CoMFA, Molecular Docking and Molecular Dynamics Studies on Cycloguanil Analogues as Potent Antimalarial Agents

2020 ◽  
Vol 21 (1) ◽  
pp. 66
Author(s):  
Isman Kurniawan ◽  
Muhammad Salman Fareza ◽  
Ponco Iswanto
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Active Compound ◽  
Md Simulation ◽  
Partial Least Square ◽  
Least Square ◽  
Field Analysis ◽  
Data Set ◽  
Comfa Model ◽  
Antimalarial Agents

Malaria is a disease that commonly infects humans in many tropical areas. This disease becomes a serious problem because of the high resistance of Plasmodium parasite against the well-established antimalarial agents, such as Artemisinin. Hence, new potent compounds are urgently needed to resolve this resistance problem. In the present study, we investigated cycloguanil analogues as a potent antimalarial agent by utilizing several studies, i.e., comparative of molecular field analysis (CoMFA), molecular docking and molecular dynamics (MD) simulation. A CoMFA model with five partial least square regressions (PLSR) was developed to predict the pIC50 value of the compound by utilizing a data set of 42 cycloguanil analogues. From statistical analysis, we obtained the r2 values of the training and test sets that were 0.85 and 0.70, respectively, while q2 of the leave-one-out cross-validation was 0.77. The contour maps of the CoMFA model were also interpreted to analyze the structural requirement regarding electrostatic and steric factors. The most active compound (c33) and least active compound (c8) were picked for molecular docking and MD analysis. From the docking analysis, we found that the attached substituent on the backbone structure of cycloguanil gives a significant contribution to antimalarial activity. The results of the MD simulation confirm the stability of the binding pose obtained from the docking simulations.

scholarly journals Design, Synthesis, Biological Evaluation, and Molecular Modeling of 2-Difluoromethylbenzimidazole Derivatives as Potential PI3Kα Inhibitors

Molecules ◽  
2022 ◽  
Vol 27 (2) ◽  
pp. 387
Author(s):  
Xiangcong Wang ◽  
Moxuan Zhang ◽  
Ranran Zhu ◽  
Zhongshan Wu ◽  
Fanhong Wu ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Molecular Modeling ◽  
3D Qsar ◽  
Binding Mode ◽  
Biological Evaluation ◽  
Field Analysis ◽  
Dynamics Simulation ◽  
Comfa Model ◽  
Qsar Models

PI3Kα is one of the potential targets for novel anticancer drugs. In this study, a series of 2-difluoromethylbenzimidazole derivatives were studied based on the combination of molecular modeling techniques 3D-QSAR, molecular docking, and molecular dynamics. The results showed that the best comparative molecular field analysis (CoMFA) model had q2 = 0.797 and r2 = 0.996 and the best comparative molecular similarity indices analysis (CoMSIA) model had q2 = 0.567 and r2 = 0.960. It was indicated that these 3D-QSAR models have good verification and excellent prediction capabilities. The binding mode of the compound 29 and 4YKN was explored using molecular docking and a molecular dynamics simulation. Ultimately, five new PI3Kα inhibitors were designed and screened by these models. Then, two of them (86, 87) were selected to be synthesized and biologically evaluated, with a satisfying result (22.8 nM for 86 and 33.6 nM for 87).

scholarly journals Simulation Studies 3D QSAR and Molecular Docking, on a Point Mutation of Protein Kinase B with Flavonoids Targeting Ovarian Cancer

2021 ◽  
Author(s):  
Suchitra Ajjarapu ◽  
Apoorv Tiwari ◽  
Gohar Taj ◽  
Dev Singh ◽  
Sakshi Singh ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Molecular Dynamics Simulation ◽  
Point Mutation ◽  
3D Qsar ◽  
Partial Least Square ◽  
Least Square ◽  
Dynamics Simulation ◽  
Molecular Networks ◽  
New Combination

