The Effect of Geometrical Isomerism of 3,5-Dicaffeoylquinic Acid on Its Binding Affinity to HIV-Integrase Enzyme: A Molecular Docking Study

A potent plant-derived HIV-1 inhibitor, 3,5-dicaffeoylquinic acid (diCQA), has been shown to undergo isomerisation upon UV exposure where the naturally occurring3trans,5trans-diCQA isomer gives rise to the3cis,5trans-diCQA,3trans,5cis-diCQA, and3cis,5cis-diCQA isomers. In this study, inhibition of HIV-1 INT by UV-induced isomers was investigated using molecular docking methods. Here, density functional theory (DFT) models were used for geometry optimization of the 3,5-diCQA isomers. The YASARA and Autodock VINA software packages were then used to determine the binding interactions between the HIV-1 INT catalytic domain and the 3,5-diCQA isomers and the Discovery Studio suite was used to visualise the interactions between the isomers and the protein. The geometrical isomers of 3,5-diCQA were all found to bind to the catalytic core domain of the INT enzyme. Moreover, thecisgeometrical isomers were found to interact with the metal cofactor of HIV-1INT, a phenomenon which has been linked to antiviral potency. Furthermore, the3trans,5cis-diCQA isomer was also found to interact with both LYS156 and LYS159 which are important residues for viral DNA integration. The differences in binding modes of these naturally coexisting isomers may allow wider synergistic activity which may be beneficial in comparison to the activities of each individual isomer.

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Petra/Osiris/Molinspiration and Molecular Docking Analyses of 3-Hydroxy-Indolin-2-one Derivatives as Potential Antiviral Agents

Current Computer - Aided Drug Design ◽

10.2174/1573409916666191226110029 ◽

2019 ◽

Vol 16 ◽

Author(s):

Taibi Ben Hadda ◽

Vesna Rastija ◽

Faisal AlMalki ◽

Abderrahim Titi ◽

Rachid Touzani ◽

...

Keyword(s):

Molecular Docking ◽

Structural Parameters ◽

Antiviral Agents ◽

Chemical Properties ◽

Docking Study ◽

Bioactive Molecules ◽

Geometrical Parameters ◽

Molecular Docking Study ◽

Catalytic Core ◽

Hiv 1

Background: Studies on the interaction between bioactive molecules and HIV-1 virus has been the focus of recent research in the scope of medicinal chemistry and pharmacology. Objective: Investigating the structural parameters and physic-chemical properties of elucidating and identifying of the antiviral pharmacophore sites. Method: A mixed computational Petra/Osiris/Molinspiration/DFT (POM/DFT) based model has been developed for the identification of physico-chemical parameters governing the bioactivity of 22 3-hydroxy-indolin-2-one derivatives of diacetyl-L-tartaric acid and aromatic amines containing combined antiviral/antitumor/antibacterial pharmacophore sites. Molecular docking study was carried out with HIV-1 integrase (pdb ID: 5KGX) in order to provide information about interactions in the binding site of enzyme. Results: The POM analyses of physic-chemical properties and geometrical parameters of compounds 3a-5j, show that they are bearing a two combined (O,O)-pockets leading to a special platform which able to coordinate two transition metals. The increased activity of series 3a-5j, as compared to standard drugs, contains an (Osp2,O sp3,O sp2)-pharmacophore site. The increase of bioactivity from 4b (R1, R2 = H, H) to 3d (R1, R2 = 4-Br, 2-OCH3) could be attributed to the existence of pi-charge transfer from para-bromo-phenyl to its amid group (COδ---NHδ+). Similar to the indole-based reference ligand (pdb: 7SK), compound 3d forms hydrogen bonding interactions between the residues Glu170, Thr174 and His171 of HIV-1 integrase in catalytic core domain of enzyme. Conclusion: Study confirmed the importance of oxygen atoms, especially from the methoxy group of the phenyl ring, and electrophilic amide nitrogen atom for formation of interactions.

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Density Functional Theory and Molecular Docking Investigations of the Chemical and Antibacterial Activities for 1-(4-Hydroxyphenyl)-3-phenylprop-2-en-1-one

Molecules ◽

10.3390/molecules26123631 ◽

2021 ◽

Vol 26 (12) ◽

pp. 3631

Author(s):

Ahmed M. Deghady ◽

Rageh K. Hussein ◽

Abdulrahman G. Alhamzani ◽

Abeer Mera

Keyword(s):

Density Functional Theory ◽

Antibacterial Activity ◽

Molecular Docking ◽

Carbonyl Group ◽

Active Sites ◽

Density Functional ◽

Chemical Reactivity ◽

Basis Set ◽

Molecular Docking Study ◽

Functional Theory

The present investigation informs a descriptive study of 1-(4-Hydroxyphenyl) -3-phenylprop-2-en-1-one compound, by using density functional theory at B3LYP method with 6-311G** basis set. The oxygen atoms and π-system revealed a high chemical reactivity for the title compound as electron donor spots and active sites for an electrophilic attack. Quantum chemical parameters such as hardness (η), softness (S), electronegativity (χ), and electrophilicity (ω) were yielded as descriptors for the molecule’s chemical behavior. The optimized molecular structure was obtained, and the experimental data were matched with geometrical analysis values describing the molecule’s stable structure. The computed FT-IR and Raman vibrational frequencies were in good agreement with those observed experimentally. In a molecular docking study, the inhibitory potential of the studied molecule was evaluated against the penicillin-binding proteins of Staphylococcus aureus bacteria. The carbonyl group in the molecule was shown to play a significant role in antibacterial activity, four bonds were formed by the carbonyl group with the key protein of the bacteria (three favorable hydrogen bonds plus one van der Waals bond) out of six interactions. The strong antibacterial activity was also indicated by the calculated high binding energy (−7.40 kcal/mol).

