Abstract:
:A dataset of 82 protein-ligand complexes of known 3D structure and binding constant Ki was analysed to elucidate the important factors that determine the strength of protein-ligand interactions. The following parameters were investigated: the number and geometry of hydrogen bonds and ionic interactions between the protein and the ligand, the size of the lipophilic contact surface, the flexibility of the ligand, the electrostatic potential in the binding site, water molecules in the binding site, cavities along the protein-ligand interface and specific interactions between aromatic rings. Based on these parameters, a new empirical scoring function is presented that estimates the free energy of binding for a protein-ligand complex of known 3D structure. The function distinguishes between buried and solvent accessible hydrogen bonds. It tolerates deviations in the hydrogen bond geometry of up to 0.25 A in the length and up to 30 degrees in the hydrogen bond angle without penalizing the score. The new energy function reproduces the binding constants (ranging from 3.7 x 10(-2) M to 1 x 10(-14) M, corresponding to binding energies between -8 and -80 kJ/mol) of the dataset with a standard deviation of 7.3 kJ/mol corresponding to 1.3 orders of magnitude in binding affinity. The function can be evaluated very fast and is therefore also suitable for the application in a 3D database search or de novo ligand design program such as LUDI. The physical significance of the individual contributions is discussed.
journal_name
J Comput Aided Mol Desjournal_title
Journal of computer-aided molecular designauthors
Böhm HJdoi
10.1023/a:1007999920146subject
Has Abstractpub_date
1998-07-01 00:00:00pages
309-23issue
4eissn
0920-654Xissn
1573-4951journal_volume
12pub_type
杂志文章,评审abstract::Water molecules in the binding pocket of a protein and their role in ligand binding have increasingly raised interest in recent years. Displacement of such water molecules by ligand atoms can be either favourable or unfavourable for ligand binding depending on the change in free enthalpy. In this study, we investigate...
journal_title:Journal of computer-aided molecular design
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abstract::ERG-associated protein with the SET domain (ESET/SET domain bifurcated 1/SETDB1/KMT1E) is a histone lysine methyltransferase (HKMT) and it preferentially tri-methylates lysine 9 of histone H3 (H3K9me3). SETDB1/ESET leads to heterochromatin condensation and epigenetic gene silencing. These functional changes are report...
journal_title:Journal of computer-aided molecular design
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journal_title:Journal of computer-aided molecular design
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-015-9890-z
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abstract::This paper describes several case studies concerning protein function inference from its structure using our novel approach described in the accompanying paper. This approach employs family-specific motifs, i.e. three-dimensional amino acid packing patterns that are statistically prevalent within a protein family. For...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-009-9277-0
更新日期:2009-11-01 00:00:00
abstract::We have undertaken molecular dynamics simulations on the d(CGCAAAAAAGCG).d(CGCTTTTTTGCG) dodecamer in solution. In this study, we focus on aspects of conformation and dynamics, including the possibility of cross-strand hydrogen bonds. We compare our results with those from crystallography as well as infrared, Raman an...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/BF00126748
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
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更新日期:1990-12-01 00:00:00
abstract::The recent outbreak of the respiratory syndrome-related coronavirus (SARS-CoV-2) is stimulating an unprecedented scientific campaign to alleviate the burden of the coronavirus disease (COVID-19). One line of research has focused on targeting SARS-CoV-2 proteins fundamental for its replication by repurposing drugs appr...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-020-00356-4
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abstract::We used blind predictions of the 47 hydration free energies in the SAMPL4 challenge to test multiple partial charge models in the context of explicit solvent free energy simulations with the general AMBER force field. One of the partial charge models, IPolQ-Mod, is a fast continuum solvent-based implementation of the ...
