Pharmaceutical Sciences and Natural Products - Research Publications
Permanent URI for this collectionhttps://kr.cup.edu.in/handle/32116/56
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Item Identification of 1,3,4-oxadiazoles as tubulin-targeted anticancer agents: a combined field-based 3D-QSAR, pharmacophore model-based virtual screening, molecular docking, molecular dynamics simulation, and density functional theory calculation approach(Taylor and Francis Ltd., 2023-09-11T00:00:00) Das, Agnidipta; Sarangi, Manaswini; Jangid, Kailash; Kumar, Vijay; Kumar, Amit; Singh, Praval Pratap; Kaur, Kamalpreet; Kumar, Vinod; Chakraborty, Sudip; Jaitak, VikasCancer is one of the most prominent causes of death worldwide and tubulin is a crucial protein of cytoskeleton that maintains essential cellular functions including cell division as well as cell signalling, that makes an attractive drug target for cancer drug development. 1,3,4-oxadiazoles disrupt microtubule causing G2-M phase cell cycle arrest and provide anti-proliferative effect. In this study, field-based 3D-QSAR models were developed using 62 bioactive anti-tubulin 1,3,4-oxadiazoles. The best model characterized by PLS factor 7 was rigorously validated using various statistical parameters. Generated 3D-QSAR model having high degree of confidence showed favourable and unfavourable contours around 1,3,4-oxadiazole core that assisted in defining proper spatial positioning of desired functional groups for better bioactivity. A five featured pharmacophore model (AAHHR_1) was developed using same ligand library and validated through enrichment analysis (BEDROC160.9 value = 0.59, Average EF 1% = 27.05, and AUC = 0.74). Total 30,212 derivatives of 1,3,4-oxadiazole obtained from PubChem database was prefiltered through validated pharmacophore model and docked in XP mode on binding cavity of tubulin protein (PDB code: 1SA0) which led into the identification of 11 HITs having docking scores between ?7.530 and ?9.719 kcal/mol while the reference compound Colchicine exerted docking score of ?7.046 kcal/mol. Following the analysis of MM-GBSA and ADME studies, HIT1 and HIT4 emerged as the two promising hits. To verify their thermodynamic stability at the target site, molecular dynamic simulations were carried out. Both HITs were further subjected to DFT analysis to determine their HOMO-LUMO energy gap for ensuring their biological feasibility. Finally, molecular docking based structural exploration for 1,3,4-oxadiazoles to set up a lead of Formula I for further advancements of tubulin polymerization inhibitors as anti-cancer agents. Communicated by Ramaswamy H. Sarma. � 2023 Informa UK Limited, trading as Taylor & Francis Group.Item Identification of terpenoids as dihydropteroate synthase and dihydrofolate reductase inhibitors through structure-based virtual screening and molecular dynamic simulations(Taylor and Francis Ltd., 2023-05-13T00:00:00) Saini, Abhishek; Kumar, Amit; Jangid, Kailash; Kumar, Vinod; Jaitak, VikasBacterial infections are rising, and antimicrobial resistance (AMR) in bacteria has worsened the scenario, requiring extensive research to find alternative therapeutic agents. Terpenoids play an essential role in protecting plants from herbivores and pathogens. The present study was designed to focus on in silico evaluation of terpenoids for their affinity towards two necessary enzymes, i.e. DHFR and DHPS, which are involved in forming 5, 6, 7, 8-tetrahydrofolate, a key component in bacterial DNA synthesis proteins. Additionally, to account for activity against resistant bacteria, their affinity towards the L28R mutant of DHFR was also assessed in the study. The structure-based drug design approach was used to screen the compound library of terpenes for their interaction with active sites of DHFR and DHPS. Further, compounds were screened based on their dock score, pharmacokinetic properties, and binding affinities. A total of five compounds for each target protein were screened, having dock scores better than their respective standard drug molecules. CNP0169378 (?8.4 kcal/mol) and CNP0309455 (?6.5 kcal/mol) have been identified as molecules with a higher affinity toward the targets of DHFR and DHPS, respectively. At the same time, one molecule CNP0298407 (?5.8 kcal/mol for DHPS, ?7.6 kcal/mol for DHFR, ?6.1 kcal/mol for the L28R variant), has affinity for both proteins (6XG5 and 6XG4). All the molecules have good pharmacokinetic properties. We further validated the docking study by binding free energy calculations using the MM/GBSA approach and molecular dynamics simulations. Communicated by Ramaswamy H. Sarma. � 2023 Informa UK Limited, trading as Taylor & Francis Group.Item Structure-based Virtual Screening and Molecular Dynamic Simulation Approach for