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Phosphate Derivatives of 3-Carboxyacylbetulin: SynThesis, In Vitro Anti-HIV and Molecular Docking Study

Biomolecules ◽

10.3390/biom10081148 ◽

2020 ◽

Vol 10 (8) ◽

pp. 1148

Author(s):

Krzysztof Marciniec ◽

Elwira Chrobak ◽

Aleksandra Dąbrowska ◽

Ewa Bębenek ◽

Monika Kadela-Tomanek ◽

...

Keyword(s):

Molecular Docking ◽

Betulinic Acid ◽

Strong Interactions ◽

Molecular Docking Study ◽

Gag Protein ◽

Terminal Domain ◽

Derivatives Of ◽

Anti Hiv ◽

Hiv 1

Lupane-type pentacyclic triterpenes such as betulin and betulinic acid play an important role in the search for new therapies that would be effective in controlling viral infections. The aim of this study was the synthesis and evaluation of in vitro anti-HIV-1 activity for phosphate derivatives of 3-carboxyacylbetulin 3–5 as well as an in silico study of new compounds as potential ligands of the C-terminal domain of the HIV-1 capsid–spacer peptide 1 (CA-CTD-SP1) as a molecular target of HIV-1 maturation inhibitors. In vitro studies showed that 28-diethoxyphosphoryl-3-O-(3′,3′-dimethylsuccinyl)betulin (compound 3), the phosphate analog of bevirimat (betulinic acid derivative, HIV-1 maturation inhibitor), has IC50 (half maximal inhibitory concentration) equal to 0.02 μM. Compound 3 inhibits viral replication at a level comparable to bevirimat and is also more selective (selectivity indices = 1250 and 967, respectively). Molecular docking was used to examine the probable interaction between the phosphate derivatives of 3-carboxyacylbetulin and C-terminal domain (CTD) of the HIV-1 capsid (CA)–spacer peptide 1 (SP1) fragment of Gag protein, designated as CTD-SP1. Compared with interactions between bevirimat (BVM) and the protein, an increased number of strong interactions between ligand 3 and the protein, generated by the phosphate group, were observed. These compounds might have the potential to also inhibit SARS-CoV2 proteins, in as far as the intrinsically imprecise docking scores suggest.

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Dual inhibitor design for HIV-1 reverse transcriptase and integrase enzymes: a molecular docking study

Journal of Biomolecular Structure and Dynamics ◽

10.1080/07391102.2019.1700166 ◽

2019 ◽

Vol 38 (2) ◽

pp. 573-580 ◽

Cited By ~ 2

Author(s):

Selami Ercan ◽

Berivan Şenyiğit ◽

Yusuf Şenses

Keyword(s):

Molecular Docking ◽

Reverse Transcriptase ◽

Docking Study ◽

Inhibitor Design ◽

Molecular Docking Study ◽

Dual Inhibitor ◽

Hiv 1

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Anti-HIV-1 Integrase Activity and Molecular Docking Study of Compounds from Caesalpinia sappan L.

Phytotherapy Research ◽

10.1002/ptr.5307 ◽

2015 ◽

Vol 29 (5) ◽

pp. 724-729 ◽

Cited By ~ 9

Author(s):

Supinya Tewtrakul ◽

Prapaporn Chaniad ◽

Somsak Pianwanit ◽

Chatchanok Karalai ◽

Chanita Ponglimanont ◽

...

Keyword(s):

Molecular Docking ◽

Docking Study ◽

Molecular Docking Study ◽

Caesalpinia Sappan ◽

Anti Hiv ◽

Hiv 1

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Prediction of HIV-1 Integrase/Viral DNA Interactions in the Catalytic Domain by Fast Molecular Docking

Journal of Medicinal Chemistry ◽

10.1021/jm0301890 ◽

2004 ◽

Vol 47 (4) ◽

pp. 821-828 ◽

Cited By ~ 41

Author(s):

Adeyemi A. Adesokan ◽

Victoria A. Roberts ◽

Keun Woo Lee ◽

Roberto D. Lins ◽

James M. Briggs

Keyword(s):

Molecular Docking ◽

Catalytic Domain ◽

Dna Interactions ◽

Viral Dna ◽

Hiv 1

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Molecular docking study of the phytol and its derivatives against COX-2 induced inflammation: A combined density functional study

Recent Research in Science and Technology ◽

10.25081/rrst.2020.12.6083 ◽

2020 ◽

pp. 1-5

Author(s):

Muhammad Torequl Islam ◽

Pranta Ray ◽

Abul Bashar Ripon Khalipha ◽

SM Hafiz Hassan ◽

Md. Roich Khan ◽

...

