scholarly journals Potential Ebola drug targets – filling the gap: a critical step forward towards the design and discovery of potential drugs

Biologia ◽  
2017 ◽  
Vol 72 (1) ◽  
pp. 1-13 ◽  
Author(s):  
Marissa Balmith ◽  
Mahmoud E.S. Soliman
Keyword(s):  
Binding Site ◽  
Active Site ◽  
Active Sites ◽  
Binding Free Energy ◽  
Three Dimensional ◽  
Computational Prediction ◽  
Homology Model ◽  
Free Energy Calculations ◽  
Biologically Active ◽  
World Health

AbstractAmong the classified neglected infectious diseases, the Ebola virus (EboV) remains a challenging epidemic. This deadly virus has been reported as a category A bioweapon organism by the World Health Organization due to the serious threat it poses. To date, Ebola drug discovery proves challenging. Proteins need to be targeted at the relevant biologically active site for drug or inhibitor binding to be effective. Due to insufficient experimental data to confirm the biologically active binding site for novel protein targets, researchers often rely on computational prediction methods to identify binding sites. Many computational studies have attempted to identify the biological active site for EboV proteins, however, the methods employed are not sufficiently validated. This has prompted us to provide a comprehensive molecular understanding of the various targets of the EboV, including three-dimensional structures, active site identification and further validation. Herein we report the account of a three-dimensional homology model of the unresolved EboV RNA-dependent RNA polymerase (RdRp), as well as a comprehensive analysis of the binding site residues of all proteins of the EboV. Docking-aided active site determination was carried out to identify possible active sites on the homology model of RdRp. Binding free energy calculations revealed subtle differences in the binding at each site. These results can also provide some potential clues for further design of novel inhibitors to treat this killer virus and is a critical cornerstone of research into the EboV.

Assessing the ligand selectivity of sphingosine kinases using molecular dynamics and MM-PBSA binding free energy calculations

2016 ◽  
Vol 12 (4) ◽  
pp. 1174-1182 ◽  
Author(s):  
Liang Fang ◽  
Xiaojian Wang ◽  
Meiyang Xi ◽  
Tianqi Liu ◽  
Dali Yin
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Model Building ◽  
Binding Free Energy ◽  
Homology Model ◽  
Free Energy Calculations ◽  
Dynamics Simulation ◽  
Ligand Selectivity ◽  
Sphingosine Kinases ◽  
Binding Free Energy Calculations

Three residues of SK1 were identified important for selective SK1 inhibitory activity via SK2 homology model building, molecular dynamics simulation, and MM-PBSA studies.

scholarly journals Molecular docking analysis of α-Topoisomerase II with δ-Carboline derivatives as potential anticancer agents

2021 ◽  
Vol 17 (1) ◽  
pp. 249-265
Author(s):  
Selvaraj Ayyamperumal ◽  
Keyword(s):  
Molecular Docking ◽  
Anticancer Agents ◽  
Active Sites ◽  
Topoisomerase Ii ◽  
Binding Free Energy ◽  
Free Energy Calculations ◽  
Dynamics Simulation ◽  
Docking Analysis ◽  
Topo Ii ◽  
Molecular Docking Analysis

The enzyme, α-topoisomerase II (α-Topo II), is known to regulate efficiently the topology of DNA. It is highly expressed in rapidly proliferating cells and plays an important role in replication, transcription and chromosome organisation. This has prompted several investigators to pursue α-Topo II inhibitors as anticancer agents. δ-Carboline, a natural product, and its synthetic derivatives are known to exert potent anticancer activity by selectively targeting α-Topo II. Therefore, it is of interest to design carboline derivatives fused with pyrrolidine-2,5-dione in this context. δ-Carbolines fused with pyrrolidine-2,5-dione are of interest because the succinimide part of fused heteroaromatic molecule can interact with the ATP binding pocket via the hydrogen bond network with selectivity towards α-Topo II. The 300 derivatives designed were subjected to the Lipinski rule of 5, ADMET and toxicity prediction. The designed compounds were further analysed using molecular docking analysis on the active sites of the α-Topo II crystal structure (PDB ID:1ZXM). Molecular dynamic simulations were also performed to compare the binding mode and stability of the protein-ligand complexes. Compounds with ID numbers AS89, AS104, AS119, AS209, AS239, AS269, and AS299 show good binding activity compared to the co-crystal ligand. Molecular Dynamics simulation studies show that the ligand binding to α-Topo II in the ATP domain is stableand the protein-ligand conformation remains unchanged. Binding free energy calculations suggest that seven molecules designed are potential inhibitors for α-Topo II for further consideration as anticancer agents.

