Identification of Adjacent NNRTI Binding Pocket in Multi-mutated HIV1- RT Enzyme Model: An in silico Study

2018 ◽  
Vol 16 (2) ◽  
pp. 121-129 ◽  
Author(s):  
R.F. Kamil ◽  
U. Debnath ◽  
S. Verma ◽  
Y.S. Prabhakar
Keyword(s):  
In Silico ◽  
Point Mutations ◽  
Homology Model ◽  
Docking Study ◽  
Binding Pocket ◽  
Docking Studies ◽  
Primary Objective ◽  
Multiple Point ◽  
Enzyme Model ◽  
Hiv 1

Introduction: A possible strategy to combat mutant strains is to have a thorough structural evaluation before and after mutations to identify the diversity in the non-nucleoside inhibitor binding pocket and their effects on enzyme-ligand interactions to generate novel NNRTI’s accordingly. Objective: The primary objective of this study was to find effects of multiple point mutations on NNRTI binding pocket. This study included the contribution of each individual mutation in NNIBP that propose an adjacent binding pocket which can be used to discover novel NNRTI derivatives. Methods: An in Silico model of HIV-1 RT enzyme with multiple mutations K103N, Y181C and Y188L was developed and evaluated. Two designed NNRTI pyridinone derivatives were selected as ligands for docking studies with the homology model through alignment based docking and residue based docking approaches. Binding pockets of wild type HIV-1 RT and multi-mutated homology model were compared thoroughly. Result and Discussion: K103N mutation narrowed the entrance of NNRTI binding pocket and forbade electrostatic interaction with α amino group of LYS103. Mutations Y181C and Y188L prevented NNRTI binding by eliminating aromatic π interactions offered by tyrosine rings. Docking study against new homology model suggested an adjacent binding pocket with combination of residues in palm and connection domains. This pocket is approximately 14.46Å away from conventional NNRTI binding site. Conclusion: Increased rigidity, steric hindrance and losses of important interactions cumulatively prompt ligands to adapt adjacent NNRTI binding pocket. The proposed new and adjacent binding pocket is identified by this study which can further be evaluated to generate novel derivatives.

Non-Nucleoside HIV-1 Reverse Transcriptase Inhibition Activity of a Series of Dihydroalkoxybenzyloxopyrimidine (DABO) Derivatives: CoMFA, CoMSIA and Docking Studies

2020 ◽  
Vol 5 (3) ◽  
pp. 265-272
Author(s):  
Bikash Kumar Sarkar ◽  
Ananda Sarkar ◽  
Atish Dipankar Jana
Keyword(s):  
3D Qsar ◽  
Docking Study ◽  
Binding Pocket ◽  
Qsar Model ◽  
Docking Studies ◽  
Field Analysis ◽  
Qsar Studies ◽  
3D Space ◽  
Pyrimidine Moiety ◽  
Hiv 1

CoMFA, CoMSIA and molecular docking studies have been carried out for a set of 42 dihydroalkoxybenzyloxopyrimidine (DABO) derivatives for which anti-HIV activity values are available. In 3D-QSAR studies-comparative molecular field analysis (CoMFA) as well as comparative molecular similarity indices analysis (CoMSIA) have been performed. Both the QSAR model nicely explains the inhibitory activities of DABO derivatives as well as provides molecular level insights revealing which regions in 3D space around the molecules are more important for their anti HIVactivities. These models have a quite high square correlation coefficient (r2 = 0.817 for CoMFA and r2 = 0.943 for CoMSIA). A docking study of the highest active molecule into the binding site of the protein HIV-1 RT (PDB ID-1RT1) shows that hydrogen bonding between pyrimidine moiety of the ligand and the Lysine-101 moiety along with Valine-106 moiety of the HIV protein play most important role for stabilizing the ligand in the binding pocket of the protein.