Abstract Cancer is the world’s dreaded disease and its prevalence is expanding globally. The study of integrated molecular networks is crucial for the basic mechanism of cancer cells and its progression. During the present investigation we have examined different flavonoids that targets protein kinases B (AKT1) protein which exerts their anticancer efficiency intriguing the role in cross talk cell signalling, by metabolic processes through in-silico approaches. Molecular dynamics simulation (MDS) was performed to analyse and evaluate the stability of the complexes under physiological conditions and the results were congruent with molecular docking. This investigation revealed the effect of a point mutation (W80R), considered based on their frequency of occurrence, with AKT1. The ligand with high docking scores and favourable behaviour on dynamic simulations are proposed as potential W80R inhibitors. A virtual screening analysis was performed with 12000flavonoids satisfying the Lipinski’s rule of 5 according to which drug-likeness is predicted based on its pharmacological and biological properties to be active and taken orally. The pharmacokinetic ADME (adsorption, digestion, metabolism and excretion) studies featured drug likeness. Subsequently, a statistical significant 3D-QSAR model of high correlation coefficient (R2) with 0.992 and cross validation coefficient (Q2) with 0.6132 at 4 component PLS (partial least square) were used to verify accuracy of the models. The molecular dynamics simulation of this study showed that the compound is Taxifolin (I-UPAC namely2-(3,4-dihydroxyphenyl)-3,4 –dihydro-2H-chromene-5,7-diol of C15H14O5, of CID ID-443637 evidenced a better interaction with docking score (-9.63Kcal/mol) exhibited the binding affinity with W80R mutant protein thus reflecting that natural inhibitor can be considered for experimental evaluation which provides targeted insights for new combination of drugs in forming a network in pharmacology.

scholarly journals Computational Investigation of Adenosine 5′- (α, β-methylene)- diphosphate (AMPCP) Derivatives as Ecto-5′-nucleotidase (CD73) Inhibitors by Using 3D-QSAR, Molecular Docking, and Molecular Dynamics Simulations

2021 ◽  
Author(s):  
Jiatong Wen ◽  
Heng Zhang ◽  
Churen Meng ◽  
Di Zhou ◽  
Gang Chen ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Molecular Docking ◽  
Tumor Cells ◽  
Binding Free Energy ◽  
3D Qsar ◽  
Qsar Model ◽  
Field Analysis ◽  
Dynamics Simulation ◽  
Comfa Model ◽  
Structure Activity

Abstract CD73, as a surface enzyme anchored on the outside of the cell membrane via glycosylphosphatidylinositol (GPI), can convert the AMP in the tumor cell microenvironment into adenosine to promote the growth of tumor cells. It has been overexpressed in many different types of human tumors, such as gastric cancer, pancreatic cancer, liver cancer and other tumor cells. Therefore, targeted inhibitors of CD73 are considered as potential tumor treatment methods. Due to the low bioavailability of nucleoside CD73 inhibitors, it is necessary to develop new inhibitors. In this study, through molecular docking, three-dimensional quantitative structure-activity relationship (3D-QSAR) and molecular dynamics (MD) simulations, a series of CD73 inhibitors were calculated and studied to reveal their structure-activity relationships. Through molecular docking studies, explore the possible mode of interaction between inhibitors and protein. Subsequently, a 3D-QSAR model was established by comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). For the best CoMFA model, the Q2 and R2 values ​​are 0.708 and 0.983, respectively, while for the best CoMSIA model, the Q2 and R2 values ​​are 0.809 and 0.992, respectively. In addition, the stability of the complex formed by the two inhibitors and CD73 was evaluated by molecular dynamics simulation, and the results are consistent with the results of molecular docking and 3D-QSAR research. Finally, the binding free energy was calculated by the surface area method (MM-GBSA), and the results are consistent with the activities that Van Der Waals and Coulomb contribute the most during the binding process of the molecule to the CD73 protein. In conclusion, our research provides valuable information for the further development of CD73 inhibitors.

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

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.

