Pharmaceutical Sciences and Natural Products - Research Publications
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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 Probing the molecular mechanisms of ?-synuclein inhibitors unveils promising natural candidates through machine-learning QSAR, pharmacophore modeling, and molecular dynamics simulations(Institute for Ionics, 2023-07-18T00:00:00) Boulaamane, Yassir; Jangid, Kailash; Britel, Mohammed Reda; Maurady, AmalParkinson�s disease is characterized by a multifactorial nature that is linked to different pathways. Among them, the abnormal deposition and accumulation of ?-synuclein fibrils is considered a neuropathological hallmark of Parkinson�s disease. Several synthetic and natural compounds have been tested for their potency to inhibit the aggregation of ?-synuclein. However, the molecular mechanisms responsible for the potency of these drugs to further rationalize their development and optimization are yet to be determined. To enhance our understanding of the structural requirements necessary for modulating the aggregation of ?-synuclein fibrils, we retrieved a large dataset of ?-synuclein inhibitors with their reported potency from the ChEMBL database to explore their chemical space and to generate QSAR models for predicting new bioactive compounds. The best performing QSAR model was applied to the LOTUS natural products database to screen for potential ?-synuclein inhibitors followed by a pharmacophore design using the representative compounds sampled from each cluster in the ChEMBL dataset. Five natural products were retained after molecular docking studies displaying a binding affinity of ? 6.0�kcal/mol or lower. ADMET analysis revealed satisfactory properties and predicted that all the compounds can cross the blood�brain barrier and reach their target. Finally, molecular dynamics simulations demonstrated the superior stability of LTS0078917 compared to the clinical candidate, Anle138b. We found that LTS0078917 shows promise in stabilizing the ?-synuclein monomer by specifically binding to its hairpin-like coil within the N-terminal region. Our dynamic analysis of the inhibitor-monomer complex revealed a tendency towards a more compact conformation, potentially reducing the likelihood of adopting an elongated structure that favors the formation and aggregation of pathological oligomers. These findings offer valuable insights for the development of novel ?-synuclein inhibitors derived from natural sources. Graphical abstract: [Figure not available: see fulltext.]. � 2023, The Author(s), under exclusive licence to Springer Nature Switzerland AG.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 Virtual screening and molecular dynamics simulation approach for the identification of potential multi-target directed ligands for the treatment of Alzheimer�s disease(Taylor and Francis Ltd., 2023-04-28T00:00:00) Jangid, Kailash; Devi, Bharti; Sahoo, Ashrulochan; Kumar, Vijay; Dwivedi, Ashish Ranjan; Thareja, Suresh; Kumar, Rajnish; Kumar, VinodAlzheimer�s disease (AD) is a multifactorial neurological disorder characterized by memory loss and cognitive impairment. The currently available single-targeting drugs have miserably failed in the treatment of AD, and multi-target directed ligands (MTDLs) are being explored as an alternative treatment strategy. Cholinesterase and monoamine oxidase enzymes are reported to play a crucial role in the pathology of AD, and multipotent ligands targeting these two enzymes simultaneously are under various phases of design and development. Recent studies have revealed that computational approaches are robust and trusted tools for identifying novel therapeutics. The current research work is focused on the development of potential multi-target directed ligands that simultaneously inhibit acetylcholinesterase (AChE) and monoamine oxidase B (MAO-B) enzymes employing a structure-based virtual screening (SBVS) approach. The ASINEX database was screened after applying pan assay interference and drug-likeness filter to identify novel molecules using three docking precision criteria; High Throughput Virtual Screening (HTVS), Standard Precision (SP), and Extra Precision (XP). Additionally, binding free energy calculations, ADME, and molecular dynamic simulations were employed to get structural insights into the mechanism of protein-ligand binding and pharmacokinetic properties. Three lead molecules viz. AOP19078710, BAS00314308 and BDD26909696 were successfully identified with binding scores of ?10.565, ?10.543 & ?8.066 kcal/mol against AChE and ?11.019, ?12.357 & ?10.068 kcal/mol against MAO-B, better score as compared to the standard inhibitors. In the near