No abstract

P21-activated kinases (PAKs) are serine/threonine protein kinase which have six different isoforms (PAK1–6). Of those, PAK1 is overexpressed in many cancers and considered to be a major chemotherapeutic target. Most of the developed PAK1 inhibitor drugs work as pan-PAK inhibitors and show undesirable toxicity due to having untargeted kinase inhibition activities. Selective PAK1 inhibitors are therefore highly desired and oncogenic drug hunters are trying to develop allosteric PAK1 inhibitors. We previously synthesized 1,2,3-triazolyl ester of ketorolac (15K) through click chemistry technique, which exhibits significant anti-cancer effects via inhibiting PAK1. Based on the selective anticancer effects of 15K against PAK1-dependent cancer cells, we hypothesize that it may act as an allosteric PAK1 inhibitor. In this study, computational analysis was done with 15K to explore its quantum chemical and thermodynamic properties, molecular interactions and binding stability with PAK1, physicochemical properties, ADMET, bioactivities, and druglikeness features. Molecular docking analysis demonstrates 15K as a potent allosteric ligand that strongly binds to a novel allosteric site of PAK1 (binding energy ranges – 8.6 to – 9.2 kcal/mol) and does not target other PAK isoforms; even 15K shows better interactions than another synthesized PAK1 inhibitor. Molecular dynamics simulation clearly supports the stable binding properties of 15K with PAK1 crystal. Density functional theory-based calculations reveal that it can be an active drug with high softness and moderate polarity, and ADMET predictions categorize it as a non-toxic drug as evidenced by in vitro studies with brine shrimp and fibroblast cells. Structure–activity relationship clarifies the role of ester bond and triazol moiety of 15K in establishing novel allosteric interactions. Our results summarize that 15K selectively inhibits PAK1 as an allosteric inhibitor and in turn shows anticancer effects without toxicity.

Sakuranetin (SKN), a naturally derived 7-O-methylated flavonoid, was first identified in the bark of the cherry tree (Prunus spp.) as an aglycone of sakuranin and then purified from the bark of Prunus puddum. It was later reported in many other plants including Artemisia campestris, Boesenbergia pandurata, Baccharis spp., Betula spp., Juglans spp., and Rhus spp. In plants, it functions as a phytoalexin synthesized from its precursor naringenin and is the only known phenolic phytoalexin in rice, which is released in response to different abiotic and biotic stresses such as UV-irradiation, jasmonic acid, cupric chloride, L-methionine, and the phytotoxin coronatine. Till date, SKN has been widely reported for its diverse pharmacological benefits including antioxidant, anti-inflammatory, antimycobacterial, antiviral, antifungal, antileishmanial, antitrypanosomal, glucose uptake stimulation, neuroprotective, antimelanogenic, and antitumor properties. Its pharmacokinetics and toxicological properties have been poorly understood, thus warranting further evaluation together with exploring other pharmacological properties such as antidiabetic, neuroprotective, and antinociceptive effects. Besides, in vivo studies or clinical investigations can be done for proving its effects as antioxidant and anti-inflammatory, antimelanogenic, and antitumor agent. This review summarizes all the reported investigations with SKN for its health-beneficial roles and can be used as a guideline for future studies.

Lambertianic acid (LA) is a diterpene bioactive compound mainly purified from different species of Pinus. It is an optical isomer of another natural compound daniellic acid and was firstly purified from Pinus lambertiana. LA can be synthesized in laboratory from podocarpic acid. It has been reported to have potential health benefits in attenuating obesity, allergies and different cancers including breast, liver, lung and prostate cancer. It exhibits anticancer properties through inhibiting cancer cell proliferation and survival, and inducing apoptosis, targeting major signalling components including AKT, AMPK, NFkB, COX-2, STAT3, etc. Most of the studies with LA were done using in vitro models, thus warranting future investigations with animal models to evaluate its pharmacological effects such as antidiabetic, anti-inflammatory and neuroprotective effects as well as to explore the underlying molecular mechanisms and toxicological profile. This review describes the chemistry, source, purification and therapeutic potentials of LA and it can therefore be a suitable guideline for any future study with LA.