From managing customers to joint venturing with customers: co-creating service value in the digital age

2021 ◽  
Vol ahead-of-print (ahead-of-print) ◽  
Author(s):  
Christine Falkenreck ◽  
Ralf Wagner
Keyword(s):  
Perceived Risk ◽  
Structural Equation ◽  
Business Models ◽  
Joint Venture ◽  
Digital Age ◽  
Partial Least Square ◽  
Least Square ◽  
Equation Modeling ◽  
Data Set ◽  
Content Type

Purpose Until today, scholars claim that the phenomenon of “co-creation” of value in an “interacted” economy and in the context of positive actor-to-actor relationships has not been adequately explored. This study aims to first to identify and separate the accessible values of internet of things (IoT)-based business models for business-to-business (B2B) and business-to-government (B2G) customer groups. It quantifies the drivers to successfully implement disruptive business models. Design/methodology/approach Data were gathered from 292 customers in Western Europe. The conceptual framework was tested using partial least square structural equation modeling. Findings Managing disruptions in the digital age is closely related to the fact that the existing trust in buyer-seller relationships is not enough to accept IoT projects. A company’s digitalization capabilities, satisfaction with the existing relationship and trust in the IoT credibility of the manufacturer drives the perceived value of IoT-based business models in B2B settings. Contrastingly, in B2G settings, money is less important. Research limitations/implications Research refers to one business field, the data set is of European origin only. Findings indicate that the drivers to engage in IoT-related projects differ significantly between the customer groups and therefore require different marketing management strategies. Saving time today is more important to B2G buyers than saving money. Practical implications The disparate nature of B2B and B2G buyers indicates that market segmentation and targeted marketing must be considered before joint-venturing in IoT business models. To joint venture supply chain partners co-creating value in the context of IoT-related business models, relationship management should be focused with buyers on the same footing, as active players and co-developers of a personalized experience in digital service projects. Originality/value Diverging from established studies focusing on the relationship within a network of actors, this study defines disruptive business models and identifies its drivers in B2B and B2G relationships. This study proposes joint venturing with B2B and B2G customers to overcome the perceived risk of these IoT-related business models. Including customers in platforms and networks may lead to the co-creation of value in joint IoT projects.

scholarly journals Entrepreneurial self-efficacy and entrepreneurial intention: The mediating role of the need for independence

2021 ◽  
Vol 17 (4) ◽  
pp. 91-119
Author(s):  
Victor Osadolor ◽  
◽  
Kalu Emmanuel Agbaeze ◽  
Ejikeme Emmanuel Isichei ◽  
Samuel Taiwo Olabosinde ◽  
...  
Keyword(s):  
Self Efficacy ◽  
Structural Equation ◽  
Entrepreneurial Intention ◽  
Partial Least Square ◽  
Least Square ◽  
Data Set ◽  
Behavioral Reasoning Theory ◽  
The Relationship ◽  
Behavioral Reasoning

PURPOSE: The paper focuses on assessing the direct effect of entrepreneurial self-efficacy and entrepreneurial intention and the indirect effect of the need for independence on the relationship between the constructs. Despite increased efforts towards steering the interest of young graduates towards entrepreneurial venture, the response rate has been rather unimpressive and discouraging, thus demanding the need to account for what factors could drive intention towards venture ownership among graduates in Nigeria. METHODOLOGY: A quantitative approach was adopted and a data set from 235 graduates was used for the study. The data was analyzed using the partial least square structural equation model (PLS-SEM). FINDINGS: It was found that self-efficacy does not significantly affect intention. It was also found that the need for independence affects entrepreneurial intention. The study found that the need for independence fully mediates the relationship between entrepreneurial self-efficacy and entrepreneurial intention. PRACTICAL IMPLICATIONS: This paper provides new insight into the behavioral reasoning theory, through its application in explaining the cognitive role of the need for independence in decision-making, using samples from a developing economy. ORIGINALITY AND VALUE: The study advances a new perspective on the underlining factors that account for an entrepreneur’s intent to start a business venture, most especially among young graduates in Nigeria, through the lens of the behavioral reasoning theory. We further support the application of the theory in entrepreneurship literature, given the paucity of studies that have adopted the theory despite its relevance.

