SYNTHESIS OF DESGLYMIDODRINE FROM MIDODRINE BY CONVENTIONAL AMIDE HYDROLYSIS METHOD

Objective:  The term prodrug involves chemically modifying inert compound which upon administration releases the active parent drug to elicit its pharmacological response within the body. Acting as a α-adrenergic agonist, desglymidodrine an active metabolite of amide prodrug midodrine is used for the treatment of essential and orthostatic hypotension. In the present study synthesis of desglymidodrine from midodrine was reported.Methods:  The synthesis was done by the conventional amide hydrolysis method.Results:  A novel synthesis of desglymidodrine was successfully achieved and spectrally elucidated by infrared spectroscopy (IR), 1H, 13C nuclear magnetic resonance (NMR) and mass analysis.Conclusion:  The acquired results were found to be accurate, the synthetic route appeared to be simple, cost-effective and time efficient. Hence the synthesized desglymidodrine can be as a reference standard for the estimation of the same

Deciphering the Possible Role of Statins as Antibacterial Agents through Molecular Modelling Approach: Role of statins as antibacterial agents

The global incidence of resistance to commonly used antibiotics was a challenging public health concern that justifies the urgency in developing novel antibacterial agents. ATP-dependent Mur ligases (MurC, MurD, MurE, and MurF) are validated targets in antibacterial drug design. Drug repurposing or drug repositioning is an alternative strategy in identifying new indications for the currently approved drugs. Statins are currently FDA-approved drugs used to treat hyperlipidemia. The pleiotropic effects of statins, along with their anticipated antibacterial properties, encouraged us to investigate them against MurD ligase of Escherichia coli and Staphylococcus aureus. The molecular docking and MMGB-SA studies revealed that amongst all selected statins, pravastatin exhibited higher binding affinity with the catalytic residues of Escherichia coli (-7.24 kcal/mol and -88.36 kcal/mol) and Staphylococcus aureus (-7.47 kcal/mol and -63.75 kcal/mol) MurD ligases. Further, 20 ns MD simulation showed stability and favorable interaction pattern of pravastatin with both enzymes

Insight into the structural requirements of thiophene-3-carbonitriles-based MurF inhibitors by 3D-QSAR, molecular docking and molecular dynamics study

<p>The discovery of clinically relevant inhibitors against MurF enzyme has proven to be a challenging task. In order to get further insight into the structural features required for the MurF inhibitory activity, we performed pharmacophore and atom-based three-dimensional quantitative structure–activity relationship studies for novel thiophene-3-carbonitriles based MurF inhibitors. The five-feature pharmacophore model was generated using 48 inhibitors having IC₅₀ values ranging from 0.18 to 663 μm. The best-fitted model showed a higher coefficient of determination (<i>R</i>² = 0.978), cross-validation coefficient (<i>Q</i>² = 0.8835) and Pearson coefficient (0.9406) at four component partial least-squares factor. The model was validated with external data set and enrichment study. The effectiveness of the docking protocol was validated by docking the co-crystallized ligand into the catalytic pocket of MurF enzyme. Further, binding free energy calculated by the molecular mechanics generalized Born surface area approach showed that van der Waals and non-polar solvation energy terms are the main contributors to ligand binding in the active site of MurF enzyme. A 10-ns molecular dynamic simulation was performed to confirm the stability of the 3ZM6-ligand complex. Four new molecules are also designed as potent MurF inhibitors. These results provide insights regarding the development of novel MurF inhibitors with better binding affinity.</p

INVESTIGATION OF ANTI-SARS COV-2 ACTIVITY OF SOME TETRAHYDROCURCUMIN DERIVATIVES: AN IN-SILICO STUDY

Objective: In the current study, an in-silico approach has been utilized to investigate the anti-SARS CoV 2 activity of some derivatives of Tetrahydro curcumin (THC), a curcumin metabolite. Methods: BioVia Draw 2017 was used to design 168 THC derivatives. All of the derivatives were docked using Maestro Schrodinger programme. Depending on the docking score, the ADME, drug likeness, and toxicity prediction of a few THC derivatives were conducted. Results: 168 THC derivatives were designed. 14 derivatives exhibited better binding score than Remdesivir. All 14 derivatives' pharmacokinetic characteristics were discovered to be within the acceptable range. Lipinski's rule of five was violated by all derivatives, including the reference drug, yet they all stayed within the recommended range. The greatest docking score among the 14 derivatives was displayed by Structure 21. A study on molecular dynamic (MD) stimulation showed that the protein ligand complex was relatively stable. Toxicity prediction showed that 14 derivatives were non-hepatotoxic, non-cytotoxic, immunotoxic (except S21), non-mutagenic (except S31) and half of the developed structures were carcinogenic, while the other half, including the standard drug, were non-carcinogenic. Conclusion: Among 168 THC derivatives, 14 derivatives exhibited better binding score than the reference drug. For all 14 derivatives, pharmacokinetic, drug likeness, and toxicity prediction were found to be satisfactory. It was discovered that the protein ligand complex was thermodynamically stable. All 14 compounds present exciting prospects for further in vitro and in vivo investigation

Pharmacophore generation, atom-based 3D-QSAR, molecular docking and molecular dynamics simulation studies on benzamide analogues as FtsZ inhibitors