Homology modeling and SAR analysis of Schistosoma japonicum cathepsin D (SjCD) with statin inhibitors identify a unique active site steric barrier with potential for the design of specific inhibitors

2005 ◽  
Vol 386 (4) ◽  
pp. 339-349 ◽  
Author(s):  
Conor R. Caffrey ◽  
Lenka Placha ◽  
Cyril Barinka ◽  
Martin Hradilek ◽  
Jiří Dostál ◽  
...  
Keyword(s):  
Schistosoma Japonicum ◽  
Active Site ◽  
Cathepsin D ◽  
Three Dimensional ◽  
Homology Model ◽  
Three Dimensional Model ◽  
Pathogenic Yeast ◽  
Active Site Cleft ◽  
Chronic Morbidity ◽  
Sar Analysis

Abstract Proteases that digest the blood-meal of the parasitic fluke Schistosoma are potential targets for therapy of schistosomiasis, a disease of chronic morbidity in humans. We generated a three-dimensional model of the cathepsin D target protease of Schistosoma japonicum (SjCD) utilizing the crystal structure of human cathepsin D (huCD) in complex with pepstatin as template. A homology model was also generated for the related secreted aspartic protease 2 (SAP2) of the pathogenic yeast, Candida albicans. An initial panel of seven statin inhibitors, originally designed for huCD [Majer et al., Protein Sci. 6 (1997), pp. 1458–1466], was tested against the two pathogen proteases. One inhibitor showed poor reactivity with SjCD. Examination of the SjCD active-site cleft revealed that the poor inhibition was due to a unique steric barrier situated between the S2 and S4 subsites. An in silico screen of 20 potential statin scaffolds with the SjCD model and incorporating the steric barrier constraint was performed. Four inhibitors (SJ1–SJ4) were eventually synthesized and tested with SjCD, bovine CD and SAP2. Of these, SJ2 and SJ3 proved moderately more specific for SjCD over bovine CD, with IC50 values of 15 and 60 nM, respectively. The unique steric barrier identified here provides a structural focus for further development of more specific SjCD inhibitors.

scholarly journals Identification of Immunodominant Epitopes in Allelic Variants VK210 and VK247 of Pakistani based Plasmodium Vivax Circumsporozoite Immunogen

2021 ◽  
Author(s):  
Shumaila Naz ◽  
Sajjad Ahmad ◽  
Sumra Wajid Abbasi ◽  
Saba Ismail ◽  
Shahid Waseem ◽  
...  
Keyword(s):  
Plasmodium Vivax ◽  
Binding Free Energy ◽  
Expression System ◽  
Three Dimensional ◽  
Cell Epitope ◽  
Docking Simulation ◽  
Free Energy Calculations ◽  
Experimental Investigations ◽  
Allelic Variants ◽  
Tropical Regions

Abstract Plasmodium vivax-induced malaria is one of the leading causes of morbidity and mortality in sub-tropical and tropical regions and known to infect 2.85 billion people globally. The continual rise and propagation of resistance against anti-malarial drugs is a prerequisite to identify a possible vaccine candidate for Plasmodium vivax (P. vivax). Circumsporozoite protein (CSP) is an important immunogen of malaria parasite that has conserved the CSP structure as an immune dominant B-cell epitope. In the current study, we focused on designing multi-epitope vaccines (MEVs) using various immunoinformatics tools against Pakistani based allelic variants VK210 and VK247 of P. vivax CSP (PvCSP) gene. Antigenicity, allergic potential and physicochemical parameters of both PvCSP variants were assessed for the designed MEVs and are within acceptable range suitable for post experimental investigations. The three-dimensional structures of both MEV shave been predicted ab initio, optimized, and validated by using different online servers. Structure and from residues perspectives, the MEVs are stable and are free from aggregation-prone regions. The stability of both MEVs has been improved by a disulfide engineering approach. To estimate the binding energy and stability of the MEVs, molecular docking simulation and binding free energy calculations with TLR-4 immune receptor have been conducted. The expression of both MEVs produced in Escherichia coli K12 expression system by in silico cloning was significant. Immune simulation revealed that the proposed MEVs induce strong humoral and cellular immunological responses, in addition to significant production of interleukins and cytokines. In conclusions, we believed that the MEVs proposed in current research, using combine approach of immunoinformatics, structural biology and biophysical approaches, could induce protective and effective immune responses against P. vivax and the experimental validation of our findings could contribute to the development of potential malaria vaccine.

