Potential of pyrroquinazoline alkaloids from Adhatoda vasica Nees. as inhibitors of 5-LOX - a computational and an in-vitro study.

Inflammation plays a major role in the onset and progression of many diseases related to the respiratory system. Cysteinyl leukotrienes, the products of 5-LOX are a potent bronchoconstrictor. Vasicine, vasicinone and deoxyvasicine are the pyrroquinazoline alkaloids of Adhatoda vasica that are well known for their bronchodilatory activity. The current investigation evaluates the 5-LOX inhibitory potential of these alkaloids. Molecular docking results indicated that these alkaloids have similar binding energy as that of Zileuton, a commercial drug. Analysis of the molecular dynamics simulations, the binding free energy derived from MM-PBSA and interaction entropy indicated that vasicinone (-8.33 kcal/mol) exhibited a binding free energy comparable to that of Zileuton (-8.52 kcal/mol). The in-vitro results indicate the potential of vasicinone as a competitive inhibitor, while the in-silico results highlighted the potential of vasicine and deoxyvasicine as allosteric inhibitors. A possible mechanism behind the activity exhibited by the plant was also determined, which emphasized the potential of these alkaloids as leads for the design of novel 5-LOX inhibitors.

Alkaloids of Adhatoda vasica Nees. as potential inhibitors of cyclooxygenases - an in-silico study.

Eicosanoid pathways play a crucial role in the progression and resolution of inflammation. NSAIDs act as anti-inflammatory agents by inhibiting both the isoforms of cyclooxygenases (COXs) whereas, COXIBs act as specific COX-2 inhibitors. Excessive usage of the same is linked with gastrointestinal bleeding and increased cardiovascular risk, respectively. The current in-silico study was aimed at evaluating the potential of major alkaloids of A. vasica (vasicine (VAS), vasicinone (VAE), and Deoxyvasicine (DOV)) as inhibitors of COXs. The results of the computed binding energy (ΔG) indicate that Celecoxib (CEL), DOV, and VAS have a higher affinity to COX-2, while VAE has a higher affinity to COX-1, and Mefenamic acid (MEF) was not selective. Among the alkaloids, VAE exhibited the best ΔG (of -8.2 kcal/mol) with COX-1, while VAS exhibited the best ΔG (of -8.2 kcal/mol) with COX-2. This was comparable to the ΔG exhibited by Mefenamic acid (-8.7 kcal/mol with both the COXs). With their potential to remain gastroprotective while having the ability to inhibit enzymes of both the prostaglandin and leukotriene pathways, the alkaloids of A. vasica could be promising leads for the design of Eicosanoid pathway modulators/inhibitors.Communicated by Ramaswamy H. Sarma.

Dual inhibitors of SARS-CoV-2 proteases: pharmacophore and molecular dynamics based drug repositioning and phytochemical leads.

SARS-related coronaviruses poses continual threat to humanity by rapidly mutating and emerging as severe pandemic outbreaks, including the current nCoV-19 pandemic. Hence a rapid drug repositioning and lead identification strategy are required to mitigate these outbreaks. We report a pharmacophore and molecular dynamics-based approach for drug repositioning and lead identification against dual targets (3CLp and PLp) of SARS-CoV-2. The pharmacophore model of 3CLp inhibitors was apolar with two aromatic and two H-bond acceptors, whereas that of PLp was relatively polar, bearing one aromatic and three H-bond acceptors. Pharmacophore-based virtual screening yielded six existing FDA-approved drugs and twelve natural products with both the pharmacophoric features. Among them are nelfinavir, tipranavir and licochalcone-D, which has shown better binding characteristics with both the proteases compared to lopinavir. The molecular dynamics revealed that the connecting loop (residues 176-199) of 3CLp is highly flexible, and hence, inhibitors should avoid high-affinity interactions with it. Lopinavir, due to its high affinity with the loop region, exhibited unstable binding. Further, the van der Waals size of the 3CLp inhibitors positively correlated with their binding affinity with 3CLp. However, the van der Waals size of a ligand should not cross a threshold of 572Å3, beyond which the ligands are likely to make high-affinity interaction with the loop and suffer unstable binding as observed in the case of lopinavir. Similarly, the total polar surface area of the ligands were found to be negatively correlated with their binding affinity with PLp.