<p>FtsZ is an appealing target for the design of antimicrobial agent that can be used to defeat the multidrug-resistant bacterial pathogens. Pharmacophore modelling, molecular docking and molecular dynamics (MD) simulation studies were performed on a series of three-substituted benzamide derivatives. In the present study a five-featured pharmacophore model with one hydrogen bond acceptors, one hydrogen bond donors, one hydrophobic and two aromatic rings was developed using 97 molecules having MIC values ranging from .07 to 957 μM. A statistically significant 3D-QSAR model was obtained using this pharmacophore hypothesis with a good correlation coefficient (<i>R</i>² = .8319), cross validated coefficient (<i>Q</i>² = .6213) and a high Fisher ratio (<i>F</i> = 103.9) with three component PLS factor. A good correlation between experimental and predicted activity of the training (<i>R</i>² = .83) and test set (<i>R</i>² = .67) molecules were displayed by ADHRR.1682 model. The generated model was further validated by enrichment studies using the decoy test and MAE-based criteria to measure the efficiency of the model. The docking studies of all selected inhibitors in the active site of FtsZ protein showed crucial hydrogen bond interactions with Val 207, Asn 263, Leu 209, Gly 205 and Asn-299 residues. The binding free energies of these inhibitors were calculated by the molecular mechanics/generalized born surface area VSGB 2.0 method. Finally, a 15 ns MD simulation was done to confirm the stability of the 4DXD–ligand complex. On a wider scope, the prospect of present work provides insight in designing molecules with better selective FtsZ inhibitory potential.</p

Pharmacophore generation, atom-based 3D-QSAR, molecular docking and molecular dynamics simulation studies on benzamide analogues as FtsZ inhibitors

<p>FtsZ is an appealing target for the design of antimicrobial agent that can be used to defeat the multidrug-resistant bacterial pathogens. Pharmacophore modelling, molecular docking and molecular dynamics (MD) simulation studies were performed on a series of three-substituted benzamide derivatives. In the present study a five-featured pharmacophore model with one hydrogen bond acceptors, one hydrogen bond donors, one hydrophobic and two aromatic rings was developed using 97 molecules having MIC values ranging from .07 to 957 μM. A statistically significant 3D-QSAR model was obtained using this pharmacophore hypothesis with a good correlation coefficient (<i>R</i>² = .8319), cross validated coefficient (<i>Q</i>² = .6213) and a high Fisher ratio (<i>F</i> = 103.9) with three component PLS factor. A good correlation between experimental and predicted activity of the training (<i>R</i>² = .83) and test set (<i>R</i>² = .67) molecules were displayed by ADHRR.1682 model. The generated model was further validated by enrichment studies using the decoy test and MAE-based criteria to measure the efficiency of the model. The docking studies of all selected inhibitors in the active site of FtsZ protein showed crucial hydrogen bond interactions with Val 207, Asn 263, Leu 209, Gly 205 and Asn-299 residues. The binding free energies of these inhibitors were calculated by the molecular mechanics/generalized born surface area VSGB 2.0 method. Finally, a 15 ns MD simulation was done to confirm the stability of the 4DXD–ligand complex. On a wider scope, the prospect of present work provides insight in designing molecules with better selective FtsZ inhibitory potential.</p

Rational design of thiazolidine-4-one-gallic acid hybrid derivatives as selective partial PPARγ modulators: an in-silico approach for type 2 diabetes treatment

Type 2 diabetes mellitus is a bipolar metabolic disorder characterized by abnormalities in insulin production from β-cells and insulin resistance. Thiazolidinediones are potent anti-diabetic agents that act through the modulation of the peroxisome proliferator-activated receptor γ (PPARγ), a nuclear receptor. However, their full agonistic activity leads to severe side effects by stabilizing Helix12 through strong hydrogen bonding with the TYR473 residue. Partial and selective PPARγ modulators (GW0072, GQ16, VSP-51, MRL-20, MBX-213, INT131) have demonstrated superior results compared to full agonists without causing adverse effects, as reported in existing data. To address this uncertainty and advance therapeutic options, we identified and designed a novel class of compounds (A1-A23) based on a hybrid structure combining phenolic and Thiazolidine-4-one’s moieties. Our rational drug design strategy incorporated structural-activity relationship principle, and validated the docking studies through calculated the root mean square deviation. Additionally, we conducted molecular docking, binding energy, molecular dynamics simulations, and post-molecular dynamics calculations to evaluate the dynamics behavior between the ligands and protein. The selected ligands demonstrated highly favorable docking scores and binding energies, comparable to the co-crystal (rosiglitazone) such as A12 (−13.9 kcal/mol and −86.2 kcal/mol), A1 (−11.1 kcal/mol and −79.5 kcal/mol), A13 (−11.3 kcal/mol and −91.4 kcal/mol), and the co-crystal itself (−9.8 kcal/mol and −76 kcal/mol), respectively. Finally, the MD revealed that, the selected ligands were equally contributed for stabilization of Helix12 and β-sheets. It was concluded, the designed ligands (A12, A1, and A13) exhibited weaker hydrogen-bond interactions with specific residue TYR473 which partially modulated the PPARγ protein. Communicated by Ramaswamy H. Sarma</p