Abstract:
:Compound P131 has been established to inhibit Cryptosporidium parvum's inosine monophosphate dehydrogenase (CpIMPDH). Its inhibitory activity supersedes that of paromomycin, which is extensively used in treating cryptosporidiosis. Through the per-residue energy decomposition approach, crucial moieties of P131 were identified and subsequently adopted to create a pharmacophore model for virtual screening in the ZINC database. This search generated eight ADMET-compliant hits that were examined thoroughly to fit into the active site of CpIMPDH via molecular docking. Three compounds ZINC46542062, ZINC58646829, and ZINC89780094, with favorable docking scores of - 8.3 kcal/mol, - 8.2 kcal/mol, and - 7.5 kcal/mol, were selected. The potential inhibitory mechanism of these compounds was probed using molecular dynamics simulation and Molecular Mechanics Generalized Poisson Boltzmann Surface Area (MM/PBSA) analyses. Results revealed that one of the hits (ZINC46542062) exhibited a lower binding free energy of - 39.52 kcal/mol than P131, which had - 34.6 kcal/mol. Conformational perturbation induced by the binding of the identified hits to CpIMPDH was similar to P131, suggesting a similarity in inhibitory mechanisms. Also, in silico investigation of the properties of the hit compounds implied superior physicochemical properties with regards to their synthetic accessibility, lipophilicity, and number of hydrogen bond donors and acceptors in comparison with P131. ZINC46542062 was identified as a promising hit compound with the highest binding affinity to the target protein and favorable physicochemical and pharmacokinetic properties relative to P131. The identified compounds can serve as a basis for conducting further experimental investigations toward the development of anticryptosporidials, which can overcome the challenges of existing therapeutic options. Graphical abstract P131 and the identified compounds docked in the NAD+ binding site of Cryptosporidium parvum IMPDH.
journal_name
J Mol Modeljournal_title
Journal of molecular modelingauthors
Omolabi KF,Iwuchukwu EA,Agoni C,Olotu FA,Soliman MESdoi
10.1007/s00894-020-04663-3subject
Has Abstractpub_date
2021-01-09 00:00:00pages
35issue
2eissn
1610-2940issn
0948-5023pii
10.1007/s00894-020-04663-3journal_volume
27pub_type
杂志文章abstract::We have recently shown that the anti-HIV activities of reverse transcriptase inhibitors can be related quantitatively to properties of the electrostatic potentials on their molecular surfaces. We now introduce the technique of using only segments of the drug molecules in developing such expressions. If an improved cor...
journal_title:Journal of molecular modeling
pub_type: 杂志文章
doi:10.1007/s00894-002-0111-z
更新日期:2003-04-01 00:00:00
abstract::The original version of this article unfortunately contained a mistake. Schemes I and II were missing. These important components are given below. ...
journal_title:Journal of molecular modeling
pub_type: 已发布勘误
doi:10.1007/s00894-017-3466-x
更新日期:2017-11-01 00:00:00
abstract::The hydration free energies, structures, and dynamics of open- and closed-shell trivalent lanthanide and actinide metal cations are studied using molecular dynamics simulations (MD) based on a polarizable force field. Parameters for the metal cations are derived from an ab initio bottom-up strategy. MD simulations of ...
journal_title:Journal of molecular modeling
pub_type: 杂志文章
doi:10.1007/s00894-014-2471-6
更新日期:2014-10-01 00:00:00
abstract::A theoretical investigation is completed on the mechanism of electrical breakdown strength increment of polyethylene. It is shown that it is one of the most important factors for increasing electrical breakdown strength of polyethylene through keto-enol isomerization of acetophenone and its analogues at the ground sta...
journal_title:Journal of molecular modeling
pub_type: 杂志文章
doi:10.1007/s00894-013-1946-1
更新日期:2013-10-01 00:00:00
abstract::Models of the hydrogenoxalate (bioxalate, charge -1) and oxalate (charge -2) anions were developed for classical molecular dynamics (CMD) simulations and parametrized against ab initio molecular dynamics (AIMD) data from our previous study (Kroutil et al. (2016) J Mol Model 22:210). The interactions of the anions with...
