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(a) RMSD versus time plot for all C a atoms at the target; (b) RMSD versus time plot for C a atoms of residues that are participating in hydrogen bonding with the inhibitor.
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The rational design of high-affinity inhibitors of poly-ADP-ribose polymerase-1 (PARP-1) is at the heart of modern anti-cancer drug design. While relevance of enzyme to DNA repair processes in cellular environment is firmly established, the structural and functional understanding of the main determinants for high-affinity ligands controlling PARP-1...
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Context 1
... RMSD values for Ca atoms can serve as a measure for relative flexibility of the binding pockets in apo and holo states of PARP-1 (Figure 4a). To illuminate the effect of a given conformation on the stability of binding pocket, we calculated the RMSD values with respect to Ca atoms of the residues comprising binding site and participating in hydrogen bonding (Figure 4b) using the protein X-ray diffraction structure. ...
Context 2
... RMSD values for Ca atoms can serve as a measure for relative flexibility of the binding pockets in apo and holo states of PARP-1 (Figure 4a). To illuminate the effect of a given conformation on the stability of binding pocket, we calculated the RMSD values with respect to Ca atoms of the residues comprising binding site and participating in hydrogen bonding (Figure 4b) using the protein X-ray diffraction structure. Two independent simulations with and without bound inhibitors, i.e. at the holo and apo states, were carried out to determine the effect of inhibitor on the protein dynamics. ...
Context 3
... RMSD values for Ca atoms of residues forming binding pocket showed a slightly higher RMSD in the apo state than in the holo state at the equilibration stage of the MD simulations. After the equilibration, the PARP-1 structure at both apo and holo forms did not display any significant conformational transitions (Figure 4). The RMSD values for all Ca atoms of the PARP-1 protein at apo and holo states fluctuated around a mean value (1.83 ...
Context 4
... RMSD values for all Ca atoms of the PARP-1 protein at apo and holo states fluctuated around a mean value (1.83 A ˚ and 1.65 A ˚ for holo and apo forms, respectively) and remained almost the same during the equilibration (Figure 4). Figure 5 illustrates per-residue RMSF values for Ca atoms of the protein. ...
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Citations
... The C-terminal catalytic (CAT) domain contains binding sites for NAD + and catalytic sites for the synthesis of PAR-(poly(ADP-ribose)). In addition, the CAT domain contains a regulatory helical subdomain (HD) and ADP-ribosyl transferase (ART), which provides a significant structural basis for the structure-based de novo design of PARP1 inhibitors [18,19]. Although many scientific issues have been addressed and significant milestones have been reached, it is still very challenging to elucidate the functional mechanism of PARP1 and to develop PARP1 inhibitors [2,4,18,20]. ...
... MD simulation has been broadly employed to unveil the detailed interaction mechanisms between drugs and target proteins [14,21,22]. Inhibitors related to the CAT domain of PARP1 have been widely studied through experiments and computational methods [2,12,19,23]. However, how the inhibitor molecules affect the conformational and functional changes in PARP1 bound to DNA is still unclear. ...
The catalytic (CAT) domain is a key region of poly (ADP-ribose) polymerase 1 (PARP1), which has crucial interactions with inhibitors, DNA, and other domains of PARP1. To facilitate the development of potential inhibitors of PARP1, it is of great significance to clarify the differences in structural dynamics and key residues between CAT/inhibitors and DNA/PARP1/inhibitors through structure-based computational design. In this paper, conformational changes in PAPR1 and differences in key residue interactions induced by inhibitors were revealed at the molecular level by comparative molecular dynamics (MD) simulations and energy decomposition. On one hand, PARP1 inhibitors indirectly change some residues of the CAT domain which interact with DNA and other domains. Furthermore, the interaction between ligands and catalytic binding sites can be transferred to the DNA recognition domain of PARP1 by a strong negative correlation movement among multi-domains of PARP1. On the other hand, it is not reliable to use the binding energy of CAT/ligand as a measure of ligand activity, because it may in some cases differs greatly from the that of PARP1/DNA/ligand. For PARP1/DNA/ligand, the stronger the binding stability between the ligand and PARP1, the stronger the binding stability between PARP1 and DNA. The findings of this work can guide further novel inhibitor design and the structural modification of PARP1 through structure-based computational design.
... was used. Ser243 was previously mentioned as one of the amino acid residues forming the binding site of PARP1 enzymes [36,37]. The atoms of the protein were fixed during the docking calculations. ...