journal_title:Journal of computer-aided molecular design
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更新日期:2014-03-01 00:00:00
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
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abstract::Furanopyrimidine 1 (IC50 = 273 nM, LE = 0.36, LELP = 10.28) was recently identified by high-throughput screening (HTS) of an in-house library (125,000 compounds) as an Aurora kinase inhibitor. Structure-based hit optimization resulted in lead molecules with in vivo efficacy in a mouse tumour xenograft model, but no or...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-014-9807-2
更新日期:2015-01-01 00:00:00
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-011-9533-y
更新日期:2012-06-01 00:00:00
abstract::The backbone conformations of the cyclic moieties of 1-[beta-mercaptopropionic acid]-oxytocin [( Mpa1]-OT), [1-beta-mercaptopropionic acid]-arginine-vasopressin [( Mpa1]-AVP), [1-(beta'-mercapto-beta,beta-cyclopentamethylene)propionic acid]-arginine-vasopressin [( Cpp1]-AVP), and [1-thiosalicylic acid]-arginine-vasopr...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/BF01532991
更新日期:1989-01-01 00:00:00
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1023/a:1008029924865
更新日期:1999-01-01 00:00:00
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1023/a:1008170432484
更新日期:1999-11-01 00:00:00
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-006-9038-2
更新日期:2006-02-01 00:00:00
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/BF00124472
更新日期:1996-10-01 00:00:00
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/BF00124387
更新日期:1992-02-01 00:00:00
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journal_title:Journal of computer-aided molecular design
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journal_title:Journal of computer-aided molecular design
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doi:10.1007/s10822-009-9298-8
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
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abstract::Inducible, microsomal prostaglandin E synthase 1 (mPGES-1), the terminal enzyme in the prostaglandin (PG) biosynthetic pathway, constitutes a promising therapeutic target for the development of new anti-inflammatory drugs. To elucidate structure-function relationships and to enable structure-based design, an mPGES-1 h...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
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journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-015-9872-1
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abstract::The preferential occurrence of certain disulphide-bridge topologies in proteins has prompted us to design a method and a program, KNOT-MATCH, for their classification. The program has been applied to a database of proteins with less than 65% homology and more than two disulphide bridges. We have investigated whether t...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1023/a:1011164224144
更新日期:2001-05-01 00:00:00
abstract::We developed a new structure-based in-silico screening method using a negative image of a ligand-binding pocket and a multi-protein-compound interaction matrix. Based on the structure of the ligand pocket of the target protein, we designed a negative image, which consists of virtual atoms whose radii are close to thos...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-006-9047-1
更新日期:2006-04-01 00:00:00
abstract::The linear finite difference Poisson-Boltzmann (FDPB) equation is applied to the calculation of the electrostatic binding free energies of a group of inhibitors to the Neuraminidase enzyme. An ensemble of enzyme-inhibitor complex conformations was generated using Monte Carlo simulations and the electrostatic binding f...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1023/a:1008197913568
更新日期:2001-02-01 00:00:00
abstract::Orientation of ten water molecules bound strongly at the contact surface of the dihydrofolate reductase-methotrexate enzyme-inhibitor complex was determined theoretically. To optimize the orientation of the water molecules, a recent method based on a simple electrostatic model was applied. The electrostatic complement...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/BF01532054
更新日期:1988-04-01 00:00:00
abstract::New designs for Magnetic Resonance Imaging contrast agents are presented. Essentially, they all are host-guest inclusion complexes between y-cyclodextrins and polyazamacrocycles of gadolinium (III) ion. Substitutions have been made to the host to optimise the host-guest association. Molecular mechanics calculations ha...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1023/a:1027347527385
更新日期:2003-07-01 00:00:00
abstract::Understanding how proteins encode ligand specificity is fascinating and similar in importance to deciphering the genetic code. For protein-ligand recognition, the combination of an almost infinite variety of interfacial shapes and patterns of chemical groups makes the problem especially challenging. Here we analyze da...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-018-0105-2
更新日期:2018-04-01 00:00:00
abstract::Anaplastic lymphoma kinase (ALK) has been thought to be a prospective target of anti-drug resistance design in treatment of tumors and specific neuron diseases. It is highly useful for the seeking of possible strategy alleviating drug resistance to probe the mutation-mediated effect on binding of inhibitors to ALK. In...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-020-00355-5
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