COMPUTER-ASSISTED DRUG DESIGNING OF TRIAZOLE DERIVATIVE OF NOSCAPINE AS TUBULIN-BINDING ANTICANCER DRUG

Objective: Microtubule-interfering drugs are commonly used to treat malignant disorders owing to indispensable role of this cytoskeletal element. These drugs include paclitaxel, docetaxel, and the Vinca alkaloids; however, owing to their non-selective action and overpolymerizing effects, these chemotherapy drugs are confounded by complications with serious toxicity (particularly, peripheral neuropathies, gastrointestinal toxicity, myelosuppression, and immunosuppression) (by taxanes) or depolymerizing effects (by Vincas) on microtubules. Thus, there is urgent need to explore novel tubulin-binding agents that are significantly effective and comparatively less toxic compared to currently available drugs for the treatment of human cancer. The current study focuses fusion of two novel anticancer compounds with low toxicity, i.e., noscapine and triazole to generate a new ligand derivative.Methods: Using computer-aided drug designing approach and molecular docking, molecular interaction of these derivatives with αβ-tubulin heterodimer was confirmed and investigated by molecular docking along with dynamics simulation.Results: A greater affinity of the newly designed ligands for binding to tubulin was predicted. The predictive binding free energy (Gbind,pred) of these derivatives (ranging from −10.5178 to −16.8473 kcal/mol) based on linear interaction energy method with a surface generalized born continuum salvation model showed improved binding affinity with tubulin as compared to the lead compound. natural α-Noscapine (−5.505 kcal/mol). The binding energy of ligand determined using LigX, i.e., MM/GBVI was found to be −23.208 kcal/mol.Conclusion: We found that designed derivative compounds have better efficacy as compared noscapine and triazole.

Download Full-text

Molecular Docking Study on the Effect on Lamin –B1 through Compounds for the Treatment of Multiple Sclerosis

International Journal for Research in Applied Science and Engineering Technology ◽

10.22214/ijraset.2021.36121 ◽

2021 ◽

Vol 9 (VI) ◽

pp. 5052-5057

Author(s):

Sachin Verma

Keyword(s):

Multiple Sclerosis ◽

Molecular Docking ◽

Demyelinating Disease ◽

The Body ◽

Computer Assisted ◽

Ligand Molecule ◽

Eye Muscle ◽

Lamin B1 ◽

Multiple Sclerosis Disease ◽

Drug Designing

Multiple sclerosis (MS) is a demyelinating disease that can disrupt or damage various parts of our body i.e. nerve cells, brain and spinal cord, etc. The damaged cells of the body can disrupt the ability of the the nervous system to transmit signals for the functioning of the body. MS may result in double vision, blindness in one eye, muscle weakness and trouble with coordination and sensation. This disease is a long-term disease that may not be cured rapidly and easily. MS may be found at an age of 20-50. Lamin B1 is a protein that is found in humans. A gene i.e LMB1 encodes for this protein. The nuclear lamina consists of a 2D matrix of protein which locates next to the inner nuclear membrane. Molecular docking is a virtual or e tool that promotes the drug designing technique in a computerized way or called computer-assisted Drug Designing [CADD]. This can be used to complete the goal of docking is to see the binding of the protein and ligands In our study, one of the naturally occurring products was used for Multiple sclerosis treatment i.e Quercetin . The Quercetin ligand molecule gives a promising way of making the drug against the Multiple Sclerosis disease. According to this study, Quercetin may be used as a drug agent against Multiple Sclerosis disease in the future.

