Flexible ligand docking: A multistep strategy approach

Wang, Jian; Kollman, Peter A.; Kuntz, Irwin D.

doi:10.1002/(sici)1097-0134(19990701)36:1<1::aid-prot1>3.0.co;2-t

Cited by 141 publications

(52 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Table 1 gives the computed root mean square deviation (RMSD) of each of the docked ligand with respect to the corresponding ligand in the original PDB structure. Six of the ligands are docked into the binding site with a RMSD in the range of 0.80 to 2.05Å, which is comparable to those obtained in other docking studies 16,21,22.…”

Section: Testing Of Invdock Docking Algorithmsupporting

confidence: 82%

Computational Method for Drug Target Search and Application in Drug Discovery

Chen

Ung

2002

J. Theor. Comput. Chem.

View full text Add to dashboard Cite

Abstract Ligand-protein inverse docking has recently been introduced as a computer method for identification of potential protein targets of a drug. A protein structure database is searched to find proteins to which a drug can bind or weakly bind. Examples of potential applications of this method in facilitating drug discovery include: (1) identification of unknown and secondary therapeutic targets of a drug, (2) prediction of potential toxicity and side effect of an investigative drug, and (3) probing molecular mechanism of bioactive herbal compounds such as those extracted from plants used in traditional medicines. This method and recent results on its applications in solving various drug discovery problems are reviewed.Index Terms-Drug binding, computer-aided drug design, ligand-protein interactions, molecular modeling, adverse drug reactions, therapeutic effects, medicinal plant drug, natural product.

show abstract

Section: Testing Of Invdock Docking Algorithmsupporting

confidence: 82%

Computational Method for Drug Target Search and Application in Drug Discovery

Chen

Ung

2002

J. Theor. Comput. Chem.

View full text Add to dashboard Cite

show abstract

“…This problem is compounded by the number of potential orientations of the antigen in the binding site. However, division of the ligand into representative fragments enables the generation of a model for the complex by examining the structures of multiple docked fragments (26). Once a fragment has been docked, it can serve as an anchor point from which the remaining ligand structure may be extended (27) Table 1).…”

Section: Generation Of the Cps-fv Complexesmentioning

confidence: 99%

Understanding the bacterial polysaccharide antigenicity ofStreptococcus agalactiaeversusStreptococcus pneumoniae

Kadirvelraj

González-Outeiriño

Foley

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Bacterial surface capsular polysaccharides (CPS) that are similar in carbohydrate sequence may differ markedly in immunogenicity and antigenicity. The structural origin of these phenomena is poorly understood. Such a case is presented by the Gram-positive bacteria Streptococcus agalactiae (Group B Streptococcus; GBS) type III (GBSIII) and Streptococcus pneumoniae (Pn) type 14 (Pn14), which share closely related CPS sequences. Nevertheless, antibodies (Abs) against GBSIII rarely cross-react with the CPS from Pn14. To establish the origin for the variation in CPS antigenicity, models for the immune complexes of CPS fragments from GBSIII and Pn14, with the variable fragment (Fv) of a GBS-specific mAb (mAb 1B1), are presented. The complexes are generated through a combination of comparative Ab modeling and automated ligand docking, followed by explicitly solvated 10-ns molecular dynamics simulations. The relationship between carbohydrate sequence and antigenicity is further quantified through the computation of interaction energies using the Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) method, augmented by conformational entropy estimates. Despite the electrostatic differences between Pn14 and GBSIII CPS, analysis indicates that entropic penalties are primarily responsible for the loss of affinity of the highly flexible Pn14 CPS for mAb 1B1. The similarity of the solution conformation of the relatively rigid GBSIII CPS with that in the immune complex characterizes the previously undescribed 3D structure of the conformational epitope. The analysis provides a comprehensive interpretation for a large body of biochemical and immunological data related to Ab recognition of bacterial polysaccharides and should be applicable to other Ab-carbohydrate interactions. S treptococcus agalactiae [Group B Streptococcus (GBS)] andStreptococcus pneumoniae (Pn) are responsible for the majority of life-threatening cases of septicemia, meningitis, and pneumonia in neonates (1, 2). Gram-positive bacteria, such as GBS and Pn, are classified into serotypes according to the unique carbohydrate sequence of the bacterial surface capsular polysaccharide (CPS) and protein antigens. Serotypes vary in antigenicity, immunogenicity, virulence, and geographical distribution (3). Quantification of the structural and dynamic properties responsible for the affinity and specificity of antigenic oligosaccharide-antibody (Ab) interactions is a crucial step in furthering the understanding of the immune response to bacterial and fungal pathogens. In GBS, the CPS is a high-molecularweight polymer composed of varying sequences of ␤-D-, and sometimes L-rhamnopyranose. The glyceryl side chain of the Neu5Ac residues may also be Oacetylated (4). In all GBS strains identified to date, the Neu5Ac residues occur in the terminal position on the side-chain branches of the polymeric repeat unit of the CPS. They play an important role in defining the antigenicity and immunogenicity of the CPS (5). Variations within the CPS sequence result in the nine kno...

show abstract

“…These ligands were docked into the protein active site using FlexX [15] docking program; FlexX uses a rigid protein and a flexible ligand. The problem of protein flexibility is addressed by minimization of docked protein ligand complex [16,17], as it is a time consuming method. Only those protein ligand complexes were chosen, where the ligands were properly docked into the active site of protein.…”

Section: Methods and Softwarementioning

confidence: 99%

Computational design of novel cyclic urea as HIV-1 protease inhibitor

Manga

Kanth

2007

Open Chemistry

View full text Add to dashboard Cite

A series of novel cyclic urea molecules 5,6-dihydroxy-1,3-diazepane-2,4,7-trione as HIV-1 protease inhibitors were designed using computational techniques. The designed molecules were compared with the known cyclic urea molecules by performing docking studies, calculating their ADME (Absorption, Distribution, Metabolism, and Excretion) properties and protein ligand interaction energy. These novel molecules were designed by substituting the P 1 /P 1 positions (4 th and 7 th position of 1, 3-diazepan-2-one) with double bonded oxygens. This reduces the molecular weight and increases the bioavailability, indicating better ADME properties. The docking studies showed good binding affinity towards HIV-1 protease. The biological activity of these inhibitors were predicted by a model equation generated by the regression analysis between biological activity (log 1/K i ) of known inhibitors and their protein ligand interaction energy. The synthetic studies are in progress.

show abstract

Flexible ligand docking: A multistep strategy approach

Cited by 141 publications

References 25 publications

Computational Method for Drug Target Search and Application in Drug Discovery

Computational Method for Drug Target Search and Application in Drug Discovery

Understanding the bacterial polysaccharide antigenicity ofStreptococcus agalactiaeversusStreptococcus pneumoniae

Computational design of novel cyclic urea as HIV-1 protease inhibitor

Contact Info

Product

Resources

About