Pharmaceutical Sciences and Natural Products - Research Publications

Permanent URI for this collectionhttps://kr.cup.edu.in/handle/32116/56

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Author: search.filters.author.Kumar, Vinod

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    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, Vikas
    Cancer 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.
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    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, Vikas
    Bacterial 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.
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    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, Vikas
    Background: 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.
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    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, Vinod
    Alzheimer�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.
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    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, Vinod
    The 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.
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    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, Vinod
    Ligands 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.
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    Morpholine substituted quinazoline derivatives as anticancer agents against MCF-7, A549 and SHSY-5Y cancer cell lines and mechanistic studies
    (Royal Society of Chemistry, 2022-04-05T00:00:00) Dwivedi, Ashish Ranjan; Kumar, Vijay; Prashar, Vikash; Verma, Akash; Kumar, Naveen; Parkash, Jyoti; Kumar, Vinod
    A series of morpholine substituted quinazoline derivatives have been synthesized and evaluated for cytotoxic potential against A549, MCF-7 and SHSY-5Y cancer cell lines. These compounds were found to be non-toxic against HEK293 cells at 25 ?M and hence display anticancer potential. In these series compounds, AK-3 and AK-10 displayed significant cytotoxic activity against all the three cell lines. AK-3 displayed IC50 values of 10.38 � 0.27 ?M, 6.44 � 0.29 ?M and 9.54 � 0.15 ?M against A549, MCF-7 and SHSY-5Y cancer cell lines. Similarly, AK-10 showed IC50 values of 8.55 � 0.67 ?M, 3.15 � 0.23 ?M and 3.36 � 0.29 ?M against A549, MCF-7 and SHSY-5Y, respectively. In the mechanistic studies, it was found that AK-3 and AK-10 inhibit the cell proliferation in the G1 phase of the cell cycle and the primary cause of death of the cells was found to be through apoptosis. Thus, morpholine based quinazoline derivatives have the potential to be developed as potent anticancer drug molecules. � 2022 RSC
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    Role of peroxisome proliferator-activated receptor gamma (Ppar?) in different disease states: Recent updates
    (Bentham Science Publishers, 2020-07-17T00:00:00) Mal, Suvadeep; Dwivedi, Ashish Ranjan; Kumar, Vijay; Kumar, Naveen; Kumar, Bhupinder; Kumar, Vinod
    Peroxisome proliferator-activated receptor (PPAR), a ligand dependant transcription factor, is a member of the nuclear receptor superfamily. PPAR exists in three isoforms i.e. PPAR alpha (PPAR?), PPAR beta (PPAR?), and PPAR gamma (PPAR?). These are multi-functional transcription factors and help in regulating inflammation, type 2 diabetes, lipid concentration in the body, metastasis, and tumor growth or angiogenesis. Activation of PPAR? causes inhibition of growth of cultured human breast, gastric, lung, prostate, and other cancer cells. PPAR? is mainly involved in fatty acid storage, glucose metabolism, and homeo-stasis and adipogenesis regulation. A large number of natural and synthetic ligands bind to PPAR? and modulate its activity. Ligands such as thiazolidinedione troglitazone, rosiglita-zone, pioglitazone effectively bind to PPAR?; however, most of these were found to display severe side effects such as hepatotoxicity, weight gain, cardiovascular complications and bladder tumor. Now the focus is shifted towards the development of dual-acting or pan PPAR ligands. The current review article describes the functions and role of PPAR? in various disease states. In addition, recently reported PPAR? ligands and pan PPAR ligands were dis-cussed in detail. It is envisaged that the present review article may help in the development of potent PPAR ligands with no or minimal side effects. � 2021 Bentham Science Publishers.
