Abstract：
:We introduce the QuanSA method for inducing physically meaningful field-based models of ligand binding pockets based on structure-activity data alone. The method is closely related to the QMOD approach, substituting a learned scoring field for a pocket constructed of molecular fragments. The problem of mutual ligand alignment is addressed in a general way, and optimal model parameters and ligand poses are identified through multiple-instance machine learning. We provide algorithmic details along with performance results on sixteen structure-activity data sets covering many pharmaceutically relevant targets. In particular, we show how models initially induced from small data sets can extrapolatively identify potent new ligands with novel underlying scaffolds with very high specificity. Further, we show that combining predictions from QuanSA models with those from physics-based simulation approaches is synergistic. QuanSA predictions yield binding affinities, explicit estimates of ligand strain, associated ligand pose families, and estimates of structural novelty and confidence. The method is applicable for fine-grained lead optimization as well as potent new lead identification.
journal_name
J Comput Aided Mol Desjournal_title
Journal of computer-aided molecular designauthors
Cleves AE,Jain ANdoi
10.1007/s10822-018-0126-xsubject
Has Abstractpub_date
2018-07-01 00:00:00pages
731-757issue
7eissn
0920-654Xissn
1573-4951pii
10.1007/s10822-018-0126-xjournal_volume
32pub_type
杂志文章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：: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 ("t...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-010-9388-7
更新日期：2010-12-01 00:00:00
abstract：:Bradykinin (BK) is a member of the kinin family, released in response to inflammation, trauma, burns, shock, allergy and some cardiovascular diseases, provoking vasodilatation and increased vascular permeability among other effects. Their actions are mediated through at least two G-protein coupled receptors, B1 a rece...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-015-9890-z
更新日期：2016-01-01 00:00:00
abstract：:In the present study, the binding free energy of a family of huprines with acetylcholinesterase (AChE) is calculated by means of the free energy perturbation method, based on hybrid quantum mechanics and molecular mechanics potentials. Binding free energy calculations and the analysis of the geometrical parameters hig...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-018-0114-1
更新日期：2018-05-01 00:00:00
abstract：:Modelling studies have been carried out on the phosphodiesterase (PDE) substrates, adenosine- and guanosine-3'5'-cyclic monophosphates, and on a number of non-specific and type III-specific phosphodiesterase inhibitors. These studies have assisted the understanding of PDE substrate differentiation and the design of po...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/BF01676955
更新日期：1987-07-01 00:00:00
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：: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：:The one-dimensional model of Hann et al. (JChem Inf Comput Sci 41(3):856–864) has been extended to include reverse binding and wrap-around interaction modes between the protein and ligand to explore the complete combinatorial matrix of molecular recognition. The cumulative distribution function of the Maxwell–Boltzman...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-013-9683-1
更新日期：2013-09-01 00:00:00
abstract：:Ligand efficiency metrics are used in drug discovery to normalize biological activity or affinity with respect to physicochemical properties such as lipophilicity and molecular size. This Perspective provides an overview of ligand efficiency metrics and summarizes thermodynamics of protein-ligand binding. Different cl...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-014-9757-8
更新日期：2014-07-01 00:00:00
abstract：:In the context of the SAMPL7 challenge, we computed, employing a non-equilibrium (NE) alchemical technique, the standard binding free energy of two series of host-guest systems, involving as a host the Isaac's TrimerTrip, a Cucurbituril-like open cavitand, and the Gilson's Cyclodextrin derivatives. The adopted NE alch...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-020-00365-3
更新日期：2021-01-04 00:00:00
abstract：:Lipophilicity, often expressed as distribution coefficients (log D) in octanol/water, is an important physicochemical parameter influencing processes such as oral absorption, brain uptake and various pharmacokinetic (PK) properties. Increasing log D values increases oral absorption, plasma protein binding and volume o...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章,评审
doi：10.1023/a:1008192010023
更新日期：2001-03-01 00:00:00
abstract：:Glucokinase (GK) is involved in normal glucose homeostasis and therefore it is a valid target for drug design and discovery efforts. GK activators (GKAs) have excellent potential as treatments of hyperglycemia and diabetes. The combined recent interest in GKAs, together with docking limitations and shortages of dockin...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-014-9740-4
更新日期：2014-05-01 00:00:00
