CYP-450 Mediated Herb-Drug Interactions of Ashwagandha and AYUSH-64 Used in COVID-19 Integrative Management: A Case Example of Remdesivir

AimWithania somnifera Dunal (WS), known as Ashwagandha and AYUSH-64, a polyherbal formulation are repurposed for the management of COVID-19. The extensive use of these botanicals as home remedy along with other drugs for managing multifarious disease conditions is increasing over nations. This raises high chances of herb-drug interactions (HDIs) which may be beneficial, harmful, or even fatal. Therefore, current study aimed to explore the CYP mediated herb-drug interactions (HDIs) of Ashwagandha and AYUSH-64 along with case example of remdesivir to harness the best of these HDIs for integrative management of COVID-19Materials and MethodsThe aqueous extract of Ashwagandha and AYUSH-64 were characterized by LC-MS/MS. The in-silico pharmacokinetic (ADME) parameters were studied by using ADME tool. The in-vitro CYP-450 (CYP3A4, 2C8, 2D6) inhibition studies of WS and AYUSH-64 alone and in combination with a remdesivir were carried out resembling clinically scenario.ResultsTotal of 11 and 24 phytoconstituents were identified from the aqueous extract of Aswagandha and AYUSH-64. The in-silico ADME studies revealed that most of the phytoconstituents showed good oral bioavailability, drug likeliness, GI affinity and some of them displayed CYP-450 inhibitory activity. The in-vitro CYP-450 studies of remdesivir showed moderate inhibitory effect on CYP3A4, 2C8, 2D6. The aqueous extract of Aswagandha did not show any inhibitory activity towards all the studied CYP’s alone and in combination with remdesivir (IC50 >100µg/ml). Whereas, AYUSH-64 also followed the same trend but showed moderate inhibitory effect on CYP2C8 (IC50 <100µg/ml).ConclusionAswagandha did not exhibit HDIs with the CYP3A4, CYP2C8 and CYP2D6 thereby seem to be safe to co-administer with respective substrates. Whereas, AYUSH-64 only showed moderate HDIs towards CYP2C8 substrate among studied CYP enzymes. Caution is therefore warranted for prescribing AYUSH 64 along with CYP2C8 substrate drugs.

Expanding the Chemical Space of Aryloxy-naphthoquinones as Potential Anti-chagasic Agents: Synthesis and Trypanosomicidal Activity

In continuation our effort to research the chemical space of aryloxy-naphthoquinones as potential anti-Chagas agents, we synthesized nine derivatives and these compounds were evaluated in vitro against the epimastigote and trypomastigote forms of Mexican strains of Trypanosoma cruzi (T. cruzi). Most of these derivatives are highly active against epimastigote forms (IC50 < 1.0 µM) compared to the reference drug benznidazole (Bzn). Then these were evaluated on trypomastigotes, which is showing better potency results than Bzn for compounds 3b and 3g. In addition, the cytotoxicity of these compounds was determined on the murine macrophage cell line J774. 3b and 3i were the most selective compounds against NINOA trypomastigote and INC-5 epimastigote forms, respectively. Further these compounds also have good oral bioavailability according to theoretical predictions. Finally, we were able to determine optimal substitution patterns using pharmacophoric models. All these results are provided very useful structural information to continue our designing of naphthoquinone derivatives against T. cruzi.

Hybridization of Curcumin Analogues with Cinnamic Acid Derivatives as Multi-Target Agents Against Alzheimer’s Disease Targets

The synthesis of the new hybrids followed a hybridization with the aid of hydroxy-benzotriazole (HOBT) and 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDCI.HCL) in dry DMF or thionyl chloride between curcumin analogues and cinnamic acid derivatives. IR, 1H-NMR, 13C-NMR, LC/MS ESI+, and elemental analysis were used for the confirmation of the structures of the novel hybrids. The lipophilicity values of compounds were calculated theoretically and experimentally via the reversed chromatography method as RM values. The novel derivatives were studied through in vitro experiments for their activity as antioxidant agents and as inhibitors of lipoxygenase, cyclooxygenase-2, and acetyl-cholinesterase. All the compounds showed satisfying anti-lipid peroxidation activity of linoleic acid induced by 2,2′-azobis(2-amidinopropane) hydrochloride (AAPH). Hybrid 3e was the most significant pleiotropic derivative, followed by 3a. According to the predicted results, all hybrids could be easily transported, diffused, and absorbed through the blood–brain barrier (BBB). They presented good oral bioavailability and very high absorption with the exception of 3h. No inhibition for CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4 was noticed. According to the Ames test, all the hybrids induced mutagenicity with the exception of 3d. Efforts were conducted a) to correlate the in vitro results with the most important physicochemical properties of the structural components of the molecules and b) to clarify the correlation of actions among them to propose a possible mechanism of action. Docking studies were performed on soybean lipoxygenase (LOX) and showed hydrophobic interactions with amino acids. Docking studies on acetylcholinesterase (AChE) exhibited: (a) hydrophobic interactions with TRP281, LEU282, TYR332, PHE333, and TYR336 and (b) π-stacking interactions with TYR336.