scholarly journals Characterization of α-Glucosidase Inhibitors from Clinacanthus nutans Lindau Leaves by Gas Chromatography-Mass Spectrometry-Based Metabolomics and Molecular Docking Simulation

Molecules ◽  
2018 ◽  
Vol 23 (9) ◽  
pp. 2402 ◽  
Author(s):  
Suganya Murugesu ◽  
Zalikha Ibrahim ◽  
Qamar-Uddin Ahmed ◽  
Nik-Idris Nik Yusoff ◽  
Bisha-Fathamah Uzir ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Gas Chromatography ◽  
Molecular Docking ◽  
Acid Methyl Ester ◽  
Docking Simulation ◽  
Partial Least Square ◽  
Least Square ◽  
Gas Chromatography Mass Spectrometry ◽  
Glucosidase Inhibitors ◽  
Clinacanthus Nutans

Background: Clinacanthus nutans (C. nutans) is an Acanthaceae herbal shrub traditionally consumed to treat various diseases including diabetes in Malaysia. This study was designed to evaluate the α-glucosidase inhibitory activity of C. nutans leaves extracts, and to identify the metabolites responsible for the bioactivity. Methods: Crude extract obtained from the dried leaves using 80% methanolic solution was further partitioned using different polarity solvents. The resultant extracts were investigated for their α-glucosidase inhibitory potential followed by metabolites profiling using the gas chromatography tandem with mass spectrometry (GC-MS). Results: Multivariate data analysis was developed by correlating the bioactivity, and GC-MS data generated a suitable partial least square (PLS) model resulting in 11 bioactive compounds, namely, palmitic acid, phytol, hexadecanoic acid (methyl ester), 1-monopalmitin, stigmast-5-ene, pentadecanoic acid, heptadecanoic acid, 1-linolenoylglycerol, glycerol monostearate, alpha-tocospiro B, and stigmasterol. In-silico study via molecular docking was carried out using the crystal structure Saccharomyces cerevisiae isomaltase (PDB code: 3A4A). Interactions between the inhibitors and the protein were predicted involving residues, namely LYS156, THR310, PRO312, LEU313, GLU411, and ASN415 with hydrogen bond, while PHE314 and ARG315 with hydrophobic bonding. Conclusion: The study provides informative data on the potential α-glucosidase inhibitors identified in C. nutans leaves, indicating the plant’s therapeutic effect to manage hyperglycemia.

scholarly journals Molecular Docking and Molecular Dynamics (MD) Simulation of Human Anti-Complement Factor H (CFH) Antibody Ab42 and CFH Polypeptide

2019 ◽  
Vol 20 (10) ◽  
pp. 2568 ◽  
Author(s):  
Bing Yang ◽  
Shu-Jian Lin ◽  
Jia-Yi Ren ◽  
Tong Liu ◽  
Yue-Ming Wang ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Monoclonal Antibody ◽  
Molecular Docking ◽  
Md Simulation ◽  
Factor H ◽  
Complement Factor H ◽  
Energy Calculation ◽  
Complement Factor ◽  
Alanine Scanning ◽  
Computational Alanine Scanning

An understanding of the interaction between the antibody and its targeted antigen and knowing of the epitopes are critical for the development of monoclonal antibody drugs. Complement factor H (CFH) is implied to play a role in tumor growth and metastasis. An autoantibody to CHF is associated with anti-tumor cell activity. The interaction of a human monoclonal antibody Ab42 that was isolated from a cancer patient with CFH polypeptide (pCFH) antigen was analyzed by molecular docking, molecular dynamics (MD) simulation, free energy calculation, and computational alanine scanning (CAS). Experimental alanine scanning (EAS) was then carried out to verify the results of the theoretical calculation. Our results demonstrated that the Ab42 antibody interacts with pCFH by hydrogen bonds through the Tyr315, Ser100, Gly33, and Tyr53 residues on the complementarity-determining regions (CDRs), respectively, with the amino acid residues of Pro441, Ile442, Asp443, Asn444, Ile447, and Thr448 on the pCFH antigen. In conclusion, this study has explored the mechanism of interaction between Ab42 antibody and its targeted antigen by both theoretical and experimental analysis. Our results have important theoretical significance for the design and development of relevant antibody drugs.