In this study, we evaluated the antiproliferative potential, DNA damage, crystal structures, and docking calculation of two spiropyrazoline derivatives. The main focus of the research was to evaluate the antiproliferative potential of synthesized compounds towards eight cancer cell lines. Compound I demonstrated promising antiproliferative properties, especially toward the HL60 cell line, for which IC50 was equal to 9.4 µM/L. The analysis of DNA damage by the comet assay showed that compound II caused DNA damage to tumor lineage cells to a greater extent than compound I. The level of damage to tumor cells of the HEC-1-A lineage was 23%. The determination of apoptotic and necrotic cell fractions by fluorescence microscopy indicated that cells treated with spiropyrazoline-based analogues were entering the early phase of programmed cell death. Compounds I and II depolarized the mitochondrial membranes of cancer cells. Furthermore, we performed simple docking calculations, which indicated that the obtained compounds are able to bind to the PARP1 active site, at least theoretically (the free energy of binding values for compound I and II were −9.7 and 8.7 kcal mol−1, respectively). In silico studies of the influence of the studied compounds on PARP1 were confirmed in vitro with the use of eight cancer cell lines. The degradation of the PARP1 enzyme was observed, with compound I characterized by a higher protein degradation activity.
... Nowadays, many researchers are attempting to find an effective PARP1 inhibitor, in this regards, many studies appeared. Here, we also try to compare our findings along with the some recently studies ( Table 10) [62][63][64][65][66][67][68][69][70]. All the mentioned studies are based on the virtual screening followed by the IC50 evaluation in either experimental or theoretical analysis. ...
The Poly [ADP-Ribose] polymerase 1 (PARP1) has recently been thought to be one of the potentially successful targets against cancer, specifically for ovarian and BRCA mutated breast cancers. Here, unprotected (N-H/N-Me) aziridine derivatives were recognized as potential anti-cancer compounds targeting the apoptotic pathway using a combined molecular descriptors (MDs) computation, prediction of activity spectra for substances (PASS), adsorption, distribution, metabolism, excretion and toxicity (ADMET) evaluation, Brain Or IntestinaL EstimateD (BOILED-Egg), Bioactivity score (BAS), docking-based virtual screening (DBVS), integral docking and molecular dynamics (MD) simulation. Twenty one N-H/N-Me aziridine derivatives were screened to identify molecules binding to the PARP1 binding pocket followed by docking and MD simulation. Compound 3a has a good binding profile along with all the targets, but potentially better interact with the PARP1 as observed by the molecular docking evaluations. The docking complexes of the lead compound 3a with the target PARP1 were found stable during molecular dynamics simulations as represented by the obtained parameters including radius of gyration (Rg) and root mean square deviation (RMSD). The compound 3a yielded good binding free energy using the analysis of molecular mechanics generalized born surface area (MM-GBSA) and molecular mechanics Poisson-Boltzmann surface area (MM-PBSA). Therefore, the finding of the studies unravels the possible compounds 3a as lead anticancer candidate against selected PARP1.
... The PDB2GMX module was used to generate the topology that had information about the unbound parameters (types of atoms and charges) and bound parameters (bonds, angles and dihedrals) within the simulation. The CHARMM36 force field [42] was used for the simulations of all RuBisCO systems following similar studies [14,43,44]. Periodic boundary conditions (PBC) were applied in all directions of a cube box with a 10 Å lateral size. ...
RuBisCO is the most abundant enzyme on earth; it regulates the organic carbon cycle in the biosphere. Studying its structural evolution will help to develop new strategies of genetic improvement in order to increase food production and mitigate CO2 emissions. In the present work, we evaluate how the evolution of sequence and structure among isoforms I, II and III of RuBisCO defines their intrinsic flexibility and residue-residue interactions. To do this, we used a multilevel approach based on phylogenetic inferences, multiple sequence alignment, normal mode analysis, and molecular dynamics. Our results show that the three isoforms exhibit greater fluctuation in the loop between αB and βC, and also present a positive correlation with loop 6, an important region for enzymatic activity because it regulates RuBisCO conformational states. Likewise, an increase in the flexibility of the loop structure between αB and βC, as well as Lys330 (form II) and Lys322 (form III) of loop 6, is important to increase photosynthetic efficiency. Thus, the cross-correlation dynamics analysis showed changes in the direction of movement of the secondary structures in the three isoforms. Finally, key amino acid residues related to the flexibility of the RuBisCO structure were indicated, providing important information for its enzymatic engineering.
