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1.
Pharmaceuticals (Basel) ; 14(11)2021 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-34832930

RESUMO

To develop new potent and highly selective MAO-B inhibitors from chalcone-thioethers, eleven chalcones-thioethers were synthesized and their monoamine oxidase (MAO) inhibition, kinetics, reversibility, and cytotoxicity of lead compounds were analyzed. Molecular dynamics were carried out to investigate the interactions. Compound TM8 showed potent inhibitory activity against MAO-B, with an IC50 value of 0.010 µM, followed by TM1, TM2, TM7, and TM10 (IC50 = 0.017, 0.021, 0.023, and 0.026 µM, respectively). Interestingly, TM8 had an extremely high selectivity index (SI; 4860) for MAO-B. Reversibility and kinetic experiments showed that TM8 and TM1 were reversible and competitive inhibitors of MAO-B with Ki values of 0.0031 ± 0.0013 and 0.011± 0.001 µM, respectively. Both TM1 and TM8 were non-toxic to Vero cells with IC50 values of 241.8 and 116.3 µg/mL (i.e., 947.7 and 402.4 µM), respectively, and at these IC50 values, both significantly reduced reactive oxygen species (ROS) levels. TM1 and TM8 showed high blood-brain barrier permeabilities in the parallel artificial membrane permeability assay. Molecular dynamics studies were conducted to investigate interactions between TM1 and TM8 and the active site of MAO-B. Conclusively, TM8 and TM1 are potent and highly selective MAO-B inhibitors with little toxicity and good ROS scavenging abilities and it is suggested that both are attractive prospective candidates for the treatment of neurological disorders.

2.
Chem Biodivers ; : e2100519, 2021 Nov 02.
Artigo em Inglês | MEDLINE | ID: mdl-34729902

RESUMO

Though multifactorial, BET and PLK1 proteins have been found to be key players in the oncogenic process leading to castration-resistant prostate cancer through regulation of AR and MYC-mediated transcription. Hence, dual inhibition of these proteins appears to be an auspicious approach for CRPC therapy. WNY0824 has been reported to exhibit nanomolar range inhibition as well as significant anti-proliferative activity on AR-positive CRPC cells in vitro. However, structural, and mechanistic events associated with its dual inhibitory and anti-proliferative mechanisms remain unclear. Utilizing integrative computer-assisted atomistic techniques, analyses revealed that the dual-inhibitory activity of WNY0824 against BRD4 and PLK1 proteins is mediated by conserved residues present in the binding cavities of both proteins which are shown to elicit various strong intermolecular interactions and thus favour binding affinity. Also, binding orientation of the ligand at the protein binding cavities allowed for important hydrophobic interactions which resulted in high binding free energy of -42.50 kcal/mol and -51.64 kcal/mol towards BRD4 and PLK1, respectively. While van der Waals interactions are very important to ligand binding in BRD4-WNY complex, electrostatic interactions are pertinent to PLK1-WNY complex. Intriguingly, WNY0824 triggered conformational alterations in both proteins through increased structural instability, decreased structural compactness and mitigation in exposure of residues to solvent surface area. Consequently, critical interactions peculiar to the oncogenic activities of BRD4 and PLK1 were inhibited, a phenomenon that results in an antagonism of CRPC progression. The mechanistic insights presented in this report would further assist in the structure-based design of improved inhibitors useful in CRPC therapy.

3.
ACS Omega ; 6(39): 25476-25485, 2021 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-34632205

RESUMO

A quantum chemical study was accomplished on the σ-hole interactions of the barely explored group IV elements, for the first time, in the absence and presence of the positively and negatively directed external electric field (EEF). The analyses of molecular electrostatic potential addressed the occurrence of the σ-hole on all the inspected tetrel atoms, confirming their salient versatility to engage in σ-hole interactions. MP2 energetic findings disclosed the occurrence of favorable σ-hole interactions within the tetrel bonding complexes. The tetrel bonding interactions became stronger in the order of C < Si < Ge < Sn for F-T-F3···FH complexes with the largest interaction energy amounting to -19.43 kcal/mol for the optimized F-Sn-F3···FH complex under the influence of +0.020 au EEF. The interaction energy conspicuously evolved by boosting the magnitude of the positively directed EEF value and declining the negatively directed EEF one. The decomposition analysis for the interaction energies was also executed in terms of symmetry-adapted perturbation theory, illuminating the dominant electrostatic contribution to all the studied complexes' interactions except carbon-based interactions controlled by dispersion forces. The outcomes that emerged from the current work reported significantly how the direction and strength of the EEF affect the tetrel-bonding interactions, leading to further improvements in the forthcoming studies of supramolecular chemistry and materials science.

