Are Coumarin Derivatives The New Keys in Depression Treatment? In silico Key-lock Fitting Analysis of Coumarin Derivatives with Monoamine Oxidase-A

The research of ligand-protein interactions with in silico molecular modeling studies on the atomic level gives an opportunity to be understood the pharmacokinetic metabolism of anti-depressant drug candidates. Monoamine oxidase (MAO) enzymes are important targets for the treatment of depressive disorder. MAOs have two isoforms as MAO-A and MAO-B being responsible for catalyzing of neurological amines. In this study a new series of coumarin derivatives were designed for selective and reversible inhibition of MAO-A enzyme. 3rd, 5th and 7th positions were selected to be placed of five different side groups. Docking procedures of each ligand in M series of these novel 125 compounds were executed with 10 runs by using AutoDock4.2 software. Docking results were analyzed via Discovery Studio 3.1 (Biovia Inc.). The most promising compounds were M118 and M123 according to selectivity index, SI (MAO-B/MAO-A)=180 fold and 209 fold and Ki values 7.25 nM and 12.01 nM, respectively. Overall, the current study provided significant knowledge for the development of new anti-depressant drugs.

Virtual screening assisted identification of small molecule against 2019 novel coronavirus protease enzyme

The 2019 novel coronavirus infection or COVID-19 can be designated as a global threat. Till date, there is a lack of dedicated therapeutics available against this fatal infection. In the present work, we performed structure-based drug design studies in order to identify clinically used molecules exhibiting crucial binding with 2019-coronavirus main protease enzyme. Based on ligand binding energy and interaction with essential amino acids, two molecules were selected. The stability of the complexed molecules with main protease enzyme was further studied by performing molecular dynamics simulation.

Development and validation of RP-HPLC/UV methods for the estimation of Risedronate sodium in pure and pharmaceutical dosage form

Recent study was conducted to develop and validate analytical methods for estimation of Risedronate sodium in pure and pharmaceutical dosage form using UV Spectroscopy and RP- HPLC method. The first method (Method A) based on the UV Spectroscopy using 0.1M Hcl as diluent lambda max was found at 261 nm. Linearity existed perceived in the concentration between 10-50 μg/ml (r 2 = 0.999) for the method. The method was validated pertaining to linearity, precision and accuracy studies, LOD and LOQ consistent with ICH guidelines. The second method (Method B), based on determination of Risedronate sodium tablet dosage form by RP-HPLC method. Chromatography separation was carried out on a C18 (150X4.6 mm x5 µ) SS Column using Methanol: Ammonium formate (85:15) as the mobile phase at a flow rate of 1.0 ml/min. The chromatographic analysis was carried out in the reflectance and absorbance mode at 254 nm and retention time of the drug was found to be 1.11 ml/min for standard and tablet. Linear responses of the drug were in the concentration range of 200-1000 µg/ml. The accuracy of the method was assessed by standard dilution method and found to be 98% to 102% .The results of the analysis were validated statistically prism software. The method established was found to be simple, precise, linear, accurate and sensitive. The developed method can be used for routine quality control analysis of Risedronate sodium in pure and pharmaceutical dosage form.

X-ray crystal structure of N'-[(1E)-1-(2,4-dihydroxyphenyl)-ethylidene]pyridine-4-carbohydrazide

Schiff’s base of isonicotinyl hydrazide with 2’,4’-dihydroxy acetophenone (INH-RA) has been designed and synthesized as a part of library enumeration targeting the NS2B-NS3 protease of Dengue virus. Slow evaporation from methanol results in the formation of monoclinic crystals C2/c space group with eight molecules in the unit cell (a=20.0165(3) Å, b=7.7594(10) Å, c=19.4809(3) Å, α=90 °, β=111.368(1) °, γ=90 ° and Z=8).Three dimensional X-ray crystallographic structure of the compound has been determined and refined using SHELXS-97 and SHELXL-2014, respectively to a final R-value of 4.64%

Stress degradation studies of hydrochlorothiazide and development of validated method by UV spectroscopy

To develop a simple, precise, accurate, and stability indicating a UV-method for estimation of Hydrochlorothiazide(HCT)in bulk and formulated dosage form.The drug was alsosubjected to stress degradation at different conditions recommended by the International Conference on Harmonization (ICH). The samples are generated and used for the degradation studies.The λmax of the HCTwas found to be 273nm.The linearity of calibration curve (Absorbance Vs Concentration) in pure solution was checked over the concentration ranges of about 5-30μg/mLwith the correlation coefficient higher than 0.99. The regression equation of the curve was Y = 0.598x + 0.0042.% RSD was found to be within the limit as per ICH guidelines. The obtained percentage recovery of HCTwas found to be within the limit100% ± SD. Stress degradation studies revealed thatitwas within the limit(5-20%).

