Molecular Modeling Of Binding Research Articles

Discovery of TRD‐93 as a novel DRAK2 inhibitor

AbstractDeath‐associated protein kinase‐related apoptosis‐inducing protein kinase 2 (DRAK2) has become a promising target for drug development. In search of novel and selective DRAK2 inhibitor motif, in vitro screen kinase assay was established performed using in‐house chemical libraries. After through hit triage procedure, N2‐(3,5‐dichlorophenyl)‐5‐fluoro‐N4‐methylpyrimidine‐2,4‐diamine (1) was selected as initial hit with structural novelty and drug‐likeness. During hit validation, structure–activity relationship of 1 was thoroughly disclosed and TRD‐93 was finally validated as hit for DRAK2 inhibition. TRD‐93 is small (mw = 290) but selectively potent to DRAK2 (IC50 = 0.16 μM) over other kinases including DAPK family kinases. Molecular binding model study of TRD‐93 to DRAK2 is also discussed.

DeepR2cov: deep representation learning on heterogeneous drug networks to discover anti-inflammatory agents for COVID-19.

Recent studies have demonstrated that the excessive inflammatory response is an important factor of death in coronavirus disease 2019 (COVID-19) patients. In this study, we propose a deep representation on heterogeneous drug networks, termed DeepR2cov, to discover potential agents for treating the excessive inflammatory response in COVID-19 patients. This work explores the multi-hub characteristic of a heterogeneous drug network integrating eight unique networks. Inspired by the multi-hub characteristic, we design 3 billion special meta paths to train a deep representation model for learning low-dimensional vectors that integrate long-range structure dependency and complex semantic relation among network nodes. Based on the representation vectors and transcriptomics data, we predict 22 drugs that bind to tumor necrosis factor-α or interleukin-6, whose therapeutic associations with the inflammation storm in COVID-19 patients, and molecular binding model are further validated via data from PubMed publications, ongoing clinical trials and a docking program. In addition, the results on five biomedical applications suggest that DeepR2cov significantly outperforms five existing representation approaches. In summary, DeepR2cov is a powerful network representation approach and holds the potential to accelerate treatment of the inflammatory responses in COVID-19 patients. The source code and data can be downloaded from https://github.com/pengsl-lab/DeepR2cov.git.

Design, Synthesis, in vitro Antiproliferative Activity, Binding Modeling of 1,2,4,-Triazoles as New Anti-Breast Cancer Agents.

This article demonstrates the synthesis of 1,2,4-triazole derivatives and their applications in medicine particularly as anti-breast cancer agents which is a major issue of the present. The synthesized compounds were characterized by elemental analysis, FT-IR and NMR. DFT was used to study the quantum chemical calculations of geometries and vibrational wave numbers of 3-hydroxynaphthyl and p-tolyl substituted 1,2,4-triazoles in the ground state. The scaled harmonic vibrational frequencies obtained from the DFT method were compared with those of the FT-IR spectra and found good agreement. The synthesized 1,2,4-triazole-naphthyl hybrids were screened for the anticancer activity against MCF-7 breast cancer lines. Among them compounds 3 and 7 showed broad spectrum anticancer activity with IC50 values 9.7 μM and 7.10 μM, respectively and their activity is comparable to that of the standard drugs. The molecular model for binding between the compounds (1-8) and the active site of BRCA2 was obtained on the basis of the computational docking results and the structure-activity relationship.

Binding mechanism of the tyrosine-kinase inhibitor nilotinib to human serum albumin determined by 1H STD NMR, 19F NMR, and molecular modeling

Drug interaction with albumins significantly affects in vivo drug transport and biological metabolism. To gain insight into the binding mechanisms of tyrosine-kinase inhibitor nilotinib (NIL) to human serum albumin (HSA), an approach combining 1H saturation-transfer difference (STD) nuclear magnetic resonance (NMR) spectroscopy, 19F NMR spectroscopy, steady-state fluorescence quenching, and molecular modeling was adopted. 19F NMR was used to determine the binding constant, and a value of 4.12×103M−1 was obtained. Fluorescence spectroscopy was also used to determine the binding constant, and the value obtained was within the same order of magnitude. The binding process was mainly driven by hydrogen bonds and van der Waals forces. Displacement experiments further showed that NIL mainly bound to the hydrophobic cavity of HSA’s subdomain IIA, also called Sudlow’s site I. Molecular docking simulation was also used to establish a molecular binding model, and findings were consistent with those of displacement and the 1H STD NMR experiments.