... The involvement of polar interactions (hydrogen bonding and pi-cation) and non-polar interaction (Pi-stacking) playing crucial roles in the higher activity of ligands in the PARP-1 active site has been documented in previous works on PARP-1 MD simulations. The van der Waals and hydrophobic interactions in the ligand-PARP-1 activities were also mentioned in previous works (Halder et al., 2015;Salmas et al., 2016;. The current study findings may provide valuable insights into the potential rational design of novel PARP-1 inhibitors for cancer treatments, including lung cancer. ...
PARP-1 has become an attractive target in cancer treatment owing to its significant role in breast and ovarian cancers. The design of highly selective and effective poly (ADP ribose) polymerase-1 inhibitors has significant therapeutic advantages and has remained the core of several PARP-1-based drug discovery research. The pharmacophoric relevance of a chlorine substituent in a recent study led to the design of compounds 11c (meta-chlorophenyl) and 11d (para-chlorophenyl). In this study, we resolved the mechanistic effects of the changes in chlorine positional orientation, which underlie the inhibitory potencies and selectivity exhibited disparately by 11c and 11d. Compared to 11d, among other multiple higher-affinity complementary interactions with key site residues, the meta-Cl positioning in 11c facilitated its optimal motion and orientation towards conserved residues Arg878 and Asp766 with consistent pi-cation and pi-anion interactions, respectively, thereby favoring the stability of the ligand towards PARP-1. These could account for the higher inhibitory potency exhibited by 11c relative to 11d against PARP-1. The thermodynamics calculation revealed that 11c had a relatively higher total binding energy (ΔGbind) than 11d. We also observed that 11d displayed high deviations, compared to 11c, indicative of its unstable binding orientation. Furthermore, we reported in this study that the high involvement of electrostatic and van der Waal effects potentiated the binding affinity and strength of 11c (ΔEvdW = −50.58 and ΔEele = −27.20) relative to 11d (ΔEvdW = −49.46 and ΔEele = −19.96) at PARP-1 binding pocket. We believe the findings in this current study would provide valuable insights into the design of selective PARP-1 inhibitors containing chlorine substituent for cancer treatment, including lung cancer.
Communicated by Ramaswamy H. Sarma
... We then tested PARP-1 inhibitory activity of TSL-1502 by enzymatic assay. Different from the highly potent inhibitory effects of TSL-1502M, the inhibitory effects of TSL-1502 on PARP1 and PARP2 were very weak (IC 50 >3000 nM), suggesting that the inability of binding to PARP1 active sites (Gly863 and Ser904) [21] caused the loss of inhibitory activity of TSL-1502. ...
Poly (ADP-ribose) polymerase (PARP) enzymes play an important role in the cellular response to DNA damage and the inhibition of PARP causes synthetic lethality in homologous recombination (HR)-deficient cancer. Multiple PARP inhibitors have been developed and have shown remarkable clinical benefits. However, treatment-related toxicities, especially the hematologic toxicities, are common and restrict the clinical applications of PARP inhibitors. In this study, we designed the first glucuronide prodrug of PARP inhibitor, TSL-1502, based on a novel and highly potent PARP inhibitor TSL-1502M. TSL-1502M exhibited promising inhibitory activity on PARP1/2, significantly induced DNA double strand breaks, G2/M arrest and apoptosis in HR-deficient cells, selectively inhibited the proliferation of HR-deficient cancer cells and sensitized both HR-deficient and HR-proficient cancer cells to conventional chemotherapy. Notably, TSL-1502M was superior to olaparib, the first-in-class PARP inhibitor, in all these processes. TSL-1502 had no inhibitory effects on PARP1/2 itself, but could selectively liberate the active drug TSL-1502M in tumor after administration in nude mice. Moreover, TSL-1502 elicited significant more potent inhibitory effects than olaparib in HR-deficient tumors, and sensitized chemotherapy in both HR-deficient and HR-proficient tumors. No severe toxicities were caused by TSL-1502 in this study. Based on the encouraging preclinical antitumor activity and the selective decomposition characteristic of TSL-1502, a clinical phase I study was initiated in China, and an Investigational New Drug (IND) was granted by the US FDA. TSL-1502 could represent a new potential therapeutic choice of PARP inhibitors.
