Abstract:
:This paper tests the performance of a simple empirical scoring function on a set of candidate designs produced by a de novo design package. The scoring function calculates approximate ligand-receptor binding affinities given a putative binding geometry. To our knowledge this is the first substantial test of an empirical scoring function of this type on a set of molecular designs which were then subsequently synthesised and assayed. The performance illustrates that the methods used to construct the scoring function and the reliance on plausible, yet potentially false, binding modes can lead to significant over-prediction of binding affinity in bad cases. This is anticipated on theoretical grounds and provides caveats on the reliance which can be placed when using the scoring function as a screen in the choice of molecular designs. To improve the predictability of the scoring function and to understand experimental results, it is important to perform subsequent Quantitative Structure-Activity Relationship (QSAR) studies. In this paper, Bayesian regression is performed to improve the predictability of the scoring function in the light of the assay results. Bayesian regression provides a rigorous mathematical framework for the incorporation of prior information, in this case information from the original training set, into a regression on the assay results of the candidate molecular designs. The results indicate that Bayesian regression is a useful and practical technique when relevant prior knowledge is available and that the constraints embodied in the prior information can be used to improve the robustness and accuracy of regression models. We believe this to be the first application of Bayesian regression to QSAR analysis in chemistry.
journal_name
J Comput Aided Mol Desjournal_title
Journal of computer-aided molecular designauthors
Murray CW,Auton TR,Eldridge MDdoi
10.1023/a:1008040323669subject
Has Abstractpub_date
1998-09-01 00:00:00pages
503-19issue
5eissn
0920-654Xissn
1573-4951journal_volume
12pub_type
杂志文章abstract::The overexpression and/or mutation of the epidermal growth factor receptor (EGFR) tyrosine kinase has been observed in many human solid tumors, and is under intense investigation as a novel anticancer molecular target. Comparative 3D-QSAR analyses using different alignments were undertaken employing comparative molecu...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1023/b:jcam.0000004622.13865.4f
更新日期:2003-08-01 00:00:00
abstract::In contrast to the computational generation of conventional tautomers, the analogous operation that would produce ring-chain tautomers is rarely available in cheminformatics codes. This is partly due to the perceived unimportance of ring-chain tautomerism and partly because specialized algorithms are required to reali...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-020-00334-w
更新日期:2020-08-24 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::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
pub_type: 杂志文章
doi:10.1007/s10822-017-0052-3
更新日期:2017-10-01 00:00:00
abstract::An empirical hydrophobic field-like 3D function has been calculated with the program HINT (hydrophobic interactions) and imported into the SYBYL implementation of CoMFA (Comparative Molecular Field Analysis). The addition of hydrophobicity appears to offer increased chemical interpretability of CoMFA models. An exampl...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/BF00135313
更新日期:1991-12-01 00:00:00
abstract::Computational prediction of the effects of residue changes on peptide-protein binding affinities, followed by experimental testing of the top predicted binders, is an efficient strategy for the rational structure-based design of peptide inhibitors. In this study we apply this approach to the discovery of competitive a...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-012-9574-x
更新日期:2012-07-01 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
更新日期:2020-12-01 00:00:00
abstract::A linear quantitative-structure activity relationship model is developed in this work using Multiple Linear Regression Analysis as applied to a series of 51 1-(3,3-diphenylpropyl)-piperidinyl phenylacetamides derivatives with CCR5 binding affinity. For the selection of the best variables the Elimination Selection-Step...