Download Full-text

Docking of FDA Approved Drugs Targeting NSP-16, N-Protein and Main Protease of SARS-CoV-2 as Dual Inhibitors

Biointerface Research in Applied Chemistry ◽

10.33263/briac113.98489861 ◽

2020 ◽

Vol 11 (3) ◽

pp. 9848-9861

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

High Throughput Screening ◽

Binding Free Energy ◽

Dynamics Simulation ◽

Structural Proteins ◽

Computer Assisted ◽

Dual Inhibitor ◽

N Protein ◽

Dual Inhibitors

At present world is lurching under the spread of new SARS-CoV-2 infection. The treatment is still elusive despite the relentless effort by the scientists against various viral structures. Whereas the 3-Chymotrypsin-like proteases cleave polyproteins and structural proteins help in viral replication. At the same time, non-structural proteins stimulate mRNA cap methylation to evade the immune response. The present study aims to identify novel dual inhibitor compounds with potential hits simultaneously against any of these three targets, including 3C-like proteases, N-protein, and NSP16 through virtual screening, molecular docking approach, and molecular dynamics. Such dual inhibitors may provide the necessary treatment to alleviate the current pandemic. We screened 265 FDA approved infectious disease drugs against three types of Covid-19 targets, i.e., 3C-like proteinase (6w63), N-protein (6vyo), and Non-structural protein 16 (6w4h) using a computer-assisted drug repurposing approach in this study. The Schrodinger suite 2019 is employed for high throughput screening, molecular docking, and binding free energy through the Glide module. We sorted 27 drugs, out of which the best common three drugs were suggested based on their virtual statistics parameters. We found three drugs that belonged to two main categories as dual inhibitors. The Plazomicin (Aminoglycoside) and Cefiderocol (Cephalosporins) are an antibiotic group of drugs, and the Vanganciclovir is antiviral. The molecular dynamics simulation studies over 30000ps for Plazomicin against NSP16 was conducted based on their promising docking scores profile. The RMSD parameter remained stable at 2.5Å for ligands for 30000ps. Thus these three compounds can be validated as a SARS-CoV-2 therapy through clinical trials.

Download Full-text

Docking studies of 3,5-disubstituted thiazolidinedione chalcones as PPAR-? agonist

JOURNAL OF PHARMACEUTICAL CHEMISTRY ◽

10.14805/jphchem.2016.art64 ◽

2016 ◽

Vol 3 (3) ◽

pp. 1

Author(s):

Fajeelath Fathima ◽

Abitha Haridas ◽

Baskar Lakshmanan

Keyword(s):

Molecular Docking ◽

Binding Free Energy ◽

Docking Studies ◽

Antidiabetic Activity ◽

Receptor Interaction ◽

Standard Drug ◽

Modern Drug ◽

Drug Designing ◽

Drug Receptor ◽

Drug Receptor Interaction

PPARs play crucial role in the regulation of cellular differentiation, development and metabolism of carbohydrates, lipids and proteins in human, of which PPAR- ? has pivotal role in glucose homeostasis. In modern drug designing, molecular docking is routinely used for understanding drug receptor interaction. In the present study molecular docking were performed on a diverse set of 3,5-disubstituted thiazolidinedione chalcone derivatives that demonstrate antidiabetic activity by stimulating PPAR- ?. Among the designed analogues, e3, a3, b3 and c3 showed significant binding free energy of -12.29, -12.04, -11.53 and -11.45 kcal/mol with predicted inhibitory constant values of 987.38 pM, 1.5, 3.53 and 4.04 nM respectively and all the selected compounds were compared with standard drug Rosiglitazone.

Download Full-text

A comprehensive in silico study towards understanding the inhibitory mechanism of Lactoperoxidase by Dapsone and Propofol

Current Computer - Aided Drug Design ◽

10.2174/1573409916666200628104134 ◽

2020 ◽

Vol 16 ◽

Author(s):

Rameez Jabeer Khan ◽

Rajat Kumar Jha ◽

Gizachew Muluneh Amera ◽

Jayaraman Muthukumaran ◽

Rashmi Prabha Singh ◽

...