Hetero-Tricyclic Lead Scaffold as Novel PDE5A Inhibitor for Antihypertensive Activity: In Silico Docking Studies

2019 ◽  
Vol 15 (4) ◽  
pp. 318-333
Author(s):  
Dipak P. Mali ◽  
Neela M. Bhatia
Keyword(s):  
In Silico ◽  
Docking Study ◽  
Docking Studies ◽  
Antihypertensive Activity ◽  
In Silico Docking ◽  
Π Stacking ◽  
Π Stacking Interaction ◽  
Nitrogen Heteroatom ◽  
Inhibitory Potential ◽  
Vlife Mds

Objective:To screen the phytochemicals for phosphodiesterase 5A (PDE5A) inhibitory potential and identify lead scaffolds of antihypertensive phytochemicals using in silico docking studies.Methods:In this perspective, reported 269 antihypertensive phytochemicals were selected. Sildenafil, a PDE5A inhibitor was used as the standard. In silico docking study was carried out to screen and identify the inhibiting potential of the selected phytochemicals against PDE5A enzyme using vLife MDS 4.4 software.Results:Based on docking score, π-stacking, H-bond and ionic interactions, 237 out of 269 molecules were selected which have shown one or more interactions. Protein residue Gln817A was involved in H-boding whereas Val782A, Phe820A and Leu804A were involved in π-stacking interaction with ligand. The selected 237 phytochemicals were structurally diverse, therefore 82 out of 237 molecules with one or more tricycles were filtered out for further analysis. Amongst tricyclic molecules, 14 molecules containing nitrogen heteroatom were selected for lead scaffold identification which finally resulted in three different basic chemical backbones like pyridoindole, tetrahydro-pyridonaphthyridine and dihydro-pyridoquinazoline as lead scaffolds.Conclusion:In silico docking studies revealed that nitrogen-containing tetrahydro-pyridonaphthyridine and dihydro-pyridoquinazoline tricyclic lead scaffolds have emerged as novel PDE5A inhibitors for antihypertensive activity. The identified lead scaffolds may provide antihypertensive lead molecules after its optimization.

Screening of phytochemicals from Curcuma longa for their inhibitory activity on SARS-CoV-2: An in-silico study

2021 ◽  
Vol 19 ◽  
Author(s):  
Preeya Negi ◽  
Lalita Das ◽  
Surya Prakash ◽  
Vaishali M. Patil
Keyword(s):  
Drug Discovery ◽  
In Silico ◽  
Curcuma Longa ◽  
Docking Studies ◽  
Primary Objective ◽  
In Silico Screening ◽  
Rational Drug ◽  
In Silico Study ◽  
Speed Up ◽  
Novel Coronavirus

Introduction: Natural products or phytochemicals have always been useful as effective therapeutics and for providing the lead for rational drug discovery approaches specific to anti-viral therapeutics. Methods: The ongoing pandemic caused by novel coronavirus has created a demand for effective therapeutics. Thus, to achieve the primary objective to search for effective anti-viral therapeutics, in silico screening of phytochemicals present in Curcuma longa extract (ex. Curcumin) has been planned. Results: The present work involves the evaluation of ADME properties and molecular docking studies. Conclusion: The application of rationalized drug discovery approaches to screen the diverse natural resources will speed up the anti-COVID drug discovery efforts and benefit the global community.

scholarly journals Synthesis, Characterization, in vitro Antimicrobial Evaluation and in silico Molecular Docking and ADME Prediction of 4-Chlorophenyl Furfuran Derivatives bearing Pyrazole Moieties

2020 ◽  
Vol 32 (6) ◽  
pp. 1482-1490
Author(s):  
Manju Mathew ◽  
Raja Chinnamanayakar ◽  
Ezhilarasi Muthuvel Ramanathan
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Docking Study ◽  
Docking Studies ◽  
Moderate Activity ◽  
Molecular Docking Study ◽  
Adme Prediction ◽  
Antimicrobial Studies ◽  
In Silico Molecular Docking

A series of 1-(5-(5-(4-chlorophenyl)furan-2-yl)-4,5-dihyropyrazol-1-yl ethanone (5a-h) was synthesized through E-(3-(5-(4-chloro-phenyl)furan-2-yl)-1-phenylprop-2-en-1-one (3a-h) with hydrazine monohydrate and sodium acetate. Totally, eight compounds were synthesized and their structures were elucidated by infrared, 1H & 13C NMR, elemental analysis, antimicrobial studies, in silico molecular docking studies and also in silico ADME prediction. Antimicrobial studies of the synthesized compounds showed good to moderate activity against the all the stains compared with standard drugs. in silico Molecular docking study was carried out using bacterial protein and BC protein. Synthesized compounds (5a-h) showed good docking score compared with ciprofloxacin. Antimicrobial study was carried out for 4-chlorophenyl furfuran pyrazole derivatives (5a-h). The results of assessment of toxicities, drug likeness and drug score profiles of compounds (5a-j) are promising

scholarly journals Inhibition of Phosphodiesterase 5 Enzyme by Pterine- 6 Carboxylic Acid from Baphia nitida –Related to Erectile Dysfunction: Computational Kinetic

