A Study on Docking Mode of HIV Protease and Their Inhibitors.

栄一, 赤穂; Morris, G.M.; Goodsell, David S.; Wong, D.; Olson, Arthur J.

doi:10.2477/jchemsoft.7.103

Cited by 11 publications

(7 citation statements)

References 17 publications

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“…The Autodock program has an empirical binding free energy estimation procedure, which yields a correlation with the experiment (the error range within 2.3 Kcal/mol) (Akaho et al, 2001). Therefore, for the key-binding site, obtaining the stronger linear correlation of estimated DG with ln K i than for other possible binding modes is important.…”

Section: Theoretical Methodsmentioning

confidence: 99%

Complement C1q‐target proteins recognition is inhibited by electric moment effectors

Roumenina

Bureeva

Kantardjiev

et al. 2007

J of Molecular Recognition

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Classical complement pathway is an important innate immune mechanism, which is usually triggered by binding of C1q to immunoglobulins, pentraxins and other target molecules. Although the activation of the classical pathway is crucial in the host defence, its undesirable and uncontrolled activation can lead to tissue damage. Thus, understanding the molecular basis of complement activation and its inhibition are of great biomedical importance. Recently, we proposed a mechanism for target recognition and classical pathway activation by C1q, which is likely governed by calcium-controlled reorientation of macromolecular electric moment vectors. Here we sought to define the mechanism of C1q inhibition by low molecular weight disulphate compounds that bind to the globular (gC1q) domain, using experimental, computational docking and theoretical modelling approaches. Our experimental results demonstrate that betulin disulphate (B2S) and 9,9-bis(4'-hydroxyphenyl)fluorene disulphate (F2S) inhibit the interaction of C1q and its recombinant globular modules with target molecules IgG1, C-reactive protein (CRP) and long pentraxin 3 (PTX3). In most C1q-inhibitor docked complexes, there is a reduction of electric moment scalar values and similarly altered direction of electric/dipole moment vectors. This could explain the inhibitory effect by impaired electrostatic steering, lacking optimal target recognition and formation of functional complex. In the presence of the inhibitor, the tilt of gC1q domains is likely to be blocked by the altered direction of the electric moment vector. Thus, the transition from the inactive (closed) towards the active (open) conformation of C1q (i.e. the complement activation signal transmission) will be impaired and the cascade initiation disrupted. These results could serve as a starting point for the exploration of a new form of 'electric moment inhibitors/effectors'.

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Section: Theoretical Methodsmentioning

confidence: 99%

Complement C1q‐target proteins recognition is inhibited by electric moment effectors

Roumenina

Bureeva

Kantardjiev

et al. 2007

J of Molecular Recognition

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“…Since most current docking programs treat the receptor and/or ligand as rigid objects, this represents an important cause of failure to predict the correct binding enzyme-substrate energies [18]. We address this problem by performing Molecular Dynamic (MD) simulations on HIV-1 protease-inhibitor complexed and using the resulting structures to calculate the binding energies by AutoDock, a ligand flexible docking program.…”

Section: Introductionmentioning

confidence: 99%

Untitled

Jenwitheesuk

Samudrala

2003

BMC Struct Biol

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BackgroundThe accurate prediction of enzyme-substrate interaction energies is one of the major challenges in computational biology. This study describes the improvement of protein-ligand binding energy prediction by incorporating protein flexibility through the use of molecular dynamics (MD) simulations.ResultsDocking experiments were undertaken using the program AutoDock for twenty-five HIV-1 protease-inhibitor complexes determined by x-ray crystallography. Protein-rigid docking without any dynamics produced a low correlation of 0.38 between the experimental and calculated binding energies. Correlations improved significantly for all time scales of MD simulations of the receptor-ligand complex. The highest correlation coefficient of 0.87 between the experimental and calculated energies was obtained after 0.1 picoseconds of dynamics simulation.ConclusionOur results indicate that relaxation of protein complexes by MD simulation is useful and necessary to obtain binding energies that are representative of the experimentally determined values.

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“…The fine docking protocol (described in Table 1) combines algorithms already applied to other docking targets [70][71][72][73][74] and has been trained to model 17 ligand-protein complexes between L99A mutant lysozyme (comprising 15 apolar and 2 slightly polar ligands, as listed in Table 3). Some additional ligand-lysozyme L99A complexes and some non-binders listed by Morton et al [25] were not modelled since the ligands contained atom types for which the CVFF force field is not able to define partial charges.…”

Section: Resultsmentioning

confidence: 99%

Design of Ligand Binding to an Engineered Protein Cavity Using Virtual Screening and Thermal Up-shift Evaluation

Machicado

López-Llano

Cuesta‐López

et al. 2005

J Comput Aided Mol Des

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Proteins could be used to carry and deliver small compounds. As a tool for designing ligand binding sites in protein cores, a three-step virtual screening method is presented that has been optimised using existing data on T4 lysozyme complexes and tested in a newly engineered cavity in flavodoxin. The method can pinpoint, in large databases, ligands of specific protein cavities. In the first step, physico-chemical filters are used to screen the library and discard a majority of compounds. In the second step, a flexible, fast docking procedure is used to score and select a smaller number of compounds as potential binders. In the third step, a finer method is used to dock promising molecules of the hit list into the protein cavity, and an optimised free energy function allows discarding the few false positives by calculating the affinity of the modelled complexes. To demonstrate the portability of the method, several cavities have been designed and engineered in the flavodoxin from Anabaena PCC 7119, and the W66F/L44A double mutant has been selected as a suitable host protein. The NCI database has then been screened for potential binders, and the binding to the engineered cavity of five promising compounds and three tentative non-binders has been experimentally tested by thermal up-shift assays and spectroscopic titrations. The five tentative binders (some apolar and some polar), unlike the three tentative non-binders, are shown to bind to the host mutant and, importantly, not to bind to the wild type protein. The three-step virtual screening method developed can thus be used to identify ligands of buried protein cavities. We anticipate that the method could also be used, in a reverse manner, to identify natural or engineerable protein cavities for the hosting of ligands of interest.

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A Study on Docking Mode of HIV Protease and Their Inhibitors.

Cited by 11 publications

References 17 publications

Complement C1q‐target proteins recognition is inhibited by electric moment effectors

Complement C1q‐target proteins recognition is inhibited by electric moment effectors

Untitled

Design of Ligand Binding to an Engineered Protein Cavity Using Virtual Screening and Thermal Up-shift Evaluation

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