future, these molecules will be synthesized and evaluated through in�vitro and in�vivo assays for their inhibition potential against AChE and MAO-B enzymes. � 2023 Informa UK Limited, trading as Taylor & Francis Group.Item Synthesis and Evaluation of Antimicrobial Activity of N-Substituted Indole Derivatives and Molecular Docking Studies(Bentham Science Publishers, 2022-11-18T00:00:00) Dwivedi, Ashish Ranjan; Kumar, Vijay; Neha; Jangid, Kailash; Devi, Bharti; Kulharia, Mahesh; Kumar, Rakesh; Kumar, VinodThe increasing burden of microbial infection and emerging resistance against the available antimicrobial drugs drives the development of new agents. Two different series of indole-based compounds (VN-1 to VN-18) were synthesized and analyzed for antimicrobial activity by calculating the diameter of the inhibition zone using the broth dilution method and well diffusion method against Escherichia coli (E. coli) and environmental microbes. Most of the compounds displayed good to moderate activity against E. coli, and VN-4 and VN-9 displayed good inhibitory activity against the tested microbes. Molecular docking and binding energy calculation studies of all the synthesized compounds have been performed for targeting FabI, where most of the compounds showed significant interactions with the aromatic nicotin-amide moiety of NAD+. In molecular dynamics studies, VN-9 stays inside the binding cavity for sufficient time to induce antimicrobial activity. Thus, these indole-based derivatives may lead to the development of new antimicrobi-al agents that may act as FabI inhibitors. � 2022 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 Flavonoids as promising anticancer agents: an in silico investigation of ADMET, binding affinity by molecular docking and molecular dynamics simulations(Taylor and Francis Ltd., 2022-09-27T00:00:00) Biharee, Avadh; Yadav, Arpita; Jangid, Kailash; Singh, Yogesh; Kulkarni, Swanand; Sawant, Devesh M.; Kumar, Pradeep; Thareja, Suresh; Jain, Akhlesh KumarCancer is one of the most concerning diseases to humankind. Various treatment strategies are being employed for its treatment, out of which use of natural products is an essential one. Flavonoids have proven to be promising anticancer targets since decades. Also, tubulin is a significant biological target for the development of anticancer agents due to its crucial role in mitosis and abundance throughout the body. In the current study, in silico ADMET parameters of 104 flavonoids were examined, followed by molecular docking with the colchicine binding site of Tubulin protein (PDB; Id 4O2B). The best conformation from each flavonoid subcategory with the best docking score (MolDock score) was further subjected to 100 ns of molecular dynamics to investigate the protein-ligand complex�s stability. Different parameters such as RMSD, RMSF, rGy and SASA were calculated for the six flavonoids using molecular dynamic studies. The top most compound from all the six subcategories of flavonoids elicited best behavior in the colchicine binding site of Tubulin protein. This in silico study employing molecular docking and molecular dynamics simulation provides strong evidence for flavonoids to be excellent anti-tubulin agents for the treatment of cancer. Communicated by Ramaswamy H. Sarma. � 2022 Informa UK Limited, trading as Taylor & Francis Group.Item Design, synthesis and evaluation of 4-phenyl-1,2,3-triazole substituted pyrimidine derivatives as antiproliferative and tubulin polymerization inhibitors(Elsevier B.V., 2022-06-26T00:00:00) Dwivedi, Ashish Ranjan; Kumar, Vijay; Yadav, Ravi Prakash; Kumar, Naveen; Jangid, Kailash; Anand, Piyush; Sharma, Deepak Kumar; Barnawal, Somesh; Kumar, VinodLigands binding to the colchicine domain of the tubulin protein act as tubulin polymerization inhibitors and arrest the cell cycle in G2/M phase. A series of 4-Phenyl-1,2,3-triazole substituted pyrimidine derivatives have been synthesized and evaluated for antiproliferative and antitubulin activities. In the series, AV-6 and AV-14 were found to be active against the three tested cancer cell lines wherein AV-6 displayed IC50 values of 1.2 �M, 5.5 �M, and 1.9 �M while AV-14 displayed IC50 values of 4.7 �M, 1.7 �M, and 1.4 �M against HCT-116, MCF-7 and HT-29 cell lines, respectively. These compounds were found to be non toxic to the normal cells (HEK-293). In the cell cycle analysis and JC-1 studies, these compounds induce mitocondria mediated apoptosis. In the tubulin polymerization inhibition studies, AV-6 displayed significant tubulin polymerization inhibition potential. In the molecular docking and simulation studies, these compounds fit well in the active site of colchicine. � 2022 Elsevier B.V.