2020 ◽  
pp. 49-55
Author(s):  
Wopara, Iheanyichukwu ◽  
S. K. Mobisson ◽  
Egelege Aziemeola Pius ◽  
A. A. Uwakwe ◽  
M. O. Wegwu
Keyword(s):  
Erectile Dysfunction ◽  
Carboxylic Acid ◽  
Active Site ◽  
In Silico ◽  
Binding Pocket ◽  
Docking Studies ◽  
Drug Candidate ◽  
In Silico Docking ◽  
In Silico Studies ◽  
Phosphodiesterase 5

Treatment of erectile dysfunction is associated with inhibition of Phosphodiesterase 5 enzyme. This study deals with the evaluation of Pterin-6-carboxylic acid inhibitory activity on phosphodiesterase 5 (PDB ID: 4OEW) using in silico docking studies. Pterin-6-carboxylic acid from Baphia nitida was isolated using GC-MS and docked into PDE5 active site. The docking result showed that pterin-6-carboxylic acid bind to the active site of phosphodiesterase 5 with the binding energy value of -7.1 and 2.05A° - 2.23A° when compared with other compound found in the plant. Moreso, docking analysis with the ligand identified specific residues such as: Ile 778, Phe 820, Gln 817, Ser 815 and Gln 775 within the binding pocket which played an important role in the ligand binding affinity to the protein. Result from our In silico studies hypothesized that pterin-6-carboxylic acid can be an inhibitory agent for PDE5 protein which could be a potential drug candidate for the treatment of erectile dysfunction.

P144 IN SILICO IDENTIFICATION OF PUTATITVE CLAUDIN CHANNEL BLOCKERS

2020 ◽  
Vol 26 (Supplement_1) ◽  
pp. S30-S30
Author(s):  
Emma Wu ◽  
Priyanka Samanta ◽  
Ye Li ◽  
Le Shen ◽  
Fatemeh Khalili ◽  
...  
Keyword(s):  
In Silico ◽  
Homology Model ◽  
Docking Studies ◽  
Channel Blockers ◽  
Barrier Dysfunction ◽  
Dynamic Simulations ◽  
Epithelial Barrier Function ◽  
In Vitro Measurements ◽  
Potential Ligand

Abstract Compromised epithelial barrier function is known to be associated with inflammatory bowel disease (IBD) and may contribute to disease development. One mechanism of barrier dysfunction is increased expression of paracellular tight junction ion and water channels formed by claudins. Claudin-2 and -15 are two such channels. We hypothesize that blocking these channels could be a viable therapeutic approach to treat diarrhea in IBD. In an effort to develop blockers of these channels, we turn to our previously developed and validated in silico models of claudin-15 (Samanta et al. 2018). We reasoned that molecules that can bind with the interior of claudin pores can limit paracellular water and ion flux. Thus, we used docking algorithms to search for putative drugs that bind in the claudin-15 pore. AutoDock Vina (Scripps Research Institute) was initially used to assess rigid docking using small molecule ligand databases. The ligands were analyzed based on binding affinity to the pore and visualized using VMD (University of Illinois at Urbana-Champaign) for their potential blockage of the channel. Overall, a total of eight candidate ligands from the databases were identified: three from the UICentre database of 10000 ligands, one chemically similar structure identified in another online database (Chemspider), and four which are modifications on the chemical structure generated using ChemDraw. The analysis revealed that the eight ligands were docked in two predominant positions. In the first position, the ligands with more rings docked in an almost linear fashion and interacted with both D55 and D64 pore residues. In the second position of binding, the ligands were more flexible and could hence fold to interact only with D55 residues, thus biding predominantly in the center of the pores. To further evaluate these ligands, we will now turn to 1) flexible claudin-15 docking studies, 2) molecular dynamic simulations and, 3) in vitro measurements using monolayers induced to express claudin -15 and claudin-15 mutants. We also developed a claudin-2 homology model on which we will perform docking studies and in vitro measurements, which we expect will result in similar candidate ligands for blocking claudin-2. Finally, other databases will be analyzed for potential ligand blockers of claudin-2 and -15.