Keyword(s):

Molecular Docking ◽

Md Simulation ◽

Binding Free Energy ◽

Protoporphyrin Ix ◽

Md Simulations ◽

Prosthetic Group ◽

Drug Molecules ◽

Group A ◽

Complex Forms ◽

Covalently Linked

Introduction: Lactoperoxidase (LPO) is a member of mammalian heme peroxidase family and is an enzyme of innate immune system. It possesses a covalently linked heme prosthetic group (a derivative of protoporphyrin IX) in its active site. LPO catalyzes the oxidation of halides and pseudohalides in the presence of hydrogen peroxide (H2O2) and shows a broad range of antimicrobial activity. Methods: In this study, we have used two pharmaceutically important drug molecules, namely dapsone and propofol, which are earlier reported as potent inhibitors of LPO. Whereas the stereochemistry and mode of binding of dapsone and propofol to LPO is still not known because of the lack of the crystal structure of LPO with these two drugs. In order to fill this gap, we utilized molecular docking and molecular dynamics (MD) simulation studies of LPO in native and complex forms with dapsone and propofol. Results: From the docking results, the estimated binding free energy (ΔG) of -9.25 kcal/mol (Ki = 0.16 μM) and -7.05 kcal/mol (Ki = 6.79 μM) was observed for dapsone, and propofol, respectively. The standard error of Auto Dock program is 2.5 kcal/mol; therefore, molecular docking results alone were inconclusive. Conclusion: To further validate the docking results, we performed MD simulation on unbound, and two drugs bounded LPO structures. Interestingly, MD simulations results explained that the structural stability of LPO-Propofol complex was higher than LPO-Dapsone complex. The results obtained from this study establish the mode of binding and interaction pattern of the dapsone and propofol to LPO as inhibitors.

Download Full-text

Design of potential IKK-β inhibitors using molecular docking and molecular dynamics techniques for their anti-cancer potential

Current Computer - Aided Drug Design ◽

10.2174/1573409916666200102121505 ◽

2020 ◽

Vol 16 ◽

Author(s):

Salam Pradeep Singh ◽

Iftikar Hussain ◽

Bolin Kumar Konwar ◽

Ramesh Chandra Deka ◽

Chingakham Brajakishor Singh

Keyword(s):

Molecular Dynamics ◽

Molecular Docking ◽

Md Simulation ◽

Inflammatory Diseases ◽

Binding Free Energy ◽

Anti Cancer ◽

Dietary Phytochemicals ◽

Toxicity Analysis ◽

The Stability ◽

Stable Trajectory

Aim and Objective: To evaluate a set of seventy phytochemicals for their potential ability to bind the inhibitor of nuclear factor kappaB kinase beta (IKK-β) which is a prime target for cancer and inflammatory diseases. Materials and Methods: Seventy phytochemicals were screened against IKK-β enzyme using DFT-based molecular docking technique and the top docking hits were carried forward for molecular dynamics (MD) simulation protocols. The adme-toxicity analysis was also carried out for the top docking hits. Results: Sesamin, matairesinol and resveratrol were found to be the top docking hits with a total score of -413 kJ/mol, -398.11 kJ/mol and 266.73 kJ/mol respectively. Glu100 and Gly102 were found to be the most common interacting residues. The result from MD simulation observed a stable trajectory with a binding free energy of -107.62 kJ/mol for matairesinol, -120.37 kJ/mol for sesamin and -40.56 kJ/mol for resveratrol. The DFT calculation revealed the stability of the compounds. The ADME-Toxicity prediction observed that these compounds fall within the permissible area of Boiled-Egg and it does not violate any rule for pharmacological criteria, drug-likeness etc. Conclusion: The study interprets that dietary phytochemicals are potent inhibitors of IKK-β enzyme with favourable binding affinity and less toxic effects. In fact, there is a gradual rise in the use of plant-derived molecules because of its lesser side effects compared to chemotherapy. The study has also provided an insight by which the phytochemicals inhibited the IKK-β enzyme. The investigation would also provide in understanding the inhibitory mode of certain dietary phytochemicals in treating cancer.

