Letters in Drug Design & Discovery - Volume 18, Issue 12, 2021

Background: In the previous study, we reported the isolation of six compounds from Sclerochloa dura and their in-vitro anti-inflammatory potential by their ability to inhibit phospholipase A2 (PLA2). The objective of current study is to inspect the effect of these compounds on other expected targets. Methods: For this purpose, various targets and percentage activities are predicted through CoFFer (QSAR) web service. All six compounds under investigation represented 99-100% activity towards carbonic anhydrases (CAs) and 90-100% activity towards anti-cancer drug targets. As active site of most of the carbonic anhydrase isozymes is conserved, we selected cytosolic human carbonic anhydrase II (hCA II) for docking studies which is ubiquitous and involved in various human disorders such as glaucoma, pulmonary edema and epilepsy. Anticancer drug targets include vascular endothelial growth factor receptor 2 (VEGFR2), glucocorticoid receptor (GR) and tyrosine protein kinase (c- SRC). Interaction of these compounds with hCA II (PDB ID:3P4V) and anti-cancer drug targets such as VEGFR2 (ID:3WZD), GR (ID:5G5W) and c-SRC (ID:2SRC), were analyzed through molecular docking studies using MOE (Molecular Operating Environment). Results: The findings suggested that most of these compounds represent excellent binding affinity with hCA II by making interaction with zinc-coordinated water molecule through sulfonic acid group or hydroxyl group present in the compounds. Similarly, five out of six compounds represented excellent interaction with VEGFR2. Interactions with GR indicated that compounds 2, 3, and 6 bind effectively as compared to their co-crystallized ligands. However, among these, the excellent binding affinity with c-SRC was demonstrated by compounds 3 and 6. Conclusion: This study revealed that all these compounds exhibited excellent interaction with the active site of hCA II, however in the light of previously reported data and due to membrane barrier, only compound 1 (due to long hydrophobic tail) and compound 4 (due to absence of bulky carbohydrate groups), can only penetrate inside the cytosol. Compounds 2, 3, 4, and 6 containing bulky carbohydrate moieties cannot penetrate inside the cell, therefore, they might have selective nature towards membrane-bounded tumor-associated hCA IX. This anti-tumor property of compounds was also proved by docking studies with VEGFR2, GR and c-SRC. Therefore, these compounds may have synergistic effects against inflammation and cancer. The ADMET studies show that compounds have moderate absorption and permeability along with slight toxicity.

Aim: The present study was expected to explore the molecular interaction of five oxidative stress (OS) associated target receptors with Alpha-Pinene and its antioxidant validation for the effective treatment of Parkinson’s disease (PD). Background: Oxidative stress (OS) via multitudinous cascades is considered to be the leading attribute to dopaminergic cell degeneration in PD. Furthermore, it is also well-linked to other mechanisms involved in the neurodegeneration process, like dysfunction of mitochondria, neuroinflammation and excitotoxicity due to NO. Objective: The present investigation was to establish a molecular association of OS-associated target receptors with the bioactive compound alpha-pinene and how this molecular interaction empowers the mitigation of PD. Materials and Methods: Five different molecular targets namely Peroxisome Proliferator-Activated Receptor- Gamma (PPARγ), Liver-X receptor beta (LXR- β), Human Monoamine Oxidase-B (MAO-B), Human Nuclear receptor related-1 protein (Nurr1) and Human Lipoprotein-associated phospholipase A2 (Lp-PLA2) were obtained from RCSB-PDB, which has some leading association in the inhibition of the OS-induced neurodegeneration. Molecular interactions were stuffed by the simulation molecular docking software. Antioxidant activity was validated by in-vitro models as per standardized procedures against 2,2- diphenyl-1- picrylhydrazyl (DPPH), 2,2'-azinobis-(3- ethylbenzothiazoline -6-sulfonic acid) (ABTS), Ferric ion (Fe3+), Hydroxyl (•OH), nitric oxide (•NO), Peroxynitrite (ONOO-) and Hypochlorous acid (HOCl). Results: Our results indicated that alpha-pinene can interact with all the five different target receptors at the active binding site. Alpha-pinene was found to show better interaction with MAO-B, Nurr1 and PPARγ with binding energy of -5.50, -4.52 and -5.25, respectively as compared to the native ligand. Furthermore, the interaction of alpha-pinene with LXR-β and Lp-PLA2 was also significant with binding energy of -5.6 and -5.12, respectively. It also capable of neutralizing all the different free radicals under consideration with significant IC50 values against HOCl and •NO. Conclusion: It might be concluded that alpha-pinene could act as a potential inhibitor and scavenger of OS which could act on the multiple target receptors under consideration.

Background: Coumarin and chalcone are important secondary plant metabolites that exhibit a range of biological activities. Accordingly, the synthetic derivatives and analogs of these molecules have attracted attention as potential pharmacological agents. Objective: This study aims to study new antidepressants with high biological activity and low side effects, and to provide a basis for the treatment of epilepsy and depression. Methods: In this study, a series of chalcone derivatives containing a coumarin moiety (2a-2s) were designed, synthesized, and evaluated using classic antidepressant and anticonvulsant mouse models. Results: Forced swimming test results revealed that all but one of the compounds tested significantly decreased immobility time at a dose of 10 mg/kg and exhibited some antidepressant activities. Furthermore, compounds 2a, 2c, 2h, and 2k exhibited relatively high antidepressant effects in a dosedependent manner from 10 to 30 mg/kg. Maximal electroshock seizure tests showed that compounds 2a, 2b, 2c, 2h, 2l, 2r, and 2s exhibited anticonvulsant activities at a dose of 30 mg/kg. Conclusion: Accordingly, compounds 2a, 2c, and 2h showed promise as antidepressant adjunct therapy agents for treating depression in patients with epilepsy. Chromatographic neurochemical analysis of the mouse brain tissue revealed that the antidepressant effects of the compounds may be mediated by an increase in serotonin level.