the Identification of Terpenoids as Potential DPP-4 Inhibitors(Bentham Science Publishers, 2023-05-16T00:00:00) Pulikkottil, Ajay Aravind; Kumar, Amit; Jangid, Kailash; Kumar, Vinod; Jaitak, VikasBackground: Diabetes mellitus is a metabolic disorder where insulin secretion is compromised, leading to hyperglycemia. DPP-4 is a viable and safer target for type 2 diabetes mellitus. Computational tools have proven to be an asset in the process of drug discovery. Objective: In the present study, tools like structure-based virtual screening, MM/GBSA, and pharmacokinetic parameters were used to identify natural terpenoids as potential DPP-4 inhibitors for treating diabetes mellitus. Methods: Structure-based virtual screening, a cumulative mode of elimination technique, was adopted, identifying the top five potent hit compounds depending on the docking score and nonbonding interactions. Results: According to the docking data, the most important contributors to complex stability are hydrogen bonding, hydrophobic interactions, and Pi-Pi stacking interactions. The dock scores ranged from-6.492 to-5.484 kcal/mol, indicating robust ligand-protein interactions. The pharmacokinetic characteristics of top-scoring hits (CNP0309455, CNP0196061, CNP0122006, CNP0 221869, CNP0297378) were also computed in this study, confirming their safe administration in the human body. Also, based on the synthetic accessibility score, all top-scored hits are easily synthesizable. Compound CNP0309455 was quite stable during molecular dynamic simulation studies. Conclusion: Virtual database screening yielded new leads for developing DPP-4 inhibitors. As a result, the findings of this study can be used to design and develop natural terpenoids as DPP-4 inhibitors for the medication of diabetes mellitus. � 2024 Bentham Science Publishers.Item Flavonoids as P-glycoprotein inhibitors for multidrug resistance in cancer: an in-silico approach(Taylor and Francis Ltd., 2022-09-19T00:00:00) Kumar, Amit; Kalra, Sourav; Jangid, Kailash; Jaitak, VikasCancer has become a leading cause of mortality due to non-communicable diseases after cardiovascular disease worldwide and is increasing day by day at a daunting pace. According to an estimate by 2040 there will be 28.4 million cancer cases. Occurrence of multidrug resistance has further worsened the scenario of available cancer treatment. Among different mechanisms of multidrug resistance efflux of xenobiotics by ABC transporter is of prime importance. P-glycoprotein (P-gp) is the major factor behind occurrence of multidrug resistance due to its wide distribution and invariably big binding cavity. Various generations of chemical inhibitors for P-gp have been designed and tested are not devoid of major side effects. Thus, in present study flavonoids a major class of natural compounds was virtually screened in order to find molecules which can be used as selective P-gp inhibitors to be used along with chemotherapeutics. After screening 4275 molecules from different classes of flavonoids i.e. flavan, flavanol, flavonone, flavone, anthocyanins, and isoflavone, through Glide docking top ten hit molecules were selected based on their binding affinity, binding energy calculation and pharmacokinetic properties. All the hit molecules were found to have docking score within the range of ?11.202 to ?9.699 kcal/mol showing very strong interaction with the amino acid residues of binding pocket. Whereas, dock score of standard P-gp inhibitor verapamil was ?4.984 kcal/mol. The ligand and protein complex were found to be quite stable while run through molecular dynamics simulations. Communicated by Ramaswamy H. Sarma. � 2022 Informa UK Limited, trading as Taylor & Francis Group.Item Reconnoitering the transformative journey of minocycline from an antibiotic to an antiepileptic drug(Elsevier Inc., 2022-01-20T00:00:00) Singh, Tanveer; Thapliyal, Surabhi; Bhatia, Shiveena; Singh, Varinder; Singh, Manjinder; Singh, Hasandeep; Kumar, Amit; Mishra, AwanishMinocycline, a second-generation tetracycline antibiotic is being widely tested in animals as well as clinical settings for the management of multiple neurological disorders. The drug has shown to exert protective action in a multitude of neurological disorders including spinal-cord injury, stroke, multiple sclerosis, amyotrophic lateral sclerosis, Huntington's disease, and Parkinson's disease. Being highly lipophilic, minocycline easily penetrates the blood brain barrier and is claimed to have excellent oral absorption (~100% bioavailability). Minocycline possesses anti-inflammatory, immunomodulatory, and anti-apoptotic properties, thereby supporting its use in treating neurological disorders. The article henceforth reviews all the recent advances in the transformation of this antibiotic