Download Full-text

Molecular Docking Study for Analyzing the Inhibitory Effect of Anti-inflammatory Plant Compound Against Tumour Necrosis Factor (TNF-α)

Current Drug Therapy ◽

10.2174/1574885513666180503145352 ◽

2019 ◽

Vol 14 (1) ◽

pp. 85-90

Author(s):

Sagarika Biswas

Keyword(s):

Molecular Docking ◽

Tumour Necrosis Factor ◽

Tumour Necrosis ◽

Docking Study ◽

Developed Countries ◽

Inhibitory Effect ◽

Molecular Docking Study ◽

Drug Designing ◽

Anti Inflammatory ◽

Necrosis Factor

Background: Rheumatoid Arthritis (RA) is an autoimmune disorder of symmetric synovial joints which is characterized by the chronic inflammation with 0.5-1% prevalence in developed countries. Presence of persistent inflammation is attributed to the major contribution of key inflammatory cytokine and tumour necrosis factor- alpha (TNF- α). Recent drug designing studies are developing TNF-α blockers to provide relief from the symptoms of the disease such as pain and inflammation. Available blockers are showing certain limitations such as it may enhance the rate of tuberculosis (TB) occurrence, lymphoma risk, cost issues and certain infections are major concern. Discussed limitations implicated a need of development of some alternative drugs which exhibit fewer side effects with low cost. Therefore, we have identified anti-inflammatory compounds in an underutilized fruit of Baccaurea sapida (B.sapida) in our previous studies. Among them quercetin have been identified as the most potent lead compound for drug designing studies of RA. Methods: In the present article, characterization of quercetin has been carried out to check its drug likeliness and molecular docking study has been carried out between TNF- α and quercetin by using AutoDock 4.2.1 software. Further, inhibitory effect of B. sapida fruit extract on RA plasma has been analysed through immunological assay ELISA. Results: Our in-silico analysis indicated that quercetin showed non carcinogenic reaction in animal model and it may also cross the membrane barrier easily. We have studied the ten different binding poses and best binding pose of TNF-α and quercetin showed -6.3 kcal/mol minimum binding energy and 23.94 µM inhibitory constant. In addition to this, ELISA indicated 2.2 down regulated expression of TNF-α in RA compared to control. Conclusion: This study may further be utilized for the drug designing studies to reduce TNF-α mediated inflammation in near future. This attempt may also enhance the utilization of this plant worldwide.

Download Full-text

A New Smoothened Antagonist Bearing the Purine Scaffold Shows Antitumour Activity In Vitro and In Vivo

International Journal of Molecular Sciences ◽

10.3390/ijms22168372 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8372

Author(s):

Ana María Zárate ◽

Christian Espinosa-Bustos ◽

Simón Guerrero ◽

Angélica Fierro ◽

Felipe Oyarzún-Ampuero ◽

...

Keyword(s):

Cancer Cells ◽

Human Cancer ◽

Antitumour Activity ◽

Anticancer Compounds ◽

Human Cancer Cells ◽

Cycle Arrest ◽

Apoptosis Inducer ◽

Purine Ring

The Smoothened (SMO) receptor is the most druggable target in the Hedgehog (HH) pathway for anticancer compounds. However, SMO antagonists such as vismodegib rapidly develop drug resistance. In this study, new SMO antagonists having the versatile purine ring as a scaffold were designed, synthesised, and biologically tested to provide an insight to their mechanism of action. Compound 4s was the most active and the best inhibitor of cell growth and selectively cytotoxic to cancer cells. 4s induced cell cycle arrest, apoptosis, a reduction in colony formation and downregulation of PTCH and GLI1 expression. BODIPY-cyclopamine displacement assays confirmed 4s is a SMO antagonist. In vivo, 4s strongly inhibited tumour relapse and metastasis of melanoma cells in mice. In vitro, 4s was more efficient than vismodegib to induce apoptosis in human cancer cells and that might be attributed to its dual ability to function as a SMO antagonist and apoptosis inducer.