abstract：:Patents from medicinal chemistry represent a rich source of novel compounds and activity data that appear only infrequently in the scientific literature. Moreover, patent information provides a primary focal point for drug discovery. Accordingly, text mining and image extraction approaches have become hot topics in pa...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-017-0061-2
更新日期：2017-09-01 00:00:00
abstract：:Computational techniques, such as Quantitative Structure-Property Relationship (QSPR) modeling, are very useful in predicting physicochemical properties of various chemicals. Building QSPR models requires calculating molecular descriptors and the proper choice of the geometry optimization method, which will be dedicat...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-016-9894-3
更新日期：2016-02-01 00:00:00
abstract：:Leishmania donovani dipeptidylcarboxypeptidsae (LdDCP), an angiotensin converting enzyme (ACE) related metallopeptidase has been identified and characterized as a putative drug target for antileishmanial chemotherapy. The kinetic parameters for LdDCP with substrate, Hip-His-Leu were determined as, Km, 4 mM and Vmax, 1...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-009-9315-y
更新日期：2010-01-01 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：:The interaction mechanism of triazolyl substituted tetrahydrobenzofuran derivatives (compound 1 (N, N-Dipropyl-1-(2-phenyl-4,5,6,7-tetrahydrobenzofuran-4-yl)-1H-1,2,3-triazole-4-methanamine) and 2 (1-(2-Phenyl-4,5,6,7-tetrahydrobenzofuran-4-yl)-4-(morpholin-4-ylmethyl)-1H-1,2,3-triazole)) with H(+),K(+)-ATPase at diff...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-015-9886-8
更新日期：2016-01-01 00:00:00
abstract：:We have used virtual screening to develop models for the binding of aryl substituted heterocycles to p38α MAPK. Virtual screening was conducted on a number of p38α MAPK crystal structures using a library of 46 known p38α MAPK inhibitors containing a heterocyclic core substituted by pyridine and fluorophenyl rings (str...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-012-9569-7
更新日期：2012-04-01 00:00:00
abstract：:In order to identify novel chemical classes of factor Xa inhibitors, five scoring functions (FlexX, DOCK, GOLD, ChemScore and PMF) were engaged to evaluate the multiple docking poses generated by FlexX. The compound collection was composed of confirmed potent factor Xa inhibitors and a subset of the LeadQuest screenin...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1023/b:jcam.0000047812.39758.ab
更新日期：2004-05-01 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：: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：: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
pub_type： 杂志文章
doi：10.1007/s10822-014-9714-6
更新日期：2014-03-01 00:00:00
abstract：:The Fas antigen, a cell surface receptor belonging to the tumor necrosis factor receptor (TNFR) superfamily, triggers programmed cell death (apoptosis) in the immune system. The three-dimensional structure of Fas and molecular details of the interaction between Fas and its ligand are currently unknown. A three-dimensi...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1023/a:1008011024584
更新日期：1997-01-01 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：:The Drug Design Data Resource (D3R) ran Grand Challenge 2015 between September 2015 and February 2016. Two targets served as the framework to test community docking and scoring methods: (1) HSP90, donated by AbbVie and the Community Structure Activity Resource (CSAR), and (2) MAP4K4, donated by Genentech. The challeng...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-016-9946-8
更新日期：2016-09-01 00:00:00
abstract：:A set of algorithms designed to enhance the display of protein binding cavities is presented. These algorithms, collectively entitled CAVITY SEARCH, allow the user to isolate and fully define the extent of a particular cavity. Solid modeling techniques are employed to produce a detailed cast of the active site region,...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/BF00117400
更新日期：1990-12-01 00:00:00
abstract：:Molecular modeling techniques and three-dimensional (3D) pattern analysis have been used to investigate the chemical and steric properties of compounds that inhibit transport of the plant hormone auxin. These compounds bind to a specific site on the plant plasma membrane characterized by its affinity for the herbicide...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/BF00126666
更新日期：1991-08-01 00:00:00
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
abstract：:For computational de novo design, a general retrospective validation work is a very challenging task. Here we propose a comprehensive workflow to de novo design driven by the needs of computational and medicinal chemists and, at the same time, we propose a general validation scheme for this technique. The study was co...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-009-9291-2
更新日期：2009-08-01 00:00:00
abstract：:We have developed quantitative structure-activity relationship (QSAR) models for 44 non-nucleoside HIV-1 reverse transcriptase inhibitors (NNRTIs) of the pyridinone derivative type. The k nearest neighbor (kNN) variable selection approach was used. This method utilizes multiple descriptors such as molecular connectivi...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-005-4789-8
更新日期：2005-04-01 00:00:00