into a potential antiepileptic/antiepileptogenic agent. The article also gives an account of all the clinical trials undertaken till now validating the antiepileptic potential of minocycline. Based on the reported studies, minocycline seems to be an important molecule for treating epilepsy. However, the practical therapeutic implementations of this molecule require extensive mechanism-based in-vitro (cell culture) and in-vivo (animal models) studies followed by its testing in randomized, placebo controlled and double-blind clinical trials in large population as well as in different form of epilepsies. � 2022Item Efficacy of p-coumaric acid in chronic constriction injury induced neuropathic pain in rats(Indian Drug Manufacturers' Association, 2021-12-14T00:00:00) Bharti, Akash; Kaur, Jaspreet; Kumar, Amit; Singh, Simranjit; Kumar, DeepakThe present research work has been designed to evaluate the effect of p-coumaric acid in chronic constriction injury (CCI) of sciatic nerve induced neuropathic pain in rats. In addition, biochemical tests such as thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and total protein were performed in sciatic nerve tissue sample. The neuropathic pain has been effi ciently and successfully induced in rat by the performance of CCI. The battery of behavioural test showed the development of neuropathic pain as an index of rising the paw and tail thermal and mechanical pain sensitivity. The treatment of p-coumaric acid at dose 50 and 100 mg kg-1, p.o. for 15 consecutive days have been shown to produce signifi cant ameliorative effect on CCI of sciatic nerve induced neuropathic pain sensitivity. In addition, CCI of sciatic nerve also induces the oxidative stress in nervous system by rising TBARS, decrease GSH and proteins levels in sciatic nerve tissue and these effects are reversed via administration of p-coumaric acid and statistically equivalent to standard drug. Hence, it may be concluded that, p-coumaric acid can be useful in the management of neuropathic pain symptoms. � 2021 Indian Drug Manufacturers' Association. All rights reserved.Item Engagement of phytoestrogens in breast cancer suppression: Structural classification and mechanistic approach(Elsevier Masson s.r.l., 2020-11-24T00:00:00) Tanwar, Ankur Kumar; Dhiman, Neha; Kumar, Amit; Jaitak, VikasCancer is the world's devastating disease, and breast cancer is the most common reason for the death of women worldwide. Many synthetic drugs and medications are provided with their beneficial actions, but all of these have side effects and resistance problems. Natural remedies are coming forward to overcome the disadvantages of synthetic drugs. Among the natural categories, phytoestrogens having a structural similarity of mammalian oestradiol proves its benefit with various mechanisms not only in the treatment of breast cancer but even to prevent the occurrence of postmenopausal symptoms. Phytoestrogens are plant-derived compounds that were utilized in ancient medications and traditional knowledge for its sex hormone properties. Phytoestrogens exert pleiotropic effects on cellular signalling and show effects on estrogen-dependent diseases. However, because of activation/inhibition of steroid hormonal receptor ER-? or ER-?, these compounds induce or inhibit steroid hormonal (estrogen) action and, therefore, have the potential to disrupt hormone (estrogen) signalling pathway. In this review, we have discussed and summarize the effect of certain phytoestrogens and their possible mechanisms that can substantiate advantageous benefits for the treatment of post-menopausal symptoms as well as for breast cancer. � 2020 Elsevier Masson SASItem Pharmacological and chemical potential of Cassia fistula L- a critical review(Elsevier GmbH, 2020-10-19T00:00:00) Sharma, Akanksha; Kumar, Amit; Jaitak, VikasCassia fistula L. (Fabaceae) is a plant species called �Aragvadha� which means �disease killer�. C. fistula consists of a large amount of medicinal properties. The plant has been used in Ayurvedic medicine since ancient periods, because it affects all three �Doshas� i.e. Vata, Pitah, and Kapha. In the last few years, the plant has been widely explored for its array of pharmacological uses which have also been experimentally proven. It contains many chemical components having important pharmacological properties. These constituents are reported to possess various biological activities such as antioxidant, antimicrobial, antidiabetic, antitumor and antimelasmic. This current article will be important to investigate Cassia fistula and explore it further for determination of new potential pharmacophores that could be responsible for its activities related to the central nervous system, heart, antitumor, antioxidant and inflammation. � 2020 Elsevier GmbH