4.
Comput Biol Chem ; 95: 107592, 2021 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-34710811

RESUMO

Cross-target effect has been one of the major mechanisms of drug toxicity, this has necessitated the design of inhibitors that are specifically tailored to target particular biomolecules. 6-(2,4-difluorophenoxy)-5-((ethylmethyl)pyridine-3-yl)-8-methylpyrrolo[1,2-a] pyrazin-1(2H)-one (Cpd38) is an inhibitor possessing high inhibition rate and tailored specificity towards bromodomain-containing protein 4 (BRD4). In this research, we used an array of computational techniques to provide insight at the atomistic level the specific targeting of BRD4 by Cpd38 relative to the binding of Cpd38 with E1A binding protein P300 (EP300); another bromodomain-containing protein (BCP). Comparatively, binding of Cpd38 improved the conformational stability and compactness of BRD4 protein when compared to the Cpd38 bound EP300. Also, Cpd38 induced a conformational change in the active site of BRD4 that facilitated a complementary pose between Cpd38 and BRD4 suitable for effective atomistic interactions. Expectedly, thermodynamic calculations revealed that the Cpd38-BRD4 system had higher binding energy (-36.11 Kcal/mol) than the Cpd38-EP300 system with a free binding energy of -15.86 Kcal/mol. Noteworthy is the opposing role Trp81 (acting as hydrogen bond acceptor) and Pro1074 (acting as hydrogen bond donor) found on the WPF and LPF loops respectively play in maintaining Cpd38 stability. Furthermore, the hydrogen bond acceptor/donator ratio was approximately 4:1 in Cpd38-BRD4 system compared with 2:1 in Cpd38-EP300 system. Taken together, atomistic insights and structural perspectives detailed in this report supplements the experimental report supporting the improved selectivity of Cpd38 for BRD4 ahead of other BCPs while providing leeway for the future design of BET selective agents with better pharmacological profile.

5.
J Biomol Struct Dyn ; : 1-12, 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34569417

RESUMO

C-C chemokine receptor 5 (CCR5), which is part of the chemokine receptor family, is a member of the G protein-coupled receptor superfamily. The interactions of CCR5 with HIV-1 during viral entry position it as an effective therapeutic target for designing potent antiviral therapies. The small-molecule Maraviroc was approved by the FDA as a CCR5 drug in 2007, while clinical trials failure has characterised many of the other CCR5 inhibitors. Thus, the continual identification of potential CCR5 inhibitors is, therefore, warranted. In this study, a structure-based discovery approach has been utilised to screen and retrieved novel potential CCR5 inhibitors from the Asinex antiviral compound (∼ 8,722) database. Explicit lipid-bilayer molecular dynamics simulation, in silico physicochemical and pharmacokinetic analyses, were further performed for the top compounds. A total of 23 structurally diverse compounds with binding scores higher than Maraviroc were selected. Subsequent molecular dynamics (MD) simulations analysis of the top four compounds LAS 51495192, BDB 26405401, BDB 26419079, and LAS 34154543, maintained stability at the CCR5 binding site. Furthermore, these compounds made pertinent interactions with CCR5 residues critical for the HIV-1 gp120-V3 loop binding such as Trp86, Tyr89, Phe109, Tyr108, Glu283 and Tyr251. Additionally, the predicted in silico physicochemical and pharmacokinetic descriptors of the selected compounds were within the acceptable range for drug-likeness. The results suggest positive indications that the identified molecules may represent promising CCR5 entry inhibitors. Further structural optimisations and biochemical testing of the proposed compounds may assist in the discovery of effective HIV-1 therapy.Communicated by Ramaswamy H. Sarma.