Keyword(s):

Molecular Docking ◽

Binding Energy ◽

Density Functional ◽

Chemical Reactivity ◽

Docking Study ◽

Functional Study ◽

Molecular Docking Study ◽

Study Results ◽

Homo And Lumo ◽

Cox 2

This study aimed to determine the activity of PYT and its derivatives against COX-2, including 5IKR protein induced inflammation by using the computational tools. PYT and its derivatives have been designed by utilizing density functional theory (DFT) and the performance of the drugs was also evaluated by molecular docking study. Results suggest that the NH2 derivative of PYT (D-NH2) showed binding energy -6.4 (Kcal/mol) with protein 5IKR of COX-2 compared to the main drug (D) that showed binding energy -5.1 (Kcal/mol) with the same protein. HOMO and LUMO energy values were also calculated to determine the chemical reactivity of all the modified drugs. Non-covalent interactions of PYT and its derivatives were essential in improving the performance. In conclusion, D-NH2 showed better preference in inhibiting to the protein 5IKR of COX-2 compared to other modified drugs and it can be claimed that D-NH2 will be the best conformer for COX-2 induced inflammation.

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3D-QASR and molecular docking study of diarylpyrimidines as HIV-1 reverse transcriptase

Human Health and Medical Engineering ◽

10.2495/hhme131032 ◽

2014 ◽

Author(s):

Li Ye ◽

Shuangxi Gu ◽

Cheng Qian ◽

Xiulian Ju

Keyword(s):

Molecular Docking ◽

Reverse Transcriptase ◽

Docking Study ◽

Molecular Docking Study ◽

Hiv 1

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Design, Synthesis and In Vitro Evaluation of 4-Oxo-6-Substituted Phenyl- 2-Thioxo1,2,3,4-Tetrahydropyrimidine-5-Carbonitrile Derivatives as HIV Integrase Strand Transfer Inhibitors

Letters in Drug Design & Discovery ◽

10.2174/1570180817999201022193325 ◽

2020 ◽

Vol 17 ◽

Author(s):

Pankaj Wadhwa ◽

Priti Jain ◽

Hemant R. Jadhav

Keyword(s):

In Silico ◽

Strand Transfer ◽

Hiv Integrase ◽

Chromosomal Dna ◽

Molecular Docking Study ◽

Design Synthesis ◽

In Vitro Evaluation ◽

Integrase Strand Transfer Inhibitors ◽

Hiv 1

Aim:: To design, synthesis and in vitro evaluation of 4-oxo-6-substituted phenyl-2-thioxo1,2,3,4- tetrahydropyrimidine-5-carbonitrile derivatives as HIV integrase strand transfer inhibitors. Background:: Human immunodeficiency virus-1 (HIV-1), a member of retroviridae family, is the primary causative agent of acquired immunodeficiency syndrome (AIDS). Three enzymes viz: integrase (IN), reverse transcriptase (RT) and protease play important role in its replication cycle. HIV-1 integrase is responsible for the incorporation of viral DNA into human chromosomal DNA by catalyzing two independent reactions, 3′-processing (3′-P) and strand transfer (ST), which are observed as the “point of no-return” in HIV infection. Objective:: To develop inhibitors against HIV integrase strand transfer step. Methods:: Our previous results indicated that tetrahydro pyrimidine-5-carboxamide derivatives are potent HIV-1 IN inhibitors (unpublished results from our laboratory). Taking clue from above studies and our own experience, we hypothesized 4- oxo-6-substituted phenyl-2-thioxo1,2,3,4-tetrahydropyrimidine-5-carbonitrile analogues (14a to 14n) as inhibitors of HIV-1 Integrase strand transfer. As shown in figure 2, prototype compound 14 can be viewed as hybrid structure having characteristics of dihydropyrimidine derivatives 10-12 and tyrphostin 13. Result:: A total of fourteen derivatives of 4-oxo-6-substituted phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carbonitrile (14a-14n) were synthesized and evaluated using HIV-1 Integrase Assay Kit (Xpressbio Life Science Products, USA). The percentage inhibition of all compounds was investigated at 10 μM concentration and IC50 value of few highly active compounds was studied. The obtained results were validated by in silico molecular docking study using Glide (maestro version 9.3, Schrödinger suite) in extra precision (XP) mode. Conclusion:: Fourteen 4-oxo-6-substituted phenyl-2-thioxo 1,2,3,4-tetrahydropyrimidine-5-carbonitrile analogues were synthesized and evaluated for HIV-1 IN inhibitory activity. Three compounds 14a, 14e, and 14h exhibited significant percentage inhibition of HIV-1 IN. There was good in vitro - in silico correlation. However, none of the derivative was active against HIV-1 and HIV-2 below their cytotoxic concentration. It needs to be seen whether these compounds can be explored further for their anti-HIV or cytotoxic potential.

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