Download Full-text

Crk and CrkL as Therapeutic Targets for Cancer Treatment

Cells ◽

10.3390/cells10040739 ◽

2021 ◽

Vol 10 (4) ◽

pp. 739

Author(s):

Taeju Park

Keyword(s):

Tumor Cell ◽

Cancer Treatment ◽

Epithelial Mesenchymal Transition ◽

Human Cancer ◽

Therapeutic Targets ◽

Viral Oncoprotein ◽

Mesenchymal Transition ◽

Chemotherapy Drugs ◽

Cell Functions

Crk and CrkL are cellular counterparts of the viral oncoprotein v-Crk. Crk and CrkL are overexpressed in many types of human cancer, correlating with poor prognosis. Furthermore, gene knockdown and knockout of Crk and CrkL in tumor cell lines suppress tumor cell functions, including cell proliferation, transformation, migration, invasion, epithelial-mesenchymal transition, resistance to chemotherapy drugs, and in vivo tumor growth and metastasis. Conversely, overexpression of tumor cells with Crk or CrkL enhances tumor cell functions. Therefore, Crk and CrkL have been proposed as therapeutic targets for cancer treatment. However, it is unclear whether Crk and CrkL make distinct or overlapping contributions to tumor cell functions in various cancer types because Crk or CrkL have been examined independently in most studies. Two recent studies using colorectal cancer and glioblastoma cells clearly demonstrated that Crk and CrkL need to be ablated individually and combined to understand distinct and overlapping roles of the two proteins in cancer. A comprehensive understanding of individual and overlapping roles of Crk and CrkL in tumor cell functions is necessary to develop effective therapeutic strategies. This review systematically discusses crucial functions of Crk and CrkL in tumor cell functions and provides new perspectives on targeting Crk and CrkL in cancer therapy.

Download Full-text

In Silico Exploration of Phytoconstituents From Phyllanthus emblica and Aegle marmelos as Potential Therapeutics Against SARS-CoV-2 RdRp

Bioinformatics and Biology Insights ◽

10.1177/11779322211027403 ◽

2021 ◽

Vol 15 ◽

pp. 117793222110274

Author(s):

Khushboo Pandey ◽

Kiran Bharat Lokhande ◽

K Venkateswara Swamy ◽

Shuchi Nagar ◽

Manjusha Dake

Keyword(s):

Molecular Docking ◽

Binding Affinity ◽

Simulation Analysis ◽

Binding Free Energy ◽

Free Energy Calculations ◽

Molecular Field ◽

Hydroxyl Groups ◽

Phyllanthus Emblica ◽

Inhibitory Potential ◽

Novel Drug

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide has increased the importance of computational tools to design a drug or vaccine in reduced time with minimum risk. Earlier studies have emphasized the important role of RNA-dependent RNA polymerase (RdRp) in SARS-CoV-2 replication as a potential drug target. In our study, comprehensive computational approaches were applied to identify potential compounds targeting RdRp of SARS-CoV-2. To study the binding affinity and stability of the phytocompounds from Phyllanthus emblica and Aegel marmelos within the defined binding site of SARS-CoV-2 RdRp, they were subjected to molecular docking, 100 ns molecular dynamics (MD) simulation followed by post-simulation analysis. Furthermore, to assess the importance of features involved in the strong binding affinity, molecular field-based similarity analysis was performed. Based on comparative molecular docking and simulation studies of the selected phytocompounds with SARS-CoV-2 RdRp revealed that EBDGp possesses a stronger binding affinity (−23.32 kcal/mol) and stability than other phytocompounds and reference compound, Remdesivir (−19.36 kcal/mol). Molecular field-based similarity profiling has supported our study in the validation of the importance of the presence of hydroxyl groups in EBDGp, involved in increasing its binding affinity toward SARS-CoV-2 RdRp. Molecular docking and dynamic simulation results confirmed that EBDGp has better inhibitory potential than Remdesivir and can be an effective novel drug for SARS-CoV-2 RdRp. Furthermore, binding free energy calculations confirmed the higher stability of the SARS-CoV-2 RdRp-EBDGp complex. These results suggest that the EBDGp compound may emerge as a promising drug against SARS-CoV-2 and hence requires further experimental validation.

Download Full-text