6.
Biomed J ; 44(4): 447-460, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34489196

RESUMO

BACKGROUND: The increase in global mortality rates from SARS-COV2 (COVID-19) infection has been alarming thereby necessitating the continual search for viable therapeutic interventions. Due to minimal microbial components, subunit (peptide-based) vaccines have demonstrated improved efficacies in stimulating immunogenic responses by host B- and T-cells. METHODS: Integrative immunoinformatics algorithms were used to determine linear and discontinuous B-cell epitopes from the S-glycoprotein sequence. End-point selection of the most potential B-cell epitope was based on highly essential physicochemical attributes. NetCTL-I and NetMHC-II algorithms were used to predict probable MHC-I and II T-cell epitopes for globally frequent HLA-A∗O2:01, HLA-B∗35:01, HLA-B∗51:01 and HLA-DRB1∗15:02 molecules. Highly probable T-cell epitopes were selected based on their high propensities for C-terminal cleavage, transport protein (TAP) processing and MHC-I/II binding. RESULTS: Preferential epitope binding sites were further identified on the HLA molecules using a blind peptide-docking method. Phylogenetic analysis revealed close relativity between SARS-CoV-2 and SARS-CoV S-protein. LALHRSYLTPGDSSSGWTAGAA242→263 was the most probable B-cell epitope with optimal physicochemical attributes. MHC-I antigenic presentation pathway was highly favourable for YLQPRTFLL269-277 (HLA-A∗02:01), LPPAYTNSF24-32 (HLA-B∗35:01) and IPTNFTISV714-721 (HLA-B∗51:01). Also, LTDEMIAQYTSALLA865-881 exhibited the highest binding affinity to HLA-DR B1∗15:01 with core interactions mediated by IAQYTSALL870-878. COVID-19 YLQPRTFLL269-277 was preferentially bound to a previously undefined site on HLA-A∗02:01 suggestive of a novel site for MHC-I-mediated T-cell stimulation. CONCLUSION: This study implemented combinatorial immunoinformatics methods to model B- and T-cell epitopes with high potentials to trigger immunogenic responses to the S protein of SARS-CoV-2.


Assuntos
COVID-19 , Epitopos de Linfócito T , Linfócitos B , Humanos , Filogenia , RNA Viral , SARS-CoV-2 , Vacinas de Subunidades , Virulência
7.
Protein J ; 40(5): 601-655, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34590194

RESUMO

Amongst the several types of brain cancers known to humankind, glioma is one of the most severe and life-threatening types of cancer, comprising 40% of all primary brain tumors. Recent reports have shown the incident rate of gliomas to be 6 per 100,000 individuals per year globally. Despite the various therapeutics used in the treatment of glioma, patient survival rate remains at a median of 15 months after undergoing first-line treatment including surgery, radiation, and chemotherapy with Temozolomide. As such, the discovery of newer and more effective therapeutic agents is imperative for patient survival rate. The advent of computer-aided drug design in the development of drug discovery has emerged as a powerful means to ascertain potential hit compounds with distinctively high therapeutic effectiveness against glioma. This review encompasses the recent advances of bio-computational in-silico modeling that have elicited the discovery of small molecule inhibitors and/or drugs against various therapeutic targets in glioma. The relevant information provided in this report will assist researchers, especially in the drug design domains, to develop more effective therapeutics against this global disease.

8.
ACS Omega ; 6(29): 19330-19341, 2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34337270

RESUMO

The versatility of the X-T-X3 compounds (where T = C, Si, and Ge, and X = F, Cl, and Br) to participate in tetrel- and halogen-bonding interactions was settled out, at the MP2/aug-cc-pVTZ level of theory, within a series of configurations for (X-T-X3)2 homodimers. The electrostatic potential computations ensured the remarkable ability of the investigated X-T-X3 monomers to participate in σ-hole halogen and tetrel interactions. The energetic findings significantly unveil the favorability of the tetrel···tetrel directional configuration with considerable negative binding energies over tetrel···halogen, type III halogen···halogen, and type II halogen···halogen analogs. Quantum theory of atoms in molecules and noncovalent interaction analyses were accomplished to disclose the nature of the tetrel- and halogen-bonding interactions within designed configurations, giving good correlations between the total electron densities and binding energies. Further insight into the binding energy physical meanings was invoked through using symmetry-adapted perturbation theory-based energy decomposition analysis, featuring the dispersion term as the most prominent force beyond the examined interactions. The theoretical results were supported by versatile crystal structures which were characterized by the same type of interactions. Presumably, the obtained findings would be considered as a solid underpinning for future supramolecular chemistry, materials science, and crystal engineering studies, as well as a fundamental linchpin for a better understanding of the biological activities of chemicals.