Design, synthesis and anti-HIV-1 evaluation of a series of 5-hydroxypyridine-4-one derivatives as possible integrase inhibitors

A series of 5-hydroxypyridine-4-one derivatives were synthesized and subjected to HIV-1 replication inhibition assay. Docking studies provide a detailed molecular binding model for this class of compounds interacting with integrase enzyme. All of the derivatives were recognized potent in the docking studies in terms of both the estimated free energy change of binding and interactions with integrase key elements. 5a, 5c, 5d, 5h and 5n exhibited good anti-HIV-1 activities in cell-based assay. Compound 5d was the most potent derivative not only in vitro but also in silico. 5c and 5h offered the highest therapeutic indices. Suboptimal lipophilicity of 6b, 6g, 6i, 6j, 6l and 5m made them inactive in assays, despite the high activity in the docking studies.

Molecular binding of self-assembling peptide EAK16-II with anticancer agent EPT and its implication in cancer cell inhibition

The current drug delivery techniques involve encapsulation, targeting and controlled release of the drug with various molecules or nanoparticles, but rarely has the drug molecular state or form been investigated. It is necessary to deliver a drug with a prescribed molecular state in order to maximize drug therapeutic effects. Here we present two facile methods to characterize molecular states of the anticancer drug ellipticine (EPT) encapsulated in the self-assembling peptide EAK, and relate the different molecular states of EPT to their respective cancer inhibition efficacies. The first method is UV-based, where drug loading capacity of a particular molecular state was determined. The experimental data corroborated a molecular binding model, where peptide–drug interaction was assumed to be electrostatic in nature. The developed model could elucidate a unique pH effect on protonated EPT loading capacity. The second method is based on fluorescence characteristics of EPT, which could differentiate the two molecular states: protonated and crystalline of EPT in situ. The inner filter effect was, however, found with this method, presenting an ineluctable obstacle in quantitative analysis of fluorescence data. A correction method for the inner filter effect was thus developed. With this approach, concentrations of EPT at different molecular states in its peptide complex solutions were determined. In vitro cytotoxicity assay was applied to evaluate the efficacy of the two molecular states of EPT, showing that protonated EPT was more efficient at killing cancer cells than crystalline EPT. The molecular binding model and two characterization methods for EAK–EPT complexation could be extended to other carrier-drug systems.

ChemInform Abstract: Advances in Indolo[2,3-a]carbazole Chemistry: Design and Synthesis of Protein Kinase C and Topoisomerase I Inhibitors

Indolo[2,3-a]carbazoles, their pyrrolo[3,4-c]anellated variants and structurally closely related bisindolylmaleimides represent a biologically highly interesting class of natural compounds which are potential anticancer agents. According to the ongoing literature new and efficient synthetic methods yield a great variety of these compounds which have been reported in detail. The biological activities and the inhibitory activities against the target enzymes protein kinase C and topoisomerase I are also discussed including structure activity relationships. A molecular binding model of the protein kinase C inhibitors with the target enzyme at the atomic level is presented and supported by X-ray crystallographic structures and by molecular modelling studies.

Discovery of a Novel CCR5 Antagonist Lead Compound Through Fragment Assembly

CCR5, as the major co-receptor for HIV-1 entry, is an attractive novel target for the pharmaceutical industry in the HIV-1 therapeutic area. In this study, based on the structures of maraviroc and 1,4-bis(4-(7-chloroquinolin-4-yl)piperazin-1-yl)butane-1,4- dione (1), which was identified using structure-based virtual screening in conjunction with a calcium mobilization assay, a series of novel small molecule CCR5 antagonists have been designed and synthesized through fragment assembly. Preliminary SARs were obtained, which are in good agreement with the molecular binding model and should prove helpful for future antagonist design. The novel scaffold presented here might also be useful in the development of maraviroc-derived second generation CCR5 antagonists.

