Abstract：
:When we build a predictive model of a drug property we rigorously assess its predictive accuracy, but we are rarely able to address the most important question, "How useful will the model be in making a decision in a practical context?" To answer this requires an understanding of the prior probability distribution ("the prior") and hence prevalence of negative outcomes due to the property being assessed. In this perspective, we illustrate the importance of the prior to assess the utility of a model in different contexts: to select or eliminate compounds, to prioritise compounds for further investigation using more expensive screens, or to combine models for different properties to select compounds with a balance of properties. In all three contexts, a better understanding of the prior probabilities of adverse events due to key factors will improve our ability to make good decisions in drug discovery, finding higher quality molecules more efficiently.
journal_name
J Comput Aided Mol Desjournal_title
Journal of computer-aided molecular designauthors
Segall M,Chadwick Adoi
10.1007/s10822-010-9388-7subject
Has Abstractpub_date
2010-12-01 00:00:00pages
957-60issue
12eissn
0920-654Xissn
1573-4951journal_volume
24pub_type
杂志文章abstract：:The electron-conformational (EC) method in QSAR problems employs a unique (based on first principles) descriptor of molecular properties that incorporates the electronic structure and topology of the molecule and is presented in a digital-matrix form suitable for computer processing, the EC matrix of congruity (ECMC)....
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-008-9191-x
更新日期：2008-06-01 00:00:00
abstract：:An evolutionary algorithm was developed for fragment-based de novo design of molecules (TOPAS, TOPology-Assigning System). This stochastic method aims at generating a novel molecular structure mimicking a template structure. A set of approximately 25,000 fragment structures serves as the building block supply, which w...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1023/a:1008184403558
更新日期：2000-07-01 00:00:00
abstract：:A structure-binding activity relationship for the intestinal bile acid transporter has been developed using data from a series of bile acid analogs in a comparative molecular field analysis (CoMFA). The studied compounds consisted of a series of bile acid-peptide conjugates, with modifications at the 24 position of th...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1023/a:1007919704457
更新日期：1997-11-01 00:00:00
abstract：:The CASE (Computer Automated Structure Evaluation) program, with the aid of a geometry index for discriminating cis and trans isomers, has been used to study a set of retinoids tested for teratogenicity in hamsters. CASE identified 8 fragments, the most important representing the non-polar terminus of a retinoid with ...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/BF00125314
更新日期：1990-06-01 00:00:00
abstract：:A new method is presented for the calculation of the Molecular Electrostatic Potential (MEP) in large systems. Based on the mixed Quantum Mechanics/Molecular Mechanics (QM/MM) approach, the method assumes both a quantum and classical description for the molecule, and the calculation of the MEP in the space surrounding...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1023/a:1008111820916
更新日期：2000-05-01 00:00:00
abstract：:The three-dimensional structure of dolastatin-10, an extremely potent cytostatic and antineoplastic peptide extracted from the mollusc Dolabella auricularia, has not yet been fully characterized in an experimental way. By means of a systematic conformational search of the natural peptide and of two mutated analogs, ca...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/BF00124000
更新日期：1995-10-01 00:00:00
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journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/BF01532991
更新日期：1989-01-01 00:00:00
abstract：:Steric complementarity is a prerequisite for ligand-receptor recognition; this implies that drugs with a common receptor binding site should possess sterically similar binding surfaces. This principle is used as the basis for an automatic and unbiased method that superposes molecules. One molecule is rotated and trans...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/BF00124319
更新日期：1995-12-01 00:00:00
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journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-007-9147-6
更新日期：2007-10-01 00:00:00
abstract：:Using the X-ray crystal structure of the human topoisomerase I (top1) - DNA cleavable complex and the Sybyl software package, we have developed a general model for the ternary cleavable complex formed with four protoberberine alkaloids differing in the substitution on the terminal phenyl rings and covering a broad ran...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-004-7878-1
更新日期：2004-12-01 00:00:00
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journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-019-00241-9
更新日期：2019-12-01 00:00:00
abstract：:A novel computational Diels-Alderase design, based on a relatively rare form of carboxylesterase from Geobacillus stearothermophilus, is presented and theoretically evaluated. The structure was found by mining the PDB for a suitable oxyanion hole-containing structure, followed by a combinatorial approach to find suita...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-012-9601-y
更新日期：2012-09-01 00:00:00
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journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-013-9703-1
更新日期：2014-01-01 00:00:00
abstract：:The process of compound selection and prioritization is crucial for both combinatorial chemistry (CBC) and high throughput screening (HTS). Compound libraries have to be screened for unwanted chemical structures, as well as for unwanted chemical properties. Property extrema can be eliminated by using property filters,...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1023/a:1008130001697
更新日期：2000-03-01 00:00:00
abstract：:Benchmarks for molecular docking have historically focused on re-docking the cognate ligand of a well-determined protein-ligand complex to measure geometric pose prediction accuracy, and measurement of virtual screening performance has been focused on increasingly large and diverse sets of target protein structures, c...