9.
Cell Biochem Biophys ; 2021 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-34453681

RESUMO

In recent years, tankyrase inhibition has gained a great focus as an anti-cancer strategy due to their modulatory effect on WNT/ß-catenin pathway implicated in many malignancies, including colorectal cancer (CRC) and non-small cell lung cancer (NSCLC). Based on the structural homology in the catalytic domain of PARP enzymes, bis-quinazolinone 5 (Cpd 5) was designed to be a potent selective tankyrase inhibitor. In this study, we employed molecular dynamics simulations and binding energy analysis to decipher the underlying mechanism of TNK-1 inhibition by Cpd 5 in comparison with a known selective tankyrase, IWR-1. The Cpd 5 had a relatively higher ΔGbind than IWR-1 from the thermodynamics analysis, revealing the better inhibitory activity of Cpd 5 compared to IWR-1. High involvement of solvation energy (ΔGsol) and the van der Waals energy (ΔEvdW) potentiated the affinity of Cpd 5 at TNK-1 active site. Interestingly, the keto group and the N3 atom of the quinazolinone nucleus of Cpd 5, occupying the NAM subsite, was able to form H-bond with Gly1185, thereby favoring the better stability and higher inhibitory efficacy of Cpd 5 relative to IWR-1. Our analysis proved that the firm binding of Cpd 5 was achieved by the quinazolinone groups via the hydrophobic interactions with the side chains of key site residues at the two subsite regions: His1201, Phe1188, Ala1191, and Ile1192 at the AD subsite and Tyr1224, Tyr1213, and Ala1215 at the NAM subsite. Thus, Cpd 5 is dominantly bound through π-π stacked interactions and other hydrophobic interactions. We believe that findings from this study would provide an important rationale towards the structure-based design of improved selective tankyrase inhibitors in cancer therapy.

10.
Antibiotics (Basel) ; 10(8)2021 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-34438984

RESUMO

Penicillin-binding proteins (PBPs) catalyze the final stages for peptidoglycan cell-wall bio-synthesis. Mutations in the PBP2a subunit can attenuate ß-lactam antibiotic activity, resulting in unimpeded cell-wall formation and methicillin-resistant Staphylococcus aureus (MRSA). A double mutation in PBP2a (i.e., N146K and E150K) is resistant to ß-lactam inhibitors; however, (E)-3-(2-(4-cyanostyryl)-4-oxoquinazolin-3(4H)-yl) benzoic acid (QNZ), a heterocyclic antibiotic devoid of a ß-lactam ring, interacts non-covalently with PBP2a allosteric site and inhibits PBP enzymatic activity. In the search for novel inhibitors that target this PBP2a allosteric site in acidic medium, an in silico screening was performed. Chemical databases including eMolecules, ChEMBL, and ChEBI were virtually screened for candidate inhibitors with a physicochemical similarity to QNZ. PBP2a binding affinities from the screening were calculated based on molecular docking with co-crystallized ligand QNZ serving as a reference. Molecular minimization calculations were performed for inhibitors with docking scores lower than QNZ (calc. -8.3 kcal/mol) followed by combined MD simulations and MM-GBSA binding energy calculations. Compounds eMol26313223 and eMol26314565 exhibited promising inhibitor activities based on binding affinities (ΔGbinding) that were twice that of QNZ (-38.5, -34.5, and -15.4 kcal/mol, respectively). Structural and energetic analyses over a 50 ns MD simulation revealed high stability for the inhibitors when complexed with the double mutated PBP2a. The pharmacokinetic properties of the two inhibitors were predicted using an in silico ADMET analysis. Calculated binding affinities hold promise for eMol26313223 and eMol26314565 as allosteric inhibitors of PBP2a in acidic medium and establish that further in vitro and in vivo inhibition experimentation is warranted.

11.
J Biomol Struct Dyn ; : 1-9, 2021 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-34463214

RESUMO

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.

