Abstract：
:Cytochrome P450 (CYP) enzymes play an important role in the metabolism of xenobiotics. Since they are connected to drug interactions, screening for potential inhibitors is of utmost importance in drug discovery settings. Our study provides an extensive classification model for P450-drug interactions with one of the most prominent members, the 2C9 isoenzyme. Our model involved the largest set of 45,000 molecules ever used for developing prediction models. The models are based on three different types of descriptors, (a) typical one, two and three dimensional molecular descriptors, (b) chemical and pharmacophore fingerprints and (c) interaction fingerprints with docking scores. Two machine learning algorithms, the boosted tree and the multilayer feedforward of resilient backpropagation network were used and compared based on their performances. The models were validated both internally and using external validation sets. The results showed that the consensus voting technique with custom probability thresholds could provide promising results even in large-scale cases without any restrictions on the applicability domain. Our best model was capable to predict the 2C9 inhibitory activity with the area under the receiver operating characteristic curve (AUC) of 0.85 and 0.84 for the internal and the external test sets, respectively. The chemical space covered with the largest available dataset has reached its limit encompassing publicly available bioactivity data for the 2C9 isoenzyme.
journal_name
J Comput Aided Mol Desjournal_title
Journal of computer-aided molecular designauthors
Rácz A,Keserű GMdoi
10.1007/s10822-020-00308-ysubject
Has Abstractpub_date
2020-08-01 00:00:00pages
831-839issue
8eissn
0920-654Xissn
1573-4951pii
10.1007/s10822-020-00308-yjournal_volume
34pub_type
杂志文章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 binding mode of (2S)-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-(7-ami dino-2- naphthyl)propanoic acid hydrochloride (DX-9065a, 4) to Factor Xa is examined using inhibition data for a series of analogs that have a hydrophobic group as well as basic or dibasic functionality. Comparative molecular field ...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1023/a:1007969517376
更新日期：1998-03-01 00:00:00
abstract：:Activity cliffs are formed by pairs or groups of structurally similar compounds with significant differences in potency. They represent a prominent feature of activity landscapes of compound data sets and a primary source of structure-activity relationship (SAR) information. Thus far, activity cliffs have only been co...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-012-9632-4
更新日期：2013-02-01 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：:The pKa is the standard measure used to describe the aqueous proton affinity of a compound, indicating the proton concentration (pH) at which two protonation states (e.g. A- and AH) have equal free energy. However, compounds can have additional protonation states (e.g. AH2+), and may assume multiple tautomeric forms, ...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-020-00280-7
更新日期：2020-05-01 00:00:00
abstract：:Mycobacterium tuberculosis (Mtb) 16.3 kDa heat shock protein 16.3 (HSP16.3) is a latency-associated antigen that can be targeted for latent tuberculosis (TB) diagnostic and therapeutic development. We have previously developed human VH domain antibodies (dAbs; clone E3 and F1) specific against HSP16.3. In this work, w...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-019-00186-z
更新日期：2019-03-01 00:00:00
abstract：:We have used the Chemical Structure DataBase (CSDB) of the NCI CADD Group, an aggregated collection of over 150 small-molecule databases totaling 103.5 million structure records, to conduct tautomerism analyses on one of the largest currently existing sets of real (i.e. not computer-generated) compounds. This analysis...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-010-9346-4
更新日期：2010-06-01 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
abstract：:The Epstein-Barr Nuclear Antigen 1 (EBNA1) is a critical protein encoded by the Epstein-Barr Virus (EBV). During latent infection, EBNA1 is essential for DNA replication and transcription initiation of viral and cellular genes and is necessary to immortalize primary B-lymphocytes. Nonetheless, the concept of EBNA1 as ...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-016-9899-y
更新日期：2016-04-01 00:00:00
abstract：:In this work the rigid-analogue approach has been used to obtain information on the active conformation(s) of the calcium antagonist verapamil. A series of semi-rigid analogues of verapamil were synthesized and their biological activities evaluated on guinea-pig heart and aorta. These molecules were analysed by means ...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/BF00119863
更新日期：1994-04-01 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：:Clarithromycin (6-O-methylerythromycin A) is a 14-membered macrolide antibiotic which is active in vitro against clinically important gram-positive and gram-negative bacteria. The selectivity of the methylation of the C-6 OH group is studied on erythromycin A derivatives. To understand the effect of the solvent on the...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1023/b:jcam.0000030037.67742.cb
更新日期：2004-02-01 00:00:00
abstract：:Fast Fourier transform (FFT) based approaches have been successful in application to modeling of relatively rigid protein-protein complexes. Recently, we have been able to adapt the FFT methodology to treatment of flexible protein-peptide interactions. Here, we report our latest attempt to expand the capabilities of t...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-017-0069-7
更新日期：2018-01-01 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：:Quantitative Structure-Activity Relationship (QSAR) models are critical in various areas of drug discovery, for example in lead optimisation and virtual screening. Recently, the need for models that are not only predictive but also interpretable has been highlighted. In this paper, a new methodology is proposed to bui...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-019-00228-6
更新日期：2019-09-01 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：:The liver is extremely vulnerable to the effects of xenobiotics due to its critical role in metabolism. Drug-induced hepatotoxicity may involve any number of different liver injuries, some of which lead to organ failure and, ultimately, patient death. Understandably, liver toxicity is one of the most important dose-li...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1023/b:jcam.0000021834.50768.c6
更新日期：2003-12-01 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：: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：:A theoretical conformational study was performed on leu-enkephalin in its zwitterionic form, both in vacuo and in the presence of a number, n, of up to 13 water molecules saturating its first hydration shell. The intramolecular energy of enkephalin as well as the intermolecular enkephalin-water and water-water interac...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/BF00129748
更新日期：1991-04-01 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：:A new computer program is described, which positions small molecules into clefts of protein structures (e.g. an active site of an enzyme) in such a way that hydrogen bonds can be formed with the enzyme and hydrophobic pockets are filled with hydrophobic groups. The program works in three steps. First it calculates int...
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
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：:Molecular dynamics simulations of complexes between Norwalk virus RNA dependent RNA polymerase and its natural CTP and 2dCTP (both containing the O5'-C5'-C4'-O4' sequence of atoms bridging the triphosphate and sugar moiety) or modified coCTP (C5'-O5'-C4'-O4'), cocCTP (C5'-O5'-C4'-C4'') substrates were produced by mean...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-013-9652-8
更新日期：2013-04-01 00:00:00
abstract：:Babesia bigemina is a protozoan parasite that causes babesiosis, a disease with a world-wide distribution in mammals, principally affecting cattle and man. The unveiling of the genome of B. bigemina is a project in active progress that has already revealed a number of new targets with potential interest for the design...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-013-9682-2
更新日期：2013-09-01 00:00:00
abstract：:This paper describes a new and efficient stochastic conformational sampling method for generating a range of low-energy molecule conformations. Sampling can be tailored to a specific structural domain (e.g., peptides) by extracting torsional profiles from specific datasets and subsequently applying them to target mole...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-007-9156-5
更新日期：2008-09-01 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：: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：: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
abstract：:Virtual Ligand Screening (VLS) has become an integral part of the drug discovery process for many pharmaceutical companies. Ligand similarity searches provide a very powerful method of screening large databases of ligands to identify possible hits. If these hits belong to new chemotypes the method is deemed even more ...
journal_title：Journal of computer-aided molecular design
pub_type： 杂志文章
doi：10.1007/s10822-007-9164-5
更新日期：2008-06-01 00:00:00
