A rapid, simple and sensitive high-performance liquid chromatography (HPLC) method has been developed for quantification of olmesartan medoxomil (OLM) and amlodipine besylate (AM) in plasma. The assay enables the measurement of OLM and AM for therapeutic drug monitoring with a minimum detectable limit of 2 ng mL. The method involves a simple, one-step extraction procedure and analytical recovery was above 50%. The separation was performed on an analytical 250 × 4.6 mm Eurospher 100 ^-5 C18 column. The wavelength was set at 239 nm. The mobile phase was a mixture of acetonitrile:0.05 M ammonium acetate buffer: 0.1 mL triethylamine at pH 6.8 was selected at a flow rate of 1.0 mL min. The calibration curve for the determination of OLM and AM in plasma was linear over the range 2-2500 and 8-10,000 ng mL AM and OLM. The coefficients of variation for interday and intraday assay were found to be <15%. The method can be applied to a pharmacokinetic and pharmacodynamic study of OLM and AM in a combined dosage form. Key words: Amlodipine besylate, high-performance liquid chromatography, olmesartan medoxomil, plasma.

The severe acute respiratory syndrome COVID-19 declared as a global pandemic by the World Health Organization has become the present wellbeing worry to the whole world. There is an emergent need to search for possible medications. Cressa cretica is reported to show antitubercular, antibacterial and expectorant property. In this research, we aim to prospect the COVID-19 main protease crystal structure (M^pro; PDB ID: 6LU7) and the active chemical constituents from Cressa cretica in order to understand the structural basis of their interactions. We examined the binding potential of active constituents of Cressa cretica plant to immensely conserved protein M^pro of SARS-CoV-2 followed by exploration of the vast conformational space of protein–ligand complexes by molecular dynamics (MD) simulations. The results suggest the effectiveness of 3,5-Dicaffeoylquinic acid and Quercetin against standard drug Remdesivir. The active chemical constituents exhibited good docking scores, and interacts with binding site residues of M^pro by forming hydrogen bond and hydrophobic interactions. 3,5-Dicaffeoylquinic acid showed the best affinity towards M^pro receptor which is one of the target enzymes required by SARS CoV-2 virus for replication suggesting it to be a novel research molecule. The potential of the active chemical constituents from Cressa cretica against the SARS-CoV-2 virus has best been highlighted through this study. Therefore, these chemical entities can be further scrutinized and provides direction for further consideration for in-vivo and in-vitro validations for the treatment of covid-19. Graphical Abstract Communicated by Ramaswamy H. Sarma

Cardiovascular diseases, including heart failure, stroke, and hypertension, affect 608 million people worldwide and cause 32% of deaths. Combination therapy is required in 60% of patients, involving concurrent Renin–Angiotensin–Aldosterone-System (RAAS) and Neprilysin inhibition. This study introduces a novel multi-target in-silico modeling technique (mt-QSAR) to evaluate the inhibitory potential against Neprilysin and Angiotensin-converting enzymes. Using both linear (GA-LDA) and non-linear (RF) algorithms, mt-QSAR classification models were developed using 983 chemicals to predict inhibitory effects on Neprilysin and Angiotensin-converting enzymes. The Box-Jenkins method, feature selection method, and machine learning algorithms were employed to obtain the most predictive model with ~ 90% overall accuracy. Additionally, the study employed virtual screening of designed scaffolds (Chalcone and its analogues, 1,3-Thiazole, 1,3,4-Thiadiazole) applying developed mt-QSAR models and molecular docking. The identified virtual hits underwent successive filtration steps, incorporating assessments of drug-likeness, ADMET profiles, and synthetic accessibility tools. Finally, Molecular dynamic simulations were then used to identify and rank the most favourable compounds. The data acquired from this study may provide crucial direction for the identification of new multi-targeted cardiovascular inhibitors.

A novel coronavirus SARS-CoV-2 has caused a worldwide pandemic and remained a severe threat to the entire human population. Researchers worldwide are struggling to find an effective drug treatment to combat this deadly disease. Many FDA-approved drugs from varying inhibitory classes and plant-derived compounds are screened to combat this virus. Still, due to the lack of structural information and several mutations of this virus, initial drug discovery efforts have limited success. A high-resolution crystal structure of important proteins like the main protease (3CLpro) that are required for SARS-CoV-2 viral replication and polymerase (RdRp) and papain-like protease (PLpro) as a vital target in other coronaviruses still presents important targets for the drug discovery. With this knowledge, scaffold library of Interbioscreen (IBS) database was explored through molecular docking, MD simulation and postdynamic binding free energy studies. The 3D docking structures and simulation data for the IBS compounds was studied and articulated. The compounds were further evaluated for ADMET studies using QikProp and SwissADME tools. The results revealed that the natural compounds STOCK2N-00385, STOCK2N-00244, and STOCK2N-00331 interacted strongly with 3CLpro, PLpro, and RdRp, respectively, and ADMET data was also observed in the range of limits for almost all the compounds with few exceptions. Thus, it suggests that these compounds may be potential inhibitors of selected target proteins, or their structural scaffolds can be further optimized to obtain effective drug candidates for SARS-CoV-2. The findings of in-silico data need to be supported by in-vivo studies which could shed light on understanding the exact mode of inhibitory action. Communicated by Ramaswamy H. Sarma