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    Genomic alterations associated with HER2+ breast cancer risk and clinical outcome in response to trastuzumab
    (Springer, 2019) Singla, H; Kaur, R.P; Shafi, G; Vashistha, R; Banipal, R.P.S; Kumar, Vinod; Munshi, Anjana
    Human epidermal growth factor receptor 2 positive (HER2+) breast cancer (BC) is an aggressive BC subtype characterized by HER2 overexpression/amplification. Genomic alterations of HER2 and others have been reported to be associated with, HER2 overexpression and prediction of trastuzumab-response. Here, we aimed at identifying germline and somatic alterations associated with HER2+ BC and evaluating their association with clinical outcome in response to trastuzumab therapy given to HER2+ BC patients. Global Sequencing Array (GSA) and polymerase chain reaction-restriction length polymorphism (PCR-RFLP) techniques were used to determine alterations in HER2 and other HER2-interacting as well as signaling-related genes in HER2+ BC. In addition, 20 formalin fixed paraffin-embedded tissue samples were also evaluated by GSA for identifying significant variations associated with HER + BC as well as response to trastuzumab therapy. A germline variant in HER2 (I655V) was found to be significantly associated with the risk of the disease (p < 0.01). A nonsense mutation in PTPN11 (K99X), a pathogenic CCND1 splice site variant (P241P), a hotspot missense mutation in PIK3CA (E542K) and a hotspot missense mutation in TP53 (R249S); were observed in 25%, 75%, 30% and 40% of the HER2+ BC tissue samples, respectively. Mutant CCND1 (P241P) and PIK3CA (E542K) were found to be significantly associated with reduced disease-free survival (DFS) in patients treated with trastuzumab (p: 0.018 and 0.005, respectively). These results indicate that HER2, PTPN11, CCND1 and PIK3CA genes are important biomarkers in HER2+ BC. Moreover, the patients harboring mutant CCND1 and PIK3CA exhibit a poorer clinical outcome as compared to those carrying wild-type CCND1 and PIK3CA. © 2018, Springer Nature B.V.
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    4,6-Diphenylpyrimidine Derivatives as Dual Inhibitors of Monoamine Oxidase and Acetylcholinesterase for the Treatment of Alzheimer's Disease
    (American Chemical Society, 2019) Kumar, B; Dwivedi, A.R; Sarkar, B; Gupta, S.K; Krishnamurthy, S; Mantha, Anil K; Parkash, Jyoti; Kumar, Vinod
    Alzheimer's disease (AD) is a neurodegenerative disorder with multifactorial pathogenesis. Monoamine oxidase (MAO) and acetylcholinesterase enzymes (AChE) are potential targets for the treatment of AD. A total of 15 new propargyl containing 4,6-diphenylpyrimidine derivatives were synthesized and screened for the MAO and AChE inhibition activities along with ROS production inhibition and metal-chelation potential. All the synthesized compounds were found to be selective and potent inhibitors of MAO-A and AChE enzymes at nanomolar concentrations. VB1 was found to be the most potent MAO-A and BuChE inhibitor with IC 50 values of 18.34 ± 0.38 nM and 0.666 ± 0.03 μM, respectively. It also showed potent AChE inhibition with an IC 50 value of 30.46 ± 0.23 nM. Compound VB8 was found to be the most potent AChE inhibitor with an IC 50 value of 9.54 ± 0.07 nM and displayed an IC 50 value of 1010 ± 70.42 nM against the MAO-A isoform. In the cytotoxic studies, these compounds were found to be nontoxic to the human neuroblastoma SH-SY5Y cells even at 25 μM concentration. All the compounds were found to be reversible inhibitors of MAO-A and AChE enzymes. In addition, these compounds also showed good neuroprotective properties against 6-OHDA- and H 2 O 2 -induced neurotoxicity in SH-SY5Y cells. All the compounds accommodate nicely to the hydrophobic cavity of MAO-A and AChE enzymes. In the molecular dynamics simulation studies, both VB1 and VB8 were found to be stable in the respective cavities for 30 ns. Thus, 4,6-diphenylpyrimidine derivatives can act as promising leads in the development of dual-acting inhibitors targeting MAO-A and AChE enzymes for the treatment of Alzheimer's disease. © 2018 American Chemical Society.