Docking and multivariate methods to explore HIV-1 drug-resistance: a comparative analysis

Almerico, Anna Maria; Tutone, Marco; Lauria, Antonino

doi:10.1007/s10822-008-9186-7

Cited by 20 publications

(13 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Lys103Asn is reported in literature as the most common mutation observed during therapy with first generation NNRTIs as if increases the stability of the closed form of the hydrophobic pocket [14,27,30,31,32,33]. Interestingly, this replacement did not seem to influence interactions between THD and most mutants (RT-1, RT-5, RT-6, RT-8, RT-9, RT-10 and RT-11) with the exception of RT-6.…”

Section: Resultsmentioning

confidence: 99%

“…Due to the importance of Lys101 on the orientation of NNRTIs in the binding pocket, and the existence of a mutation at this position in HIV-1 infected patients, we performed a molecular docking in the enzyme presenting the Lys101Glu mutation, the most common according to the literature [32] (Figure 4). The evaluation of the best docking pose showed that the hydrogen bond with the residue of position 101 is maintained in the presence of mutation probably because the hydrogen bond occurs between the hydroxyl of THD and the carbonyl oxygen of the residue backbone.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Molecular Docking Studies of Marine Diterpenes as Inhibitors of Wild-Type and Mutants HIV-1 Reverse Transcriptase

et al. 2013

View full text Add to dashboard Cite

AIDS is a pandemic responsible for more than 35 million deaths. The emergence of resistant mutations due to drug use is the biggest cause of treatment failure. Marine organisms are sources of different molecules, some of which offer promising HIV-1 reverse transcriptase (RT) inhibitory activity, such as the diterpenes dolabelladienotriol (THD, IC50 = 16.5 µM), (6R)-6-hydroxydichotoma-3,14-diene-1,17-dial (HDD, IC50 = 10 µM) and (6R)-6-acetoxydichotoma-3,14-diene-1,17-dial (ADD, IC50 = 35 µM), isolated from a brown algae of the genus Dictyota, showing low toxicity. In this work, we evaluated the structure-activity relationship (SAR) of THD, HDD and ADD as anti HIV-1 RT, using a molecular modeling approach. The analyses of stereoelectronic parameters revealed a direct relationship between activity and HOMO (Highest Occupied Molecular Orbital)-LUMO (Lowest Unoccupied Molecular Orbital) gap (ELUMO–EHOMO), where antiviral profile increases with larger HOMO-LUMO gap values. We also performed molecular docking studies of THD into HIV-1 RT wild-type and 12 different mutants, which showed a seahorse conformation, hydrophobic interactions and hydrogen bonds with important residues of the binding pocket. Based on in vitro experiments and docking studies, we demonstrated that mutations have little influence in positioning and interactions of THD. Following a rational drug design, we suggest a modification of THD to improve its biological activity.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Molecular Docking Studies of Marine Diterpenes as Inhibitors of Wild-Type and Mutants HIV-1 Reverse Transcriptase

et al. 2013

View full text Add to dashboard Cite

show abstract

“…The development of the commercially available inhibitors, such as: saquinavir (ROCHE); lopinavir; ritonavir and tipranavir; are based on such structural analysis, occasionally combined with quantum theoretical methods [211,212]. The HIV protease database contains structures of the HIV protease and their complexes with inhibitors, together with analysis tools and information about AIDS: http://mcl1.ncifcrf.gov/hivdb/.…”

Section: Human Immunodeficiency Virusmentioning

confidence: 99%

Structural Bioinformatics: From the Sequence to Structure and Function

Wiltgen

2009

CBIO

View full text Add to dashboard Cite

Proteins are the molecules of life which are involved in cellular processes. The functional specificity of a protein is linked to its structure. A great section of bioinformatics deals with the prediction, analysis and visualization of protein 3D structures. High-throughput methods for the determination of protein structures provide the information needed to build structure-activity relationships. The accessibility of these structural data together with genomic and clinical data is of crucial importance for the application of bioinformatics in medical research. The experimental methods are supplemented by homology modelling, where new protein structures are predicted by exploiting structural information from known configurations. Computer visualization of protein models provide insights into biological processes which can not be adequately explained otherwise. For the analysis of protein-protein interactions, Voronoi tessellations are used to quantify the macromolecular interfaces. Details at the atomic and electronic levels of the protein molecules, needed for a deeper understanding of properties that remain unrevealed after structural elucidation, are provided by methods based on quantum theoretical calculations. Many proteins are of immediate medical and pharmacological relevance. The structural analysis is therefore of special interest to understand diseases at a molecular level, which is the prerequisite for new developments in diagnosis and therapy.

show abstract

“…The molecular docking and molecular dynamics (MD) simulation were often used to understand the binding conformations of ligands in the active sites of HIV-1-related proteins. Furthermore, a comparative analysis with the combination of docking and multivariate methods was used to study the drug resistance of HIV-1 inhibitors and to further design new compounds with appropriate structural features (Almerico et al, 2008). To further explore the essential structural and pharmacological features of the novel DHPYs as HIV-1 NNRTIs in this study, the combination of 3D-QSAR models, molecular docking, and MD simulation was applied to analyze the 3D-QSARs of these DHPYs and their binding modes in the HIV-1 RT.…”

Section: Introductionmentioning

confidence: 99%

In silico Design of Novel HIV-1 NNRTIs Based on Combined Modeling Studies of Dihydrofuro[3,4-d]pyrimidines

et al. 2020

View full text Add to dashboard Cite

A novel series of dihydrofuro[3,4-d]pyrimidine (DHPY) analogs have recently been recognized as promising HIV-1 non-nucleoside reverse transcriptase (RT) inhibitors (NNRTIs) with potent antiviral activity. To better understand the pharmacological essentiality of these DHPYs and design novel NNRTI leads, in this work, a systematic in silico study was performed on 52 DHPYs using three-dimensional quantitative structure-activity relationship (3D-QSAR), molecular docking, virtual screening, absorption-distribution-metabolism-excretion (ADME) prediction, and molecular dynamics (MD) methods. The generated 3D-QSAR models exhibited satisfactory parameters of internal validation and well-externally predictive capacity, for instance, the q 2 , R 2 , and r pred 2 of the optimal comparative molecular similarity indices analysis model were 0.647, 0.970, and 0.751, respectively. The docking results indicated that residues Lys101, Tyr181, Tyr188, Trp229, and Phe227 played important roles for the DHPY binding. Nine lead compounds were obtained by the virtual screening based on the docking and pharmacophore model, and three new compounds with higher docking scores and better ADME properties were subsequently designed based on the screening and 3D-QSAR results. The MD simulation studies further demonstrated that the newly designed compounds could stably bind with the HIV-1 RT. These hit compounds were supposed to be novel potential anti-HIV-1 inhibitors, and these findings could provide significant information for designing and developing novel HIV-1 NNRTIs.

show abstract

Docking and multivariate methods to explore HIV-1 drug-resistance: a comparative analysis

Cited by 20 publications

References 22 publications

Molecular Docking Studies of Marine Diterpenes as Inhibitors of Wild-Type and Mutants HIV-1 Reverse Transcriptase

Molecular Docking Studies of Marine Diterpenes as Inhibitors of Wild-Type and Mutants HIV-1 Reverse Transcriptase

Structural Bioinformatics: From the Sequence to Structure and Function

In silico Design of Novel HIV-1 NNRTIs Based on Combined Modeling Studies of Dihydrofuro[3,4-d]pyrimidines

Contact Info

Product

Resources

About