scholarly journals Identification of Bioactive Phytoconstituents from the Plant Euphorbia hirta as Potential Inhibitor of SARS-CoV-2: an In-Silico Approach

2021 ◽  
Vol 12 (2) ◽  
pp. 1385-1396
Keyword(s):  
Molecular Docking ◽  
In Silico ◽  
Biological Activities ◽  
Specific Treatment ◽  
Docking Study ◽  
Docking Studies ◽  
Molecular Docking Study ◽  
Standard Drug ◽  
Euphorbia Hirta ◽  
Main Protease

Currently, the entire globe is under the deadliest pandemic of Covid-19 caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). At present, no specific treatment is available to combat COVID-19 infection. Euphorbia hirta (Euphorbiaceae) have been reported for a variety of biological activities, including antiviral. The present investigation aimed to identify potential phytoconstituents of the plant E. hirta from the category flavonoids and coumarins against the SARS-CoV-2 using in silico approach. The molecular docking studies were performed using two different targets of SARS-CoV-2, namely Main protease (Mpro; PDB ID: 6M2N) and RNA-dependent RNA polymerase (RdRp; PDB ID: 7BW4). Based on the molecular docking study in comparison with standard drug, four compounds, namely Euphrobianin, Quercetin, 3-o-alpha-rhamnoside, Isoquercitrin, and rutin, were screened against the target Mpro. Three phytoconstituents, euphorbianin, myricetin, and rutin, were screened against the target RdRp. In the in silico toxicity studies of screened phytoconstituents, except myrectin all were predicted safe. Results of euphorbianin and rutin were found more interesting as both compounds had high binding affinity against both targets. Finally, we want to conclude that euphrobianin, quercetin 3-o-alpha-rhamnoside, isoquercitrin, and rutin could be further explored rapidly as they may have the potential to fight against COVID-19.

SYNTHESIS AND ANTI-HIV EVALUATION OF SUBSTITUTED INDOLE-3-CARBALDEHYDE DERIVATIVES

INDIAN DRUGS ◽  
2020 ◽  
Vol 57 (02) ◽  
pp. 18-26
Author(s):  
Pankaj Wadhwa ◽  
Priti Jain ◽  
Hemant R Jadhav
Keyword(s):  
Reverse Transcriptase ◽  
In Silico ◽  
Docking Studies ◽  
Significant Inhibition ◽  
Hiv Integrase ◽  
Starting Point ◽  
Hiv Integrase Inhibitors ◽  
Anti Hiv ◽  
Hiv 1

In the present study, a series of indole-3-carbaldehydes having substituted N-sulfonyl phenyl or Nphenacyl group was synthesized and evaluated for anti-HIV activity, in particular, in vitro and in silico HIV-1 integrase inhibition. Three compounds (8b, 8c and 8g) exhibited significant inhibition of HIV-1 IN (IC50 ≤5.32 μM). Molecular docking studies were also performed to justify the IN inhibition and in vitro in silico correlation was drawn. Compound 8b exhibited significant anti-HIV activity against HIV-1 strain IIIB (IC50 3.16 μM). HIV integrase inhibitors are also reported to inhibit reverse transcriptase. When 8b was further examined against various single and double mutant reverse transcriptase (RT) strains, it showed promising activity against E138K with IC50 value of 2.43 μM with safety index of 3. Therefore, compound 8b can be a starting point for the development of dual inhibitors of HIV integrase as well as reverse transcriptase.

scholarly journals In Vitro and In Silico Approaches for the Antileishmanial Activity Evaluations of Actinomycins Isolated from Novel Streptomyces smyrnaeus Strain UKAQ_23

Antibiotics ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 887
Author(s):  
Kamal A. Qureshi ◽  
Ibrahim Al Nasr ◽  
Waleed S. Koko ◽  
Tariq A. Khan ◽  
M. Qaiser Fatmi ◽  
...  
Keyword(s):  
In Silico ◽  
Leishmania Major ◽  
Actinomycin D ◽  
Leishmania Species ◽  
Binding Pocket ◽  
Docking Studies ◽  
Antileishmanial Activity ◽  
Target Protein ◽  
Lutzomyia Longipalpis

