LBP and thus serving as a "gatekeeper".The phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) signaling pathway is a frequently dysregulated pathway in human cancer, and PI3Kα is one of the most frequently mutated kinases in human cancer. A PI3Kα-selective inhibitor may provide the opportunity to spare patients the side effects associated with broader inhibition of the class I PI3K family.  https://www.selleckchem.com/products/paeoniflorin.html  Here, we describe our efforts to discover a PI3Kα-selective inhibitor by applying structure-based drug design (SBDD) and computational analysis. A novel series of compounds, exemplified by 2,2-difluoroethyl (3S)-3-[2'-amino-5-fluoro-2-(morpholin-4-yl)-4,5'-bipyrimidin-6-yl]amino-3-(hydroxymethyl)pyrrolidine-1-carboxylate (1) (PF-06843195), with high PI3Kα potency and unique PI3K isoform and mTOR selectivity were discovered. We describe here the details of the design and synthesis program that lead to the discovery of 1.We present a Gaussian-basis implementation of orbital-free density-functional theory (OF-DFT) in which the trust-region image method (TRIM) is used for optimization. This second-order optimization scheme has been constructed to provide benchmark all-electron results with very tight convergence of the particle-number constraint, associated chemical potential, and electron density. It is demonstrated that, by preserving the saddle-point nature of the optimization and simultaneously optimizing the density and chemical potential, an order of magnitude reduction in the number of iterations required for convergence is obtained. The approach is compared and contrasted with a new implementation of the nested optimization scheme put forward by Chan, Cohen, and Handy. Our implementation allows for semilocal kinetic-energy (and exchange-correlation) functionals to be handled self-consistently in all-electron calculations. The all-electron Gaussian-basis setting for these calculations will enable direct comparison with a wide range of standard high-accuracy quantum-chemical methods as well as with Kohn-Sham density-functional theory. We expect that the present implementation will provide a useful tool for analyzing the performance of approximate kinetic-energy functionals in finite systems.Sickle cell disease (SCD) is a genetic disorder caused by a single point mutation (β6 Glu → Val) on the β-chain of adult hemoglobin (HbA) that results in sickled hemoglobin (HbS). In the deoxygenated state, polymerization of HbS leads to sickling of red blood cells (RBC). Several downstream consequences of polymerization and RBC sickling include vaso-occlusion, hemolytic anemia, and stroke. We report the design of a noncovalent modulator of HbS, clinical candidate PF-07059013 (23). The seminal hit molecule was discovered by virtual screening and confirmed through a series of biochemical and biophysical studies. After a significant optimization effort, we arrived at 23, a compound that specifically binds to Hb with nanomolar affinity and displays strong partitioning into RBCs. In a 2-week multiple dose study using Townes SCD mice, 23 showed a 37.8% (±9.0%) reduction in sickling compared to vehicle treated mice. 23 (PF-07059013) has advanced to phase 1 clinical trials.Indole (1) is a heterocyclic aromatic compound consisting of a pyrrole ring (5MR) fused with a benzene ring (6MR). This compound is highly stable, found in several natural products, and is used as a building block for the synthesis of novel organic compounds. On the other hand, its isomers isoindole (2) and indolizine (3) are much less stable and are normally isolated when bonded to other stable compounds. The stability of these compounds has been analyzed in terms of local aromaticity using magnetic, geometric, and delocalization criteria. All criteria used indicate that there is a continuing reduction in aromaticity of the 6MR, whereas for the 5MR the aromaticity increases when going from 1 to 3. This is confirmed by Natural Resonance theory calculations indicating that the resonant structures which retain the aromaticity of the 5MR are the ones having the largest contribution. The results obtained suggest that the relative stability of indole isomers is a consequence of the Glidewell-Lloyd rule.