Factors that trigger bullying amongst subcontractors toward intention to quit in the construction projects

2019 ◽  
Vol 10 (1) ◽  
pp. 140-152
Author(s):  
Alireza Jalali ◽  
Nur Izzati Hidzir ◽  
Mastura Jaafar ◽  
Norziani Dahalan
Keyword(s):  
Construction Projects ◽  
Workplace Bullying ◽  
Construction Project ◽  
Partial Least Square ◽  
Least Square ◽  
Intention To Quit ◽  
Equation Modeling ◽  
Key Factors ◽  
Data Set ◽  
Content Type

Purpose The purpose of this paper is to examine the relationships between three key factors that cause workplace bullying among subcontractor managers toward intention to quit the undertaken project within the context of Malaysia. Design/methodology/approach This study utilized the simple sampling method to select its study sample, while the questionnaire survey approach was implemented amidst 500 G6 and G7 contractor managers across Peninsular Malaysia. A total of 210 completed questionnaires were returned. Partial least square-structural equation modeling was administered to analyze the data via SmartPls 3.0 software. Findings This study discovered three significant factors (main contractor leadership, construction culture, work organization and job design) that displayed positive effect on workplace bullying among subcontractor managers toward intention to quit. The study outcomes can serve as a direction for policy makers to reduce bullying within the construction project environment. Practical implications This study serves as an instruction for main contractors to reinvent their style of management in overcoming bullying in construction projects. This paper guides that collaborative relationship among various parties in construction projects, including the representatives of main contractors and subcontractor managers, may assist in addressing the hostile environment of construction project, in order to create a constructive relationship between them that leads to overall project success. Originality/value Recognition of the three key factors that lead to workplace bullying among subcontractor managers in the construction industry, which are bound to enhance intention to quit based on the data set with strong statistical results, has made the research original.

scholarly journals Qsar studies of angiotensin converting enzyme inhibitors using CoMFA, CoMSIA and molecular docking

2020 ◽  
pp. 72-72
Author(s):  
Jian-Bo Tong ◽  
Tian-Hao Wang ◽  
Yi Feng ◽  
Guo-Yan Jiang
Keyword(s):  
Molecular Docking ◽  
Angiotensin Converting Enzyme ◽  
Ace Inhibitors ◽  
Active Site ◽  
Cross Validation ◽  
External Validation ◽  
Field Analysis ◽  
Receptor Protein ◽  
Converting Enzyme ◽  
Data Set

In order to better understand the biochemical interactions governing their activities in lowering blood pressure, multiple quantitative structure-activity relationship (QSAR) models were developed from a data set of 58 angiotensin converting enzyme (ACE) inhibitors. The models were built by using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques. The best CoMFA model had a cross-validation q2 value of 0.940, a non cross-validation r2 value of 0.952 and an external validation statistic Qext2 value of 0.920. For the best CoMSIA model the values were with q2 = 0.872, r2 = 0.926 and Qext2 = 0.868. Based on the contour maps, eight new ACE inhibitors were designed. Molecular docking was employed to further explore the binding requirements between the ligands and the receptor protein which included several hydrogen bonds between the ACE inhibitors and active site residues. This study showed extensive interactions between ACE inhibitors and residues of HIS383, GLU384, HIS513, TYR520 and LYS511 in the active site of ACE. The design of potent new inhibitors of ACE can get useful insights from these results.

Sign in / Sign up

Export Citation Format

Share Document