Pharmacoinformatics approaches in the discovery of drug-like antimicrobials of plant origin.

Medicinal plants have served as an important source for addressing the ailments of humans and animals alike. The emergence of advanced technologies in the field of drug discovery and development has helped in isolating various bioactive phytochemicals and developing them as drugs. Owing to their significant pharmacological benefits and minimum adverse effects, they not only serve as good candidates for therapeutics themselves but also help in the identification and development of related drug like molecules against various metabolic and infectious diseases. The ever-increasing diversity, severity and incidence of infectious diseases has resulted in an exaggerated mortality and morbidity levels. Geno-proteomic mutations in microbes, irrational prescribing of antibiotics, antimicrobial resistance and human population explosion, all call for continuous efforts to discover and develop alternated therapeutic options against the microbes. This review article describes the pharmacoinformatics tools and methods which are currently used in the discovery of bioactive phytochemicals, thus making the process more efficient and effective. The pharmacological aspects of the drug discovery and development process have also been reviewed with reference to the in silico activities. Communicated by Ramaswamy H. Sarma.

In-vitro evaluation and in-silico studies applied on newly synthesized amide derivatives of N-phthaloylglycine as Butyrylcholinesterase (BChE) inhibitors.

Amide derivatives of N-phthaloylglycine were synthesized under Schotten Baumann reaction condition. The structures of synthesized compounds (4a-d) were characterized by using FTIR, 1HNMR and EI-MS. The compounds were evaluated for their in-vitro Butyrylcholinesterase inhibition and all of them exhibited good activity against this enzyme. Compound 4a (IC50 = 6.5 ±â€¯0.1) was found to be most potent compared with the reference compound Galantamine (IC50 = 6.6 ±â€¯0.00038) and the other compounds (4b,4c,4d) were also possess that activity and hence can be employed for the discovery of lead compounds against Alzheimer's disease. The depth analysis of the binding mechanism of these newly synthesized compounds inside the binding gorge of BChE, an in silico technique, molecular docking was performed. All the compounds were found to be well accommodated within the binding pocket of BChE. Compounds 4a, 4b and 4c showed hydrogen bonding interaction with binding site residue TYR332. Moreover, hydrophobic and π-π interaction assisted the compounds to attain their enzyme inhibitory activity. These theoretical studies showed significant correlation with experimental results.

Protease-activated receptor 4 deficiency offers cardioprotection after acute ischemia reperfusion injury.

Protease-activated receptor (PAR)4 is a low affinity thrombin receptor with less understood function relative to PAR1. PAR4 is involved in platelet activation and hemostasis, but its specific actions on myocyte growth and cardiac function remain unknown. This study examined the role of PAR4 deficiency on cardioprotection after myocardial ischemia-reperfusion (IR) injury in mice. When challenged by in vivo or ex vivo IR, PAR4 knockout (KO) mice exhibited increased tolerance to injury, which was manifest as reduced infarct size and a more robust functional recovery compared to wild-type mice. PAR4 KO mice also showed reduced cardiomyocyte apoptosis and putative signaling shifts in survival pathways in response to IR. Inhibition of PAR4 expression in isolated cardiomyocytes by shRNA offered protection against thrombin and PAR4-agonist peptide-induced apoptosis, while overexpression of wild-type PAR4 significantly enhanced the susceptibility of cardiomyocytes to apoptosis, even under low thrombin concentrations. Further studies implicate Src- and epidermal growth factor receptor-dependent activation of JNK on the proapoptotic effect of PAR4 in cardiomyocytes. These findings reveal a pivotal role for PAR4 as a regulator of cardiomyocyte survival and point to PAR4 inhibition as a therapeutic target offering cardioprotection after acute IR injury.