Leishmaniasis, a Neglected Tropical Parasitic Disease (NTPD), is induced by several Leishmania species and is disseminated through sandfly (Lutzomyia longipalpis) bites. The parasite has developed resistance to currently prescribed antileishmanial drugs, and it has become pertinent to the search for new antileishmanial agents. The current study aimed to investigate the in vitro and in silico antileishmanial activity of two newly sourced actinomycins, X2 and D, produced by the novel Streptomyces smyrnaeus strain UKAQ_23. The antileishmanial activity conducted on promastigotes and amastigotes of Leishmania major showed actinomycin X2 having half-maximal effective concentrations (EC50), at 2.10 ± 0.10 μg/mL and 0.10 ± 0.0 μg/mL, and selectivity index (SI) values of 0.048 and 1, respectively, while the actinomycin D exhibited EC50 at 1.90 ± 0.10 μg/mL and 0.10 ± 0.0 μg/mL, and SI values of 0.052 and 1. The molecular docking studies demonstrated squalene synthase as the most favorable antileishmanial target protein for both the actinomycins X2 and D, while the xanthine phosphoribosyltransferase was the least favorable target protein. The molecular dynamics simulations confirmed that both the actinomycins remained stable in the binding pocket during the simulations. Furthermore, the MMPBSA (Molecular Mechanics Poisson-Boltzmann Surface Area) binding energy calculations established that the actinomycin X2 is a better binder than the actinomycin D. In conclusion, both actinomycins X2 and D from Streptomyces smyrnaeus strain UKAQ_23 are promising antileishmanial drug candidates and have strong potential to be used for treating the currently drug-resistant leishmaniasis.

An in silico Approach Towards Crop Improvement by ACC Synthase Inhibition Declining Ethylene Production

2017 ◽  
Vol 13 (1) ◽  
pp. 11-19
Author(s):  
Jasarat Ali ◽  
Rupesh K. Mishra ◽  
Chhedi L. Gupta ◽  
Dinesh C. Sharma ◽  
Preeti Bajpai ◽  
...  
Keyword(s):  
Binding Energy ◽  
Organic Contaminants ◽  
In Silico ◽  
Growth Promotion ◽  
Crop Improvement ◽  
3D Structure ◽  
Acc Synthase ◽  
Docking Study ◽  
Primary Objective ◽  
Hydrogen Bond Interaction

Introduction: The increased level of ethylene inhibits root elongation and causes physiological damage, thereby reduces ethylene level imparts a positive support against various biotic and abiotic stresses viz. phytopathogens, extreme temperatures, hyper salinity, flooding, drought, metal/organic contaminants and insect predation. The metabolic pathways showed the involvement of ACC synthase inhibition for ethylene suppression in plants. Objective: The primary objective of this study focused towards the use of In-silico approach to assess the inhibitory effect of S-adenosyl methionine (SAM) analogue on ACC synthase activity. Methods: The 3D structure of ACC synthase of Pisum sativum was constructed using modeler 9v11 software. The reliability of developed model was evaluated by PROCHECK, ERRAT and ProSA web servers. Furthermore the molecular interactions between substrate SAM and inhibitors were performed. Result: The docking study demonstrated that the binding energy of the substrate SAM is -5.37 Kcal/mol. The SAM analogue (Inhibitors) considered in this study were 3-dzSAHC, SAHC, sinefungin, SIBA, 7-dz-SIBA, 1-dz-SIBA,3-dz-SIBA and S-n-Butyladenosine. Among these analogues, 7-dz-SIBA was found to be most effective on ACC synthase as inhibitor due to lowest binding energy (- 5.51Kcal/mol) and strong Ki value (91.74M). The LYS276 amino acid residue of ACC synthase was observed in the interaction with both substrates SAM and 7-dz-SIBA (S-isobutyl-7-deazaadenosine) demonstrates as most crucial catalytic residue for molecular interaction. Conclusion: This study successfully screened most potent inhibitor for ACC synthase which have indicated the compounds 7-dz- SIBA as effective inhibitor with lowest binding energy, better hydrogen bond interaction and strong inhibition constant compared to others compounds studied. Thus 7-dz-SIBA can be projected to use as a growth enhancer for overall crop improvement. It may help in plant growth promotion, prevents the plants from various environmental stress and phytopathogenic infections etc.

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