journal_title:Journal of molecular modeling
pub_type: 杂志文章
doi:10.1007/s00894-017-3490-x
更新日期:2017-10-28 00:00:00
abstract::In this paper, we theoretically studied the geometries, stabilities, and the electronic and thermodynamic properties of 4H-cyclopenta[2,1-b,3;4-b']dithiopene S-oxide derivatives (BTO-X, with X = BH(2), SiH(2), S, S=O, or O) using semi-empirical methods, ab initio methods, and density functional theory. The geometries ...
journal_title:Journal of molecular modeling
pub_type: 杂志文章
doi:10.1007/s00894-011-1291-1
更新日期:2012-06-01 00:00:00
abstract::The substituted effect on excited-state intramolecular proton transfer (ESIPT) of o-LHBDI derivatives (4R-o-LHBDI) was investigated by DFT and TD-DFT methods. The structures of 4R-o-LHBDI (R: OH, NH2, CN, NO2, CF3) were fully optimized, and the H-bond distances, bond angles, and infrared spectra of the atoms involved ...
journal_title:Journal of molecular modeling
pub_type: 杂志文章
doi:10.1007/s00894-020-04378-5
更新日期:2020-04-23 00:00:00
abstract::In this paper, coupled cluster methods CC2, CCSD, CCSDR(3) and EOM-CCSD(T) have been benchmarked against CC3 for the transition energies of nucleobases. Beside presenting vertical excitation energies for about 30 singlet transitions of four molecules, the results are analyzed statistically and problematic cases have b...
journal_title:Journal of molecular modeling
pub_type: 杂志文章
doi:10.1007/s00894-014-2503-2
更新日期:2014-11-01 00:00:00
abstract::Using ligand and receptor based virtual screening approaches we have identified potential virtual screening hits targeting type II dehydroquinase from Mycobacterium tuberculosis, an effective and validated anti-mycobacterial target. Initially, we applied a virtual screening workflow based on a combination of 2D struct...
journal_title:Journal of molecular modeling
pub_type: 杂志文章
doi:10.1007/s00894-009-0595-x
更新日期:2010-04-01 00:00:00
abstract::We studied the structure and dynamics of star-shaped polymers by means of coarse-grained molecular dynamics simulations and analysis of structural transitions of semi-flexible macromolecules confined in nano-channels. The conformation of star arms in narrow channels is given by the channel width, arm flexibility and n...
journal_title:Journal of molecular modeling
pub_type: 杂志文章
doi:10.1007/s00894-015-2735-9
更新日期:2015-07-01 00:00:00
abstract::Leishmaniasis is an endemic disease caused by infection with one of several different species of protozoan parasite Leishmania. Oligopeptidase B (OPB) is a serine peptidase which plays a vital role in survival of the Leishmania parasite in the host (human) macrophage and help in attaining complete virulence. Inhibitio...
journal_title:Journal of molecular modeling
pub_type: 杂志文章
doi:10.1007/s00894-014-2099-6
更新日期:2014-03-01 00:00:00
abstract::Temperature dependences of the spontaneous polarization and the dielectric constant are calculated near the paraelectric-ferroelectric (cubic-tetragonal) transition in BaTiO3 using our mean field model. By expanding the free energy in terms of the spontaneous polarization (order parameter), expressions for the tempera...
journal_title:Journal of molecular modeling
pub_type: 杂志文章
doi:10.1007/s00894-013-1927-4
更新日期:2013-09-01 00:00:00
abstract::The aqueous solvation of Th and Np in the IV oxidation state was examined using cluster models generated by Monte Carlo simulations and density functional theory embedded within the COSMO continuum model to approximate the effect of bulk water. Our results suggest that the coordination number (CN) for both Th(IV) and ...
journal_title:Journal of molecular modeling
pub_type: 杂志文章
doi:10.1007/s00894-017-3252-9
更新日期:2017-03-01 00:00:00
abstract::We report a study of the structure of (+)-catechin, which belongs to the family of the flavan-3-ols-one of the five most widely distributed phenolic groups. The biological activities and pharmaceutical utility of these compounds are related to antioxidant activity due to their ability to scavenge free radicals. A brea...