Atom-based and Pharmacophore-based 3D – QSAR Studies on Vitamin D Receptor (VDR)

2018 ◽  
Vol 21 (5) ◽  
pp. 329-343 ◽  
Author(s):  
Selvaraman Nagamani ◽  
Chandrasekhar Kesavan ◽  
Karthikeyan Muthusamy
Keyword(s):  
Vitamin D ◽  
Vitamin D Receptor ◽  
Binding Free Energy ◽  
3D Qsar ◽  
Free Energy Calculations ◽  
Biologically Active ◽  
Hydroxyl Group ◽  
Qsar Studies ◽  
Vitamin D Analogues ◽  
Semi Empirical

Aim and Objective: Vitamin D3 (1,25(OH)2D3) is a biologically active metabolite and plays a wide variety of regulatory functions in human systems. Currently, several Vitamin D analogues have been synthesized and tested against VDR (Vitamin D Receptor). Electrostatic potential methods are greatly influence the structure-based drug discovery. In this study, ab inito (DFT, HF, LMP2) and semi-empirical (RM1, AM1, PM3, MNDO, MNDO/d) charges were examined on the basis of their concert in predicting the docking pose using Induced Fit Docking (IFD) and binding free energy calculations against the VDR. Materials and Methods: Initially, we applied ab initio and semi-empirical charges to the 38 vitamin D analogues. Further, the charged analogues have been docked in the VDR active site. We generated the structure-based 3D-QSAR from the docked conformation of vitamin D analogues. On the other hand, we performed pharmacophore-based 3D-QSAR. Results: The result shows that, AM1 is the good charge model for our study and AM1 charge based QSAR produced more accurate ligand poses. Furthermore, the hydroxyl group in the side chain of vitamin D analogues played an important role in the VDR antagonistic activity. Conclusion: Overall, we found that charge-based optimizations of ligands were out performed than the pharmacophore based QSAR model.

ACTIVE SITE PREDICTION FOR COMPARATIVE MODEL STRUCTURES WITH THEMATICS

2005 ◽  
Vol 03 (01) ◽  
pp. 127-143 ◽  
Author(s):  
IHSAN A. SHEHADI ◽  
ALEXEJ ABYZOV ◽  
ALPER UZUN ◽  
YING WEI ◽  
LEONEL F. MURGA ◽  
...  
Keyword(s):  
Active Site ◽  
Active Sites ◽  
Triosephosphate Isomerase ◽  
Three Dimensional ◽  
Comparative Modeling ◽  
Dimensional Structure ◽  
Titration Curves ◽  
Poisson Boltzmann ◽  
Comparative Model ◽  
Model Structures

THEMATICS (Theoretical Microscopic Titration Curves) is a simple, reliable computational predictor of the active sites of enzymes from structure. Our method, based on well-established Finite Difference Poisson–Boltzmann techniques, identifies the ionisable residues with anomalous predicted titration behavior. A cluster of two or more such perturbed residues is a very reliable predictor of the active site. The protein does not have to bear any resemblance in sequence or structure to any previously characterized protein, but the method does require the three-dimensional structure. We now present evidence that THEMATICS can also locate the active site in structures built by comparative modeling from similar structures. Results are given for a total of 21 sets of proteins, including 21 templates and 83 comparative model structures. Detailed results are presented for three sets of orthologous proteins (Triosephosphate isomerase, 6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase, and Aspartate aminotransferase) and for one set of human homologues of Aldose reductase with different functions. THEMATICS correctly locates the active site in the model structures. This suggests that the method can be applicable to a much larger set of proteins for which an experimentally determined structure is unavailable. With a few exceptions, the predicted active sites in the comparative model structures are similar to that of the corresponding template structure.

scholarly journals Structure of l-Xylulose-5-Phosphate 3-Epimerase (UlaE) from the Anaerobic l-Ascorbate Utilization Pathway of Escherichia coli: Identification of a Novel Phosphate Binding Motif within a TIM Barrel Fold

2008 ◽  
Vol 190 (24) ◽  
pp. 8137-8144 ◽  
Author(s):  
Rong Shi ◽  
Marco Pineda ◽  
Eunice Ajamian ◽  
Qizhi Cui ◽  
Allan Matte ◽  
...  
Keyword(s):  
Escherichia Coli ◽  
Binding Site ◽  
Active Site ◽  
Active Sites ◽  
Triosephosphate Isomerase ◽  
Pentose Phosphate ◽  
Binding Motif ◽  
Phosphate Binding ◽  
Activity Measurements ◽  
Tim Barrel