Background: Epilepsy is one of the most common and devastating neurological diseases affecting about 1% of the world’s population at any time. Herein, we have reported rationale design and synthesis of 5-acetyl-3-((4-substitutedphenyl)imino)indolin-2-one analogues 3(a-k) as antiseizure agents. Objective: These analogues were designed as four component pharmacophoric model by clubbing structural fragments of potent antiepileptic drugs. The Aim of this study is to synthesize structurally designed isatin analogues and screen them for anticonvulsant activity and neurotoxicity. Methods: Designed derivatives were synthesized using bulky scale feasible and inexpensive microwave methodology. All the synthesized compounds were then characterized by multiple spectroscopic techniques and screened for anticonvulsant activity through preclinical in-vivo experiments. Results: The compound 3d have exhibited good anticonvulsant activity in preclinical seizure models with better toxicity profile when compared to standard drugs (3d: ED50 = 31.5 mg/kg, MES test; ED50 = 37.4 mg/kg, scPTZ test; TD50 = 384.3 mg/kg,). Compound 3d have also shown good binding affinity at crucial amino acids of GluN1 subunit of NMDAR (Docking score = -9.30) and fit adequately in the cavity of the receptor (Amino acids involved and H-bonding distance = GLY93: acetyl >C=O, 2.38Å; PHE92: acetyl >C=O, 2.22Å; and THR26: >C=O of isatin, 1.71Å). Results of molecular docking supported the structural features present over isatins to persuade potent antiseizure activity. Conclusion: Rationale designing strategy, in-vivo pharmacological profile, and computational studies make us anticipate the emergence of these molecules as novel antiseizure agents, which can be further explored to develop probes for the treatment of epilepsy.

Background: Bruton’s tyrosine kinase (BTK) plays an important role in cell development and proliferation. BTK inhibitors are encouraging novel agents against B-cell malignancies and autoimmune diseases. Although BTK inhibitors have been approved by the FDA to lower off-target effects and reduce emerging resistances, it is necessary to develop novel BTK inhibitors with better outcomes and minimum side effects. Objective: The present study includes pharmacophore hypothesis, 3D QSAR, virtual screening, docking, ADME analysis, and screening of potential imidazo[1,5-a]pyrazine derivatives as BTK inhibitors. Methods: Generation of pharmacophore hypothesis, virtual screening, 3D QSAR, molecular docking, and ADME analysis were conducted. Results: The pharmacophore study generated 20 pharmacophore hypotheses as BTK inhibitors. The five-point hypothesis DPRRR_1 was selected, consisting of one hydrogen bond donor, one positive ionic, and three-ring aromatic features. 3D QSAR study of the compounds provided the best model with high Q2 (0.8683), R2 (0.983), and R2CV (0.5338) values. The developed pharmacophore model was further taken for screening of ZINC database ligands for evaluation of docking interaction and physiochemical properties. Potent compounds of the series 15, 27, 8n, and 38 showed good docking scores -8.567, -7.465, -6.922, -6.137, respectively. Conclusion: All the pharmacokinetic parameters analyzed, including human oral absorption of active compounds of the series, were found to be within the permissible range. The present geometry and features included in the pharmacophore hypothesis can be used for the development of novel BTK inhibitors as anticancer agents.

Background: Infections caused by drug-resistant microorganisms have been increasing worldwide, thereby being one of the major causes of morbidity in the 21st century. Klebsiella pneumoniae is one such bacteria causing lung inflammation, lung injury and death. The emergence of hyper-virulent and drug-resistant species, such as ESBL and CRKP, has made this microbe a serious and urgent threat. The pace of emergence of these species is outgrowing the development of novel drug and vaccine candidates, thereby shifting the research focus towards the drug repurposing approach. Objective: The study aimed at Homology Modeling of Thymidylate Synthase, verification of modeled structure, Molecular Docking and Molecular Dynamic Simulation of the docked complex, and finally, in vitro analysis of 5-FU activity against Klebsiella pneumonia. Methods: The 3D structure of Thymidylate Synthase was predicted using the Swiss model server and validated by in silico approaches. The protein-protein interactions were determined using the STRING database. Molecular Docking has been carried out and MD simulations of 5-FU with the predicted structure of thymidylate synthase have been conducted. Finally, in vitro antimicrobial drug sensitivity assay has been carried out at different concentrations. Results: Hydrogen bond was observed in Molecular Docking, protein-ligand complex remained stable during simulation, while 5-FU showed antimicrobial activity against Klebsiella pneumonia during the in vitro study. Conclusion: Both in silico as well as in vitro analysis have indicated that 5-FU can potentially be developed as an antimicrobial agent towards Klebsiella pneumonia.