journal_title:Journal of molecular modeling
pub_type: 杂志文章
doi:10.1007/s00894-014-2105-z
更新日期:2014-02-01 00:00:00
abstract::In the past several years, halogen bonds have been shown to be relevant in crystal engineering and biomedical applications. One of the reasons for the utility of these types of noncovalent interactions in the development of, for example, pharmaceutical ligands is that their strengths and geometric properties are very ...
journal_title:Journal of molecular modeling
pub_type: 杂志文章
doi:10.1007/s00894-011-1015-6
更新日期:2011-12-01 00:00:00
abstract::Cyclin-dependent kinases (Cdks) play important roles in the regulation of the cell cycle. Their inhibitors have entered clinical trials to treat cancer. Very recently, Davis et al. (Nat Struct Biol 9:745-749, 2002) have found a ligand NU6102, which has a high affinity with cyclin-dependent kinase 2 (K(i) = 6 nM) but a...
journal_title:Journal of molecular modeling
pub_type: 杂志文章
doi:10.1007/s00894-005-0263-8
更新日期:2005-11-01 00:00:00
abstract::High-level quantum chemical techniques have been utilized to accurately describe the geometrical parameters, vibrational frequencies and dissociation pathways of the X (2)A″, 1 (2)A', 2 (2)A', 2 (2)A″ states of S(2)Cl; X (1)A', 1 (3)A″, 1 (1)A″, 1 (3)A' states of S(2)Cl(+); X (1)A', 1 (3)A', (1)A″ states of S(2)Cl(-),...
journal_title:Journal of molecular modeling
pub_type: 杂志文章
doi:10.1007/s00894-012-1422-3
更新日期:2012-09-01 00:00:00
abstract::Ankyrin repeat proteins (ARPs) appear to be abundant in organisms from all phyla, and play critical regulatory roles, mediating specific interactions with target biomolecules and thus ordering the sequence of events in diverse cellular processes. ARPs possess a non-globular scaffold consisting of repeating motifs name...
journal_title:Journal of molecular modeling
pub_type: 杂志文章
doi:10.1007/s00894-008-0300-5
更新日期:2008-08-01 00:00:00
abstract::The geometrical structure and electronic properties of bis(10-hydroxybenzo[h]quinolinato)beryllium (Bebq2) molecule and its dimer both in the neutral and in the positively and negatively charged states were studied using quantum-chemical calculations. It is found that the excess charge in the charged systems is locali...
journal_title:Journal of molecular modeling
pub_type: 杂志文章
doi:10.1007/s00894-014-2397-z
更新日期:2014-08-01 00:00:00
abstract::The CFIm25 subunit of the heterotetrameric cleavage factor Im (CFIm) is a critical factor in the formation of the poly(A) tail at mRNA 3' end, regulating the recruitment of polyadenylation factors, poly(A) site selection, and cleavage/polyadenylation reactions. We previously reported the homologous protein (EhCFIm25) ...
journal_title:Journal of molecular modeling
pub_type: 杂志文章
doi:10.1007/s00894-018-3729-1
更新日期:2018-07-12 00:00:00
abstract::Vertical ionization energies (VIEs) of medazepam, nordazepam and their molecular subunits have been calculated using the electron propagator method in the P3/CEP-31G* approximation. Vertical electron affinities (VEAs) have been obtained with a ∆SCF procedure at the DFT-B3LYP/6-31+G* level of theory. Excellent correlat...
journal_title:Journal of molecular modeling
pub_type: 杂志文章
doi:10.1007/s00894-010-0723-7
更新日期:2011-02-01 00:00:00
abstract::In an attempt to analyze structure, function and evolution of HIV-1 GP120 V3, interactions among the Hartree-Fock energy, the conformational entropy and the Shannon entropy were determined for the 1NJ0 set of antibody-bound V3 loop conformers. The Hartree-Fock energy of each conformer was determined at the MINI level ...