12.
J Mol Model ; 27(8): 231, 2021 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-34312718

RESUMO

The Retinoid X Receptor (RXR) is an attractive target in the treatment of colon cancer. Different therapeutic binders with high potency have been used to specifically target RXR. Among these compounds is a novel analogue of berberine, B12. We provided structural and molecular insights into the therapeutic activity properties of B12 relative to its parent compound, berberine, using force field estimations and thermodynamic calculations. Upon binding of B12 to RXR, the high instability elicited by RXR was markedly reduced; similar observation was seen in the berberine-bound RXR. However, our analysis revealed that B12 could have a more stabilizing effect on RXR when compared to berberine. Interestingly, the mechanistic behaviour of B12 in the active site of RXR opposed its impact on RXR protein. This disparity could be due to the bond formation and breaking elicited between B12/berberine and the active site residues. We observed that B12 and berberine could induce a disparate conformational change in regions Gly250-Asp258 located on the His-RXRα/LBD domain. Comparatively, the high agonistic and activation potential reported for B12 compared to berberine might be due to its superior binding affinity as evidenced in the thermodynamic estimations. The total affinity for B12 (-25.76 kcal/mol) was contributed by electrostatic interactions from Glu243 and Glu239. Also, Arg371, which plays a crucial role in the activity of RXR, formed a strong hydrogen bond with B12; however, a weak interaction was elicited between Arg371 and berberine. Taken together, our study has shown the RXRα activating potential of B12, and findings from this study could provide a framework in the future design of RXRα binders specifically tailored in the selective treatment of colon cancer.

13.
Chem Biodivers ; 18(9): e2100204, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34252268

RESUMO

Parkinson's disease (PD) is one of the most targeted neurodegenerative diseases in clinical research. Awareness of research is due to its increasing number of affected people worldwide. The pathology of PD has been linked to several key proteins upregulation such as the catechol O-Methyltransferase (COMT). Hence, the synthesis of compounds possessing inhibitory capacity has been the frontline of research in recent years. Several compounds have been synthesized among which is the nitrocatechol. However, major limitations associated with the nitrocatechol scaffold include the inability to possess adequate CNS penetration properties and hepatic toxicity associated with the compounds. However, a series of bicyclic hydroxypyridones compounds were synthesized to evaluate their inhibitory potentials on COMT protein with compound 38 (c38) 2-[(2,4-dichlorophenyl)methyl]-7-hydroxy-1,2,3,4-tetrahydro-8H-pyrido[1,2-a]pyrazin-8-one shown to have a 40 fold increase level coverage in its IC50 over brain exposure when compared to the other synthesized compound. The molecular dynamics method was employed to understand the nature of interaction exhibited by c38. Molecular mechanics of c38 revealed a disruptive effect on the secondary structure of COMT protein. Per residue decomposition analysis revealed similar crucial residues involved in the favorable binding of c38 and tolcapone implicated its increased inhibitory capacity on COMT in preventing PD. Free binding energy (ΔGbind ) of c38 further revealed the inhibitory capacity towards COMT protein in comparison to the FDA approved tolcapone. Ligand mobility analysis of both compounds showed a timewise different mobility pattern across the simulation time frame at the active site pocket of the protein connoting the different inhibitory potency exhibited by c38 and tolcapone. Findings from this study revealed optimization of c38 could facilitate the discovery of new compounds with enhanced inhibitory properties towards COMT in treating PD.


Assuntos
Antiparkinsonianos/farmacologia , Inibidores de Catecol O-Metiltransferase/farmacologia , Catecol O-Metiltransferase/metabolismo , Simulação de Dinâmica Molecular , Doença de Parkinson/tratamento farmacológico , Antiparkinsonianos/química , Inibidores de Catecol O-Metiltransferase/química , Humanos , Estrutura Molecular , Doença de Parkinson/metabolismo , Termodinâmica
14.
J Biomol Struct Dyn ; : 1-17, 2021 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-34182889