Ubrogepant: a new era in migraine treatment

Migraine is the most common neurological disorder that leads to incapacitating neurological symptoms. Acute attacks of migraine have been dealt with effectively with non-steroidal anti-inflammatory drugs (NSAIDs), ergot derivatives and triptans since long, but their use is limited by various adverse effects. Recent studies have shown that a neuropeptide, calcitonin gene related peptide (CGRP) plays a major role in pathophysiology of migraine by increasing the pain perception, both at the peripheral and central nervous system levels. So, in the last few years, some CGRP antagonists have found their way in the treatment of both episodic and chronic migraine. Ubrogepant is the first oral CGRP antagonist, that was approved by USFDA (United States food and drug administration) in December 2019, for the acute treatment of migraine with or without aura. It is more potent than the earlier CGRP receptor antagonists, has a good oral bioavailability and the risk of hepatotoxicity is also lesser than the previous Gepants.

Prediction of ADME-Tox properties and toxicological endpoints of triazole fungicides used for cereals protection

Within this study we have considered 9 triazole fungicides that are approved to be used in European Union for protecting cereals: cyproconazole, epoxiconazole, flutriafol, metconazole, paclobutrazole, tebuconazole, tetraconazole, triadimenol and triticonazole. We have summarized the few available data that support their effects on humans and used various computational tools to obtain a widely view concerning their possible harmful effects on humans. The results of our predictive study reflect that all triazole fungicides considered in this study reveal good oral bioavailability, are envisaged as being able to penetrate the blood brain barrier and to interact with P-glycoprotein and with hepatic cytochromes. The predictions concerning the toxicological endpoints for the investigated triazole fungicides reveal that they. reflect potential of skin sensitization, of blockage of the hERG K+ channels and of endocrine disruption, that they have not mutagenic potential and their carcinogenic potential is not clear. Epoxiconazole and triadimenol are predicted to have the highest potentials of producing numerous harmful effects on humans and their use should be avoided or limited.

Computational design of drug candidates for influenza A virus subtype H1N1 by inhibiting the viral neuraminidase-1 enzyme

It is critical to seek potential alternative treatments for H1N1 infections by inhibiting neuraminidase-1 enzyme. One of the viable options for inhibiting the activity of neuraminidase- 1 is peptide drug design. In order to increase peptide stability, cyclization is necessary to prevent its digestion by protease enzyme. Cyclization of peptide ligands by formation of disulfide bridges is preferable for designing inhibitors of neuraminidase-1 because of their high activity and specificity. Here we designed ligands by using molecular docking, drug scan and dynamics computational methods. Based on our docking results, short polypeptides of cystein-arginine-methionine-tyrosine- -proline-cysteine (CRMYPC) and cysteine-arginine-aspargine- phenylalanine-proline-cysteine (CRNFPC) have good residual interactions with the target and the binding energy ΔGbinding of -31.7402 and -31.0144 kcal mol-1, respectively. These values are much lower than those of the standards, and it means that both ligands are more accessible to ligand-receptor binding. Based on drug scan results, both of these ligands are neither mutagenic nor carcinogenic. They also show good oral bioavailability. Moreover, both ligands show relatively stable molecular dynamics progression of RMSD vs. time plot. However, based on our metods, the CRMYPC ligand has sufficient hydrogen bonding interactions with residues of the active side of neuraminidase-1 and can be therefore proposed as a potential inhibitor of neuraminidase-1

Development of oxopyrrolidine-based anti-cancer compounds: DNA binding, in silico, cell line studies, drug-likeness and mechanism at supra-molecular level

Due to an increasing demand for effective anti-cancer drugs, an oxopyrrolidine-based ligand, sodium 1-(3-(2-aminoethylamino)propyl)-5-oxopyrrolidine-2-carboxylate, was synthesised by the sodium hydride-assisted coupling of pyroglutamic acid with 1,3-diiodopropane under a nitrogen atmosphere. The intermediate thus formed was allowed to react with ethylenediamine in acetonitrile. The ligand formed individual complexes with Cu(II) and Ni(II) metal ions, respectively. The complexes were relatively resistant to degradation in PBS at physiological pH. The DNA-binding constants (K b) for the ligand, copper and nickel complexes were 2.09 × 104 M-1, 2.37 × 104 M-1 and 2.11 × 104 M-1, respectively, revealing the strong binding of these complexes with DNA. Haemolysis assays indicated that the ligand and its complexes were less toxic to rabbit RBCs than doxorubicin. Lipinski’s parameters calculated for the reported compounds indicated their good oral bioavailability. All the compounds exhibited good activities towards MCF-7 (wild type) cancer cell lines. The results of in silico studies, DNA-binding and anti-cancer activities indicated that the reported compounds might be interacting with DNA as one of their possible mechanisms of action.