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
abstract::In this work, we present a case study to explore the challenges associated with finding novel molecules for a receptor that has been studied in depth and has a wealth of chemical information available. Specifically, we apply a previously described protocol that incorporates explicit water molecules in the ligand bindi...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-016-9963-7
更新日期:2016-10-01 00:00:00
abstract::Chemical space networks (CSNs) have recently been introduced as an alternative to other coordinate-free and coordinate-based chemical space representations. In CSNs, nodes represent compounds and edges pairwise similarity relationships. In addition, nodes are annotated with compound property information such as biolog...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-015-9872-1
更新日期:2015-10-01 00:00:00
abstract::The design of molecules with desired properties is still a challenge because of the largely unpredictable end results. Computational methods can be used to assist and speed up this process. In particular, genetic algorithms have proved to be powerful tools with a wide range of applications, e.g. in the field of drug d...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1023/a:1021928016359
更新日期:2002-08-01 00:00:00
abstract::Two new continuum solvation models have been presented recently, and in this paper they are explained and reviewed in detail with further examples. Solvation Model 2 (AM1-SM2) is based on the Austin Model 1 and Solvation Model 3 (PM3-SM3) on the Parameterized Model 3 semiempirical Hamiltonian. In addition to the incor...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/BF00126219
更新日期:1992-12-01 00:00:00
abstract::We report the implementation of molecular modeling approaches developed as a part of the 2016 Grand Challenge 2, the blinded competition of computer aided drug design technologies held by the D3R Drug Design Data Resource ( https://drugdesigndata.org/ ). The challenge was focused on the ligands of the farnesoid X rece...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-017-0085-7
更新日期:2018-01-01 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::We describe the performance of multiple pose prediction methods for the D3R 2016 Grand Challenge. The pose prediction challenge includes 36 ligands, which represent 4 chemotypes and some miscellaneous structures against the FXR ligand binding domain. In this study we use a mix of fully automated methods as well as hum...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-017-0053-2
更新日期:2018-01-01 00:00:00
abstract::Combining Lipinski's rule with the docking and steered molecular dynamics simulations and using the PubChem data base of about 1.4 million compounds, we have obtained DNA dyes Hoechst 34580 and Hoechst 33342 as top-leads for the Alzheimer's disease. The binding properties of these ligands to amyloid beta (Aβ) fibril w...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-016-9932-1
更新日期:2016-08-01 00:00:00
abstract::Dengue and related flaviviruses represent a significant global health threat. The envelope glycoprotein E mediates virus attachment to a host cell and the subsequent fusion of viral and host cell membranes. The fusion process is driven by conformational changes in the E protein and is an essential step in the virus li...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-009-9263-6
更新日期:2009-06-01 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::All-atom molecular dynamics computer simulations were used to blindly predict the hydration free energies of a range of chloro-organic compounds as part of the SAMPL3 challenge. All compounds were parameterized within the framework of the OPLS-AA force field, using an established protocol to compute the absolute hydra...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-011-9527-9
更新日期:2012-05-01 00:00:00
abstract::Here, we report our results from quantitative structure-activity relationship studies on tyrosinase inhibitors. Interactions between benzoic acid derivatives and tyrosinase active sites were also studied using a molecular docking method. These studies indicated that one possible mechanism for the interaction between b...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-008-9187-6
更新日期:2008-05-01 00:00:00
abstract::Electrostatic potential complementarity between ligands and their receptor sites is evaluated by the superposition of the electrostatic potential, generated by the receptor, onto the ligand potential over the ligand van der Waals surface. We would like to examine which structural factors generate this pattern of super...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/BF00123665
更新日期:1994-10-01 00:00:00
abstract::New methods for docking, template fitting and building pseudo-receptors are described. Full conformational searches are carried out for flexible cyclic and acyclic molecules. QXP (quick explore) search algorithms are derived from the method of Monte Carlo perturbation with energy minimization in Cartesian space. An ad...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1023/a:1007907728892
更新日期:1997-07-01 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
abstract::A MD simulation protocol was developed to model halogen bonding in protein-ligand complexes by inclusion of a charged extra point to represent the anisotropic distribution of charge on the halogen atom. This protocol was then used to simulate the interactions of cathepsin L with a series of halogenated and non-halogen...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-014-9802-7
更新日期:2015-01-01 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::Utilization of coupling constants as restraints in computational structure refinement is reviewed. In addition, we address the effect of conformational averaging and examine different approaches to apply the restraints when the experimental observable is obviously a result of averaging. Here, two different computation...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/BF00124347
更新日期:1994-02-01 00:00:00
abstract::The kinase-regulatory cell signaling networks play a central role in the pathogenesis of human cervical cancer (hCC). However, only few kinase inhibitors have been successfully developed for treatment of this cancer to date. Considering that the active sites of protein kinases are highly conserved and small-molecule i...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-019-00211-1
更新日期:2019-07-01 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::Drug discovery is an expensive and time-consuming process. To make this process more efficient quantum chemistry methods can be employed. The electrophilicity index is one property that can be calculated by quantum chemistry methods, and if calculated correctly gives insight into the reactivity of covalent inhibitors....
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-020-00342-w
更新日期:2020-10-05 00:00:00
abstract::To rigorously assess the tools and protocols that can be used to understand and predict macromolecular recognition, and to gain more structural insight into three newly discovered allosteric binding sites on a critical drug target involved in the treatment of HIV infections, the Olson and Levy labs collaborated on the...
journal_title:Journal of computer-aided molecular design
pub_type: 杂志文章
doi:10.1007/s10822-014-9709-3
更新日期:2014-04-01 00:00:00