ABSTRACT Three catabolic enzymes, UlaD, UlaE, and UlaF, are involved in a pathway leading to fermentation of l-ascorbate under anaerobic conditions. UlaD catalyzes a β-keto acid decarboxylation reaction to produce l-xylulose-5-phosphate, which undergoes successive epimerization reactions with UlaE (l-xylulose-5-phosphate 3-epimerase) and UlaF (l-ribulose-5-phosphate 4-epimerase), yielding d-xylulose-5-phosphate, an intermediate in the pentose phosphate pathway. We describe here crystallographic studies of UlaE from Escherichia coli O157:H7 that complete the structural characterization of this pathway. UlaE has a triosephosphate isomerase (TIM) barrel fold and forms dimers. The active site is located at the C-terminal ends of the parallel β-strands. The enzyme binds Zn2+, which is coordinated by Glu155, Asp185, His211, and Glu251. We identified a phosphate-binding site formed by residues from the β1/α1 loop and α3′ helix in the N-terminal region. This site differs from the well-characterized phosphate-binding motif found in several TIM barrel superfamilies that is located at strands β7 and β8. The intrinsic flexibility of the active site region is reflected by two different conformations of loops forming part of the substrate-binding site. Based on computational docking of the l-xylulose 5-phosphate substrate to UlaE and structural similarities of the active site of this enzyme to the active sites of other epimerases, a metal-dependent epimerization mechanism for UlaE is proposed, and Glu155 and Glu251 are implicated as catalytic residues. Mutation and activity measurements for structurally equivalent residues in related epimerases supported this mechanistic proposal.

scholarly journals Computational Study of Scorpion Venom (Lychas Mucronatus) Activity as Antimicrobial Peptides (AMPs) to the SARS-CoV-2 Main Protease for the Future Coronavirus Disease (COVID-19) Inhibitors

Molekul ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. 125
Author(s):  
Taufik Muhammad Fakih
Keyword(s):  
Antimicrobial Peptides ◽  
Computational Study ◽  
Binding Free Energy ◽  
Scorpion Venom ◽  
Computational Approach ◽  
Free Energy Calculations ◽  
World Health ◽  
Peptide Docking ◽  
Main Protease ◽  
Molecular Stability

The 2019 coronavirus pandemic disease (COVID-19) is still declared a global pandemic by the World Health Organization (WHO). Therefore, an effort that is considered effective in finding therapeutic agents is needed to prevent the spread of COVID-19 infection. One of the steps that can be chosen is by utilizing antimicrobial peptides (AMPs) from animal venom by targeting the specific receptor of SARS-CoV-2, namely the main protease (Mpro). Through this research, a computational approach will be conducted to predict antiviral activity, including protein-peptide docking using PatchDock algorithm, to identify, evaluate, and explore the affinity and molecular interactions of four types of antimicrobial peptides (AMPs), such as Mucroporin, Mucroporin-M1, Mucroporin-S1, and Mucroporin-S2 derived from scorpion venom (Lychas mucronatus) against main protease (Mpro) SARS-CoV-2. These results were then confirmed using protein-peptide interaction dynamics simulations for 50 ns using Gromacs 2016 to observe the molecular stability to the binding site of SARS-CoV-2 Mpro. Based on protein-peptide docking simulations, it was proven that the Mucroporin S-1 peptides have a good affinity against the active site area of SARS-CoV-2 Mpro, with an ACE score of −779.56 kJ/mol. Interestingly, Mucroporin-S1 was able to maintain the stability of its interactions based on the results of RMSD, RMSF, and MM/PBSA binding free energy calculations. The results of the computational approach predict that the Mucroporin-S1 peptide is expected to be useful for further research in the development of new antiviral-based AMPs for the COVID-19 infectious disease. 

scholarly journals Enhancing Paraoxon Binding to Organophosphorus Hydrolase Active Site

2021 ◽  
Author(s):  
Léa El Khoury ◽  
David Mobley ◽  
Dongmei Ye ◽  
Susan Rempe
Keyword(s):  
Active Site ◽  
Binding Free Energy ◽  
Hot Spot ◽  
Circulatory System ◽  
Kinetic Studies ◽  
Md Simulations ◽  
Binding Mode ◽  
Hydrolytic Activity ◽  
Free Energy Calculations ◽  
Organophosphorus Hydrolase