Conformation-opioid activity relationships of bicyclic guanidines from 3D similarity analysis

Conformation of bicyclic guanidines with kappa-opioid receptor activity derived in our laboratory from a positional scanning synthetic combinatorial library is presented in this work. We propose a common bioactive conformation and putative pharmacophoric features by means of 3D similarity methods. Our ‘Y’ shape molecular binding model explains structure–activity relationships and suggests that the guanidine functionality and a 4-methoxybenzyl group may be involved in key interactions with the receptor. Comparison of our model with known opiates suggest a similar binding mode showing that the bicyclic guanidines presented in this work are suitable scaffolds for further development of new opioid receptors ligands.

Molecular modeling of binding between amidinobenzisothiazoles, with antidegenerative activity on cartilage, and matrix metalloproteinase-3

The aim of the work was to investigate the mechanism of binding between human metalloproteinase-3 (MMP-3) and new compounds belonging to the benzisothiazolylamidines class. In vitro tests suggest that these molecules, endowed with antinflammatory and cartilage antidegenerative activity, could act as ligands toward MMP-3. In lack of experimental structural informations, we performed molecular docking simulations to probe the interactions of benzisothiazolylamidines with matrix metalloproteinase-3, using the docking package GOLD and the software HINT as a post-process scoring function. Both GOLD and HINT predicted a binding mode for the compounds under analysis within the hydrophobic S1′ pocket of MMP-3, without interaction with the catalytic Zn 2+ ion. The scores assigned by the programs to the interaction between the tested benzisothiazolylamidines and human MMP-3 were consistent with a potential direct enzyme inhibitory activity. The highest affinity was predicted for the N–(benzo[ d]isothiazol-3-yl)-4-chlorobenzamidine ( 2), emerged as the most active derivative also in the in vitro tests.

Advances in lndolo[2,3-a]carbazole Chemistry: Design and Synthesis of Protein Kinase C and Topoisomerase I Inhibitors

Abstract: lndolo[2,3-a]carbazoles, their pyrrolo[3,4-c]anellated variants and structurally closely related bisindolylmaleimides represent a biologically highly interesting class of natural compounds which are potential anticancer agents. According to the ongoing literature new and efficient synthetic methods yield a great variety of these compounds which have been reported in detail. The biological activities and the inhibitory activities against the target enzymes protein kinase C and topoisomerase I are also discussed including structure activity relationships. A molecular binding model of the protein kinase C inhibitors with the target enzyme at the atomic level is presented and supported by X-ray crystallographic structures and by molecular modelling studies.

Spectator fermion binding of bosons

We propose a simple molecular binding model for the bosons by considering two heavy charges Ze with mass M 2 embedded into electron gas with mass m. In the lowest order approximation we derive a closed form expression V eff ( r) for the binding potential which has short-range repulsion followed by attraction. In the classical limit M 2 ⪢ m, we calculate the bond length R and cohesive energy E for the lithium metal to be R = 3.1 A ̊ , E = −.9 eV. The same interaction for two holes in a parabolic band with M 2 ⪢ m gives quantum mechanical bound state which one may interprete as a boson appearing in high- T c superconductors such as 123.

Protein-bound calcium in human serum. Quantitative examination of binding and its variables by a molecular binding model and clinical chemical implications for measurement of ionized calcium.

Ultrafiltration and spectrophotometric methods have shown that protein binding of calcium (CaPr) in normal serum follows a simple mass law with an apparent maximum binding capacity of 0.12 mmol Ca/g protein, 90% being due to albumin. The effects of pH, temperature, and magnesium ions on CaPr have been quantitatively described by a previously suggested albumin-calcium binding model. CaPr was highly predictable in normo-, but not in dysproteinaemic subjects. The implications for interpretation of S-Ca values and the limited indications for (Ca++) measurements have been discussed.