... This BPA substituent used in thermal paper occupied the same binding site reported for PARP1 inhibitors. The shared contact residues of these interactions were TYR907B, ILE872B, TYR896B, ALA880B, and ALA989B and a hydrogen bond with GLY863B (Salmas et al. 2016). Therefore, structural moieties of BPPH could be useful for the development of new and safe inhibitors of this protein. ...
Background:
Bisphenol A analogs and derivatives (BPs) have emerged as new contaminants with little or no information about their toxicity. These have been found in numerous everyday products, from thermal paper receipts to plastic containers, and measured in human samples.
Objectives:
The objectives of this research were to identify in silico new protein targets of BPs associated with seven noncommunicable diseases (NCDs), and to study their protein-ligand interactions using computer-aided tools.
Methods:
Fifty BPs were identified by a literature search and submitted to a virtual high-throughput screening (vHTS) with 328 proteins associated with NCDs. Protein-protein interactions between predicted targets were examined using STRING, and the protocol was validated in terms of binding site recognition and correlation between in silico affinities and in vitro data.
Results:
According to the vHTS, several BPs may target proteins associated with NCDs, some of them with stronger affinities than bisphenol A (BPA). The best affinity score (the highest in silico affinity absolute value) was obtained after docking 4,4'-bis(N-carbamoyl-4-methylbenzensulfonamide)diphenylmethane (BTUM) on estradiol 17-beta-dehydrogenase 1 (
-
13.7
kcal
/
mol
). However, other molecules, such as bisphenol A bis(diphenyl phosphate) (BDP), bisphenol PH (BPPH), and Pergafast 201 also exhibited great affinities (top 10 affinity scores for each disease) with proteins related to NCDs.
Discussion:
Molecules such as BTUM, BDP, BPPH, and Pergafast 201 could be targeting key signaling pathways related to NCDs. These BPs should be prioritized for in vitro and in vivo toxicity testing and to further assess their possible role in the development of these diseases. https://doi.org/10.1289/EHP7466.
... Evidences obtained from different site-directed mutagenesis studies of the important catalytic amino acids at the hPARP1 active site were used to construct different mutants as E988A, E988D, E988K, E988Q, G863A, H862A, H862D, K903A, K903E, K903Q, S904A, Y896A, Y896N, Y907A, Y907N to understand the importance of these amino acid residues on 4NCO binding [47][48][49]. In silico mutagenesis studies of the hPARP1 protein was carried out using "mutate protein" module in DS 2.5 [50]. ...
... The per-residue interaction energy for contributions to protein-ligand complex formation was then evaluated using a cut off distance of 10 Å. For hydrogen bonds the angle cut off values considered were b20°with the distance cut off being 3.0 Å [36,47]. One-way Analysis of Variance (ANOVA) was carried out to compare the interaction energies (IE) of the binding site amino acids of PARP1 with 4NCO. ...
Flavones are important bioactive compounds, many of which are effective in cancer therapy for their ability to target enzymes related to DNA repair and cell proliferation. In this report, the interaction of a synthetic nitroflavone, 2,4-nitrophenylchromen-4-one (4NCO) with human poly (ADP-ribose) polymerase 1 (hPARP1) was investigated to explore its inhibitory action. Its interaction with hPARP1 was compared with that of other inhibitors through molecular docking studies. Further insight into the 4NCO-hPARP1 interaction was obtained from competitive docking and molecular dynamic simulation studies. In silico mutagenesis studies and per-residue interaction energy calculations were carried out. Quantitative Structure Activity Relationship analysis was also performed to calculate its predictive percent inhibitory activity. Our results indicated that 4NCO exhibited competitive mode of binding to hPARP1. It formed a stable interaction with the protein thereby hindering any further molecular interaction to render it inactive with a predictive inhibition of 96%. It also had good ADMET properties and showed best Autodock binding free energy values compared to other known inhibitors. 4NCO showed good hPARP1 inhibitory properties with higher bioavailability and lower probability of getting effluxed. Development of inhibitors against hPARP1 is important for cell proliferative disorders, where 4NCO can be predicted as a potential new drug.
... 48 Standard PARP1 inhibitors are known to bind the nicotinamide ribose binding site, or NI site. 32,49 Previous in-silico study of the catalytic domain of PARP-1 has revealed that hydrogen bond formation between residues Gly 863, Arg 878 and Ser 904 and the ligand is necessary for binding pocket stability. 49,50 Speci¯cally, the residues Gly 863 and Ser 904 are reported to be primarily responsible for the establishment of inhibitory capacity of the PARP-1 inhibitors. ...