<p>Organophosphorus (OP) compounds are among the most toxic of chemical substances and widely used as insecticides, pesticides, and chemical warfare agents. The most important enzyme inhibited by OP compounds is acetylcholinesterase (AChe). Inactivation of AChe function results in the accumulation of neurotransmitter, leading to death due to serious respiratory disorders. Organophosphorus hydrolase (OPH), also called phosphotriesterase, is a homo-dimeric metalloenzyme that can hydrolyze various OP agents in the circulatory system, resulting in products that are generally of reduced toxicity. The best OPH substrate found to date is the insecticide diethyl p-nitrophenyl phosphate (paraoxon). Most structural and kinetic studies assume that the binding orientation of paraoxon is identical to that of diethyl 4-methylbenzylphosphonate, which is the only substrate analog co-crystallized with OPH. In the current work, we used a combined docking and molecular dynamics (MD) approach to predict the likely binding mode of paraoxon in the OPH active site. We identified a potential binding mode of paraoxon that does not match the binding mode of diethyl 4-methylbenzylphosphonate. Then, we used the predicted binding mode to run MD simulations on the wild type (WT) OPH complexed with paraoxon, and OPH mutants complexed with paraoxon. Additionally, we identified 3 hot-spot residues (D253, H254, and I255) involved in the stability of the OPH active site. To further assess these predictions, we then experimentally assayed single and double mutants involving these residues (D253E, H254S, I255S, D253E-H254R and D253E-I255G) for hydrolytic activity against paraoxon. Computational structural analysis of protein-substrate dynamics shows different hydrogen bonding profiles for mutants involving D253 (D253E, D253E-H254R, and D253E-I255G) compared to WT OPH. Additionally, the binding free energy calculations and the experimental kinetics (particularly, <i>k</i><sub>cat</sub> and <i>K<sub>M</sub></i>) of the reactions between each OPH mutant and paraoxon show that mutated forms D253E, D253E-H254R, and D253E-I255G exhibit enhanced activity over WT OPH. Interestingly, our experimental results show that the activity of the double mutant D253E-H254R increased by 19-fold compared to WT OPH.</p>

scholarly journals Chemical IN04 Inhibits the Kinase Domain not the ROC Domain of LRRK1: Results from Homology Modeling and Molecular Docking

2020 ◽  
Vol 16 ◽  
Author(s):  
Zhenhang Chen ◽  
Weirong Xing ◽  
Li Fan
Keyword(s):  
Bone Loss ◽  
Active Site ◽  
Active Sites ◽  
Structural Model ◽  
Osteoporotic Fractures ◽  
Salt Bridge ◽  
Homology Model ◽  
The Elderly ◽  
Kinase Domain ◽  
Binding Modes

Background: Bone loss is the most common reason for broken bones among the elderly. An ideal agent for treatment of bone loss should have both osteoclast inhibitory and osteoblast stimulatory functions. Leucine rich repeat kinase 1 (LRRK1) is a novel target for alternative anti-resorptive drugs to treat osteoporosis and osteoporotic fractures. Recently a chemical IN04, Methyl 3-[(([5-(3,5-dimethoxyphenyl)-1,3,4-oxadiazol-2-yl]-thio-acetyl)-amino]-benzoate, has been identified as a potential LRRK1 inhibitor. Objective: The aim of this work is to investigate how the chemical IN04 interacts with LRRK1 and inhibits its activity. Methods: A structural model of LRRK1 kinase domain was constructed with SWISS-MODEL. The human protein kinase ROCO4 (PDB ID: 4YZN) was chosen as the template based on sequence homology, structural and phylogenetic analysis. In addition, a homology model of the LRRK1 ROC domain was also prepared based on the LRRK2 ROC domain structure (PDB ID: 2ZEJ). The interactions of IN04 with the active sites in the LRRK1 kinase domain and ROC domain were investigated by SwissDock. Results: IN04 was docked into the active site of the LRRK1 kinase domain with similar interactions as ATP comparable to the ligand bound to homologous kinases. Many rational binding modes of IN04 to LRRK1 kinase domain were investigated and the most likely binding pose containing multiple hydrogen bonds and a salt bridge was discovered. However, IN04 cannot fit into the GDP-binding site of the ROC domain. Conclusion: Chemical IN04 inhibits LRRK1 by binding to the active site of the kinase domain but not the ROC domain.

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