RESUMO

Due to the unavailability specific drugs or vaccines (FDA approved) that can cure COVID-19, the development of potent antiviral drug candidates/therapeutic molecules against COVID-19 is urgently required. This study was aimed at in silico screening and study of polyphenolic phytochemical compounds in a rational way by virtual screening, molecular docking and molecular dynamics studies against SARS-CoV-2 main protease (Mpro) and papain-like protease (PLpro) enzymes. The objective of the study was to identify plant-derived polyphenolic compounds and/or flavonoid molecules as possible antiviral agents with protease inhibitory potential against SARS-CoV-2. In this study, we report plant-derived polyphenolic compounds (including flavonoids) as novel protease inhibitors against SARS-CoV-2. From virtual docking and molecular docking study, 31 polyphenolic compounds were identified as active antiviral molecules possessing well-defined binding affinity with acceptable ADMET, toxicity and lead-like or drug-like properties. Six polyphenolic compounds, namely, enterodiol, taxifolin, eriodictyol, leucopelargonidin, morin and myricetin were found to exhibit remarkable binding affinities against the proteases with taxifolin and morin exhibiting the highest binding affinity toward Mpro and PLpro respectively. Molecular dynamics simulation studies of these compounds in complex with the proteases showed that the binding of the compounds is characterized by structural perturbations of the proteases suggesting their antiviral activities. These compounds can therefore be investigated further by in vivo and in vitro techniques to assess their potential efficacy against SARS-CoV-2 and thus serve as the starting point for the development of potent antiviral agents against the deadly COVID-19.Communicated by Ramaswamy H. Sarma.

15.
Biomed J ; 44(3): 317-337, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34154948

RESUMO

BACKGROUND: The ongoing search for viable treatment options to curtail Epstein Barr Virus (EBV) pathogenicity has necessitated a paradigmatic shift towards the design of peptide-based vaccines. Potential B-cell and T-cell epitopes were predicted for nine antigenic EBV proteins that mediate epithelial cell-attachment and spread, capsid self-assembly, DNA replication and processivity. METHODS: Predictive algorithms incorporated in the Immune Epitope Database (IEDB) resources were used to determine potential B-cell epitopes based on their physicochemical attributes. These were combined with a string-kernel method and an antigenicity predictive AlgPred tool to enhance accuracy in the end-point selection of highly potential antigenic EBV B-cell epitopes. NetCTL 1.2 algorithms enabled the prediction of probable T-cell epitopes which were structurally modeled and subjected to blind peptide-protein docking with HLA-A*02:01. All-atom molecular dynamics (MD) simulation and Molecular Mechanics Generalized-Born Surface Area methods were used to investigate interaction dynamics and affinities of predicted T-cell peptide-protein complexes. RESULTS: Computational predictions and sequence overlapping analysis yielded 18 linear (continuous) and discontinuous (conformational) subunit epitopes from the antigenic proteins with characteristic surface accessibility, flexibility and antigenicity, and predictive scores above the threshold value (1) set. A novel site was identified on HLA-A*02:01 with preferential affinity binding for modeled BMRF2, BXLF1 and BGLF4 T-cell epitopes. Interaction dynamics and energies were also computed in addition to crucial residues that mediated complex formation and stability. CONCLUSION: This study implemented an integrative meta-analytical approach to model highly probable B-cell and T-cell epitopes as potential peptide-vaccine candidates for the treatment of EBV-related diseases.


Assuntos
Epitopos de Linfócito T , Infecções por Vírus Epstein-Barr , Linfócitos B , Herpesvirus Humano 4 , Humanos , Vacinas de Subunidades
16.
Chem Biodivers ; 2021 May 12.
Artigo em Inglês | MEDLINE | ID: mdl-33982420

RESUMO

Recently, Vorasidenib (AG-881) has been reported as a therapeutic alternative that exerts potent dual inhibitory activity against mIDH1/2 towards the treatment of low-grade glioma. However, structural and dynamic events associated with its dual inhibition mechanism remain unclear. As such, we employ integrative computer-assisted atomistic techniques to provide thorough structural and dynamic insights. Our analysis proved that the dual-targeting ability of AG-881 is mediated by Val255/Val294 within the binding pockets of both mIDH1 and mIDH2 which are shown to elicit a strong intermolecular interaction, thus favoring binding affinity. The structural orientations of AG-881 within the respective hydrophobic pockets allowed favorable interactions with binding site residues which accounted for its high binding free energy of -28.69 kcal/mol and -19.89 kcal/mol towards mIDH1 and mIDH2, respectively. Interestingly, upon binding, AG-881 was found to trigger systemic alterations of mIDH1 and mIDH2 