Docking studies of tetra substituted pyrazolone derivatives as potential antiviral agents

In an attempt to find potential antiviral agents, a series of pyrazolones (PA1-PA6& PC1-PC6) were designed and evaluated for their DENVNS5 (RNA-dependent RNA polymerase) inhibitory activity. Molecular docking studies of all the designed compounds into the binding site of DENVNS5 (PDB Code: 4C11) were performed to gain a comprehensive understanding into rational binding modes. These compounds were also screened for in silico drug-likeliness properties on the basis of the absorption, distribution, metabolism and excretion (ADME) prediction. Among all the synthesized compounds, analogue PA6showed superior inhibitory activity against RNA dependent RNA polymerase. SAR study indicated that the presence of an electron withdrawing substitution on pyrazolone derivatives significantly improves its binding interaction with the protein.Results of ADME prediction revealed that most of these compounds showed in silico drug-likeliness.

Formulation, method development and validation of water soluble vitamins B1, B2 & B6 in bulk and tablet dosage form by HPTLC method

In the present study we are reporting dissolution, method development and validation of water soluble vitamins B1, B2 & B6 in bulk and tablet dosage form by HPTLC method. The method is based on separation of the three vitamins using HPTLC. Thin layer chromatographic plates coated with silica gel 60F254 as the stationary phase and acetonitrile:water (6:4 v/v) as mobile phase. The chromatographic analysis was carried out in the reflectance and absorbance mode at 280 nm. The method was validated with respect to linearity, accuracy and precision, limit of detection and limit of quantitation. It was then applied for analysis of vitamins B1, B2 & B6 in combined tablet dosage form. The above method developed was reproducible with good resolution and the results of analysis have been validated with correlation coefficient of 0.9990

De novo Design and in-silico Studies of Coumarin Derivatives as Inhibitors of Cyclin Dependent Kinase-2

In the present study, around sixty-two novel coumarin derivatives were designed as CDK-2 inhibitors based on essential pharmacophoric requirements. All the designed compounds were subjected to docking study using AutoDock 4.2 against CDK-2 protein (PDB ID: 1HCK). Molinspiration and Osiris property explorer were used to predict Lipinski’s rule of five and toxicity profile. The Structure Activity Relationship study revealed that, the substitution at R1 and R4 of coumarin nucleus enhances the binding energy and inhibitory constant values from nanomolar to picomolar range. Among the designed analogues, compound 15, 28, 43 and 59 showed significant binding energy and inhibitory constant values as compared to the standard drug Olomoucine and Deschloroflavopiridol. Most of the designed analogues showed similar binding mode and orientation inside the active site of the protein as that of the standard drug, which strongly indicates that the designed molecules may emerge as potent inhibitors of CDK-2. Next, molecular dynamics study of the significantly active molecule 15 was studied for 10 ns, in order to determine the stability of the coumarin molecules inside the binding cavity of the protein. In-silico investigations suggest that the de novo designed coumarin derivatives were potentially in-silico bioactive and need to be synthesized and tested further.

In-silico screening of 2,3-diphenylquinozaline derivatives as C-met kinase inhibitors

Quinoxaline, an important class of heterocylic compounds drawn greater attention due to their wide spectrum of biological activities. They are considered as an important chemical scaffold for anticancer drug design due to their potential inhibitory activity against C-met tyrosine kinase. C-met kinase inhibitors are a class of small molecules that having therapeutic potential in the treatment of various types of cancers. The present study aims to focus on the chemistry of quinoxaline derivatives, their potential activities against C-met tyrosine kinase, and in-silico screening of designed compounds. A series of twelve compounds were designed and docked against C-met tyrosine kinase for their binding energy. All compounds were found to be interacting well with the protein. Compound NQ1 was found to have good binding energy showing an estimated Ki value of 1.1μm. SAR study indicated the presence of an electron withdrawing substitution on benzilidine phenyl ring of quinoxaline greatly improves its binding interaction with the protein.

In silico development of a novel putative inhibitor of the 3C protease of Coxsackievirus B3 with a benzene sulfonamide skeleton

Availability of X-ray crystal structure of 3C protease of several enteroviruses provided an opportunity for in silico drug design and development approach. Presented study is aimed at designing a novel compound targeting 3C protease of Coxsackievirus (CVB3), which is reported frequently to cause myocarditis in North America and Europe. A pthalimido-sulfonamide derivative (ZINC13799063) was identified through high-throughput virtual screening (HTVS) approach from the top HITs. A small library of phalimido-sulphonamides was enumerated to find a potential LEAD. Compound 17 from the library was found to inhibit CVB3 selectively in cell based antiviral assay at a concentration of EC50=1.0±0.1 µM with a selectivity index of >140. Molecular dynamics study was performed to investigate the selective inhibition of CVB3 over CVB4.