... 32,49 Previous in-silico study of the catalytic domain of PARP-1 has revealed that hydrogen bond formation between residues Gly 863, Arg 878 and Ser 904 and the ligand is necessary for binding pocket stability. 49,50 Speci¯cally, the residues Gly 863 and Ser 904 are reported to be primarily responsible for the establishment of inhibitory capacity of the PARP-1 inhibitors. 49 Most synthetic PARP-1 inhibitors compete with NAD þ to bind the catalytic domain and tend to block di®erent enzymatic pathways which involve NAD þ . ...
... 49,50 Speci¯cally, the residues Gly 863 and Ser 904 are reported to be primarily responsible for the establishment of inhibitory capacity of the PARP-1 inhibitors. 49 Most synthetic PARP-1 inhibitors compete with NAD þ to bind the catalytic domain and tend to block di®erent enzymatic pathways which involve NAD þ . 51 Also, high toxicity and other side e®ects associated with synthetic PARP-1 inhibitors necessitate the development of novel PARP-1 inhibitors. ...
Poly (ADP-ribose) polymerase-1 (PARP-1) reverses DNA damage by repairing DNA nicks and breaks in the normal cellular environment. However, during abnormal conditions like stroke and other neurological disorders, overactivation of PARP-1 leads to neuronal cell death via a caspase-independent programmed cell death pathway. Strategies involving inhibition or knockout of PARP-1 have proved beneficial in combating neuro-cytotoxicity. In this study, we performed in-silico analysis of 27 phytochemicals of Withania somnifera (Ashwagandha), to investigate their inhibition efficiency against PARP-1. Out of 27 phytochemicals, we report 12 phytochemicals binding to the catalytic domain of PARP-1 with an affinity higher than FR257517, PJ34 and Talazoparib (highly potent inhibitors of the enzyme). Among these 12 compounds, five phytochemicals namely Stigmasterol, Withacnistin, Withaferin A, Withanolide G and Withanolide B show an exceptionally high binding affinity for the catalytic domain of PARP-1 and bind to the enzyme with similar hydrogen bond formation and hydrophobic interaction pattern as their inhibitors. All of these phytochemicals are BBB permeable so that they can be further developed into potential future neuro-therapeutic drugs against neurodegenerative disorders involving neuronal cell death.
... Many in silico and in vitro investigations were performed on the PARP enzymes in recent years in order to shed light on inhibition mechanism of these receptors as well as to discover the novel high potent PARP inhibitors (Halder, Saha, Saha, & Jha, 2015). In our previous study, we focused on the PARP- 1 enzyme using combined theoretical approaches in order to better understand the molecular mechanism of actions of PARP inhibitors (Salmas, Unlu, Yurtsever, Noskov, & Durdagi, 2015). Hannigan et al. used a ligand database and they screened these compounds in silico at the binding pocket of PARP-1 enzyme. ...
Poly(ADP-ribose) polymerase-1 (PARP-1) enzyme has critical roles in DNA replication repair and recombination. Thus, PARP-1 inhibitors play an important role in the cancer therapy. In the current study we have performed combination of in silico and in vitro studies in order to discover novel inhibitors against PARP-1 target. Structure-based virtual screening was carried out for an available small molecules database. 257951 ligands from Otava database were screened at the binding pocket of PARP-1 using high throughput virtual screening (HTVS) techniques. Filtered structures based on predicted binding energy results were then used in more sophisticated molecular docking simulations (i.e., Glide/SP, Glide/XP, Induced Fit Docking- IFD, and Quantum Mechanics Polarized Ligand Docking- QPLD). Potential high binding affinity compounds that are predicted by molecular simulations were then tested by in vitro methods. Computationally proposed compounds as PARP-1 inhibitors (Otava Compound Codes: 7111620047 and 7119980926) were confirmed by in vitro studies. In vitro results showed that compounds 7111620047 and 7119980926 have IC50 values of 0.56 µM and 63 µM against PARP-1 target, respectively. The molecular mechanism analysis, Free Energy Perturbation calculations using long multiple molecular dynamics (MD) simulations for the discovered compounds which showed high binding affinity against PARP-1 enzyme, as well as structure-based pharmacophore development (E-pharmacophore) studies were also studied.