journal_title:Journal of molecular modeling
pub_type: 杂志文章
doi:10.1007/s00894-005-0054-2
更新日期:2006-02-01 00:00:00
abstract::Aluminum enriched 1, 1-diamino-2, 2-dinitroethylene (Al-FOX-7) crystal, as a new high energy density material (HEDM), was designed and investigated using grand canonical monte carlo (GCMC), NVT+NPT-molecular dynamics (MD) and GGA-PBE-density functional theory (DFT) methods. The results show that, Al atoms break out H-...
journal_title:Journal of molecular modeling
pub_type: 杂志文章
doi:10.1007/s00894-012-1533-x
更新日期:2013-01-01 00:00:00
abstract::Cystic fibrosis (CF), the most common lethal genetic disease among Caucasians, is caused by mutations in cystic fibrosis transmembrane conductance regulator (CFTR). CFTR's main role is to transport chloride ions across epithelial cell membranes. It also regulates many cell functions. However, the exact role of CFTR in...
journal_title:Journal of molecular modeling
pub_type: 杂志文章
doi:10.1007/s00894-011-1029-0
更新日期:2012-01-01 00:00:00
abstract::Density functional theory (DFT) was used to study the stereochemistry, thermodynamic stability, and spectra of recently synthesized bis-Betti base derivatives of 2,3-dihydroxynaphthalene obtained through multicomponent reactions of 2,3-dihydroxynaphthalene with aminoisoxazole and benzaldehyde derivatives. The stereoch...
journal_title:Journal of molecular modeling
pub_type: 杂志文章
doi:10.1007/s00894-016-2936-x
更新日期:2016-04-01 00:00:00
abstract::We have used density-functional theory to investigate the neighboring-group stabilization of iodine, arsenic, and phosphorus-centered oxyanion moieties in species such as deprotonated 2-iodoxybenzoic acid (IBX) and its analogs. The magnitudes of different stabilizing effects and further candidates for analogous stabil...
journal_title:Journal of molecular modeling
pub_type: 杂志文章
doi:10.1007/s00894-009-0567-1
更新日期:2010-03-01 00:00:00
abstract::Bicyclo[3.3.1]nonylidenebicyclo[3.3.1]nonane (1) and adamantylideneadamantane (Ad=Ad) are two caged olefins with closely related structures at the double bond. Both compounds react instantaneously with Br2 in chlorinated hydrocarbon solvents to give mixtures of olefin-Br2 aggregates identified as the 1:1 pi-complex an...
journal_title:Journal of molecular modeling
pub_type: 杂志文章
doi:10.1007/s00894-005-0038-2
更新日期:2006-07-01 00:00:00
abstract::The chain tacticity of a polymer is a key influence on its structure and dynamics, which ultimately determine its properties. While they have great potential to elucidate the influence of chain tacticity, all-atom molecular simulations are often restricted to short chains and small systems. In this work, two typical s...
journal_title:Journal of molecular modeling
pub_type: 杂志文章
doi:10.1007/s00894-014-2377-3
更新日期:2014-08-01 00:00:00
abstract::Metallo-β-lactamases (MβLs) can hydrolyze and deactivate lactam-containing antibiotics, which are the major mechanism to cause drug resistance in the treatment of bacterial infections. This has become a global concern due to the lack of clinically approved inhibitors so far. SMB-1 from Serratia marcescents is a novel ...
journal_title:Journal of molecular modeling
pub_type: 杂志文章
doi:10.1007/s00894-020-4330-y
更新日期:2020-03-07 00:00:00
abstract::A density functional theory investigation of adsorption of monomer, dimer and trimer forms of pyrrole on the outer surface of zigzag (7,0) single-walled carbon nanotube (SWCNT) has been reported. Geometries of the complexes were optimized using the M06-2X functional and the 6-31G(d,p) basis set. Moreover, 6-311G(d,p),...
journal_title:Journal of molecular modeling
pub_type: 杂志文章
doi:10.1007/s00894-014-2414-2
更新日期:2014-09-01 00:00:00