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：:De novo ligand design supports the search for novel molecular scaffolds in medicinal chemistry projects. This search can either be based on structural information of the targeted active site (structure-based approach) or on similarity to known binders (ligand-based approach). In the absence of structural information o...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-011-9473-6
更新日期：2011-10-01 00:00:00
abstract：:Aligning and overlaying two or more bio-active molecules is one of the key tasks in computational drug discovery and bio-activity prediction. Especially chemical-functional molecule characteristics from the view point of a macromolecular target represented as a 3D pharmacophore are the most interesting similarity meas...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-006-9078-7
更新日期：2006-12-01 00:00:00
abstract：:In the absence of a 3D structure of the target biomolecule, to propose the 3D requirements for a small molecule to exhibit a particular bioactivity, one must supply both a bioactive conformation and a superposition rule for every active compound. Our strategy identifies both simultaneously. We first generate and optim...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/BF00141577
更新日期：1993-02-01 00:00:00
abstract：:Molecular modeling methodologies such as molecular docking, pharmacophore modeling, and 3D-QSAR, rely on conformational searches of small molecules as a starting point. All of these methodologies seek conformations of the small molecules as they bind to target proteins, i.e., their active conformations. Thus the quest...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1023/a:1016320106741
更新日期：2002-02-01 00:00:00
abstract：:The worldwide spread of beta-lactamases with hydrolytic activity extended to last resort carbapenems is aggravating the antibiotic resistance problem and endangers the successful antimicrobial treatment of clinically relevant pathogens. As recently highlighted by the World Health Organization, new strategies to contai...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-018-0182-2
更新日期：2019-02-01 00:00:00
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journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/BF00124387
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journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-011-9458-5
更新日期：2011-08-01 00:00:00
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journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1023/b:jcam.0000022559.72848.1c
更新日期：2004-01-01 00:00:00
abstract：:Hydrogen bonds are the most specific, and therefore predictable of the intermolecular interactions involved in ligand-protein binding. Given the structure of a molecule, it is possible to estimate the positions at which complementary hydrogen-bonding atoms could be found. Crystal-survey data are used in the design of ...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1023/a:1007900527102
更新日期：1997-05-01 00:00:00
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journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-014-9759-6
更新日期：2014-11-01 00:00:00
abstract：:Molecular modeling studies were carried out by a combined use of conformational analysis and 3D-QSAR methods of identify molecular features common to a series of hydroxyacetophenone (HAP) and non-hydroxyacetophenone (non-HAP) peptide leukotriene (pLT) receptor antagonists. In attempts to develop a ligand-binding model...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/BF00124498
更新日期：1996-08-01 00:00:00
abstract：:The "embedded cluster reference interaction site model" (EC-RISM) integral equation theory is applied to the problem of predicting aqueous pKa values for drug-like molecules based on an ensemble of tautomers. EC-RISM is based on self-consistent calculations of a solute's electronic structure and the distribution funct...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-018-0140-z
更新日期：2018-10-01 00:00:00
abstract：:Recent progress in molecular biology has revealed that many non-coding RNAs regulate gene expression or catalyze biochemical reactions in tumors, viruses and several other diseases. The tertiary structure of RNA molecules and RNA-RNA/protein interaction sites are of increasing importance as potential targets for new m...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-019-00195-y
更新日期：2019-05-01 00:00:00
abstract：:A major problem in modelling (biological) macromolecules is the search for low-energy conformations. The complexity of a conformational search problem increases exponentially with the number of degrees of freedom which means that a systematic search can only be performed for very small structures. Here we introduce a ...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/BF00129422
更新日期：1992-04-01 00:00:00
abstract：:Multipoint interactions between synthetic and natural polymers provide a promising platform for many topical applications, including therapeutic blockage of virus-specific targets. Docking may become a useful tool for modelling of such interactions. However, the rigid docking cannot be correctly applied to synthetic p...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-012-9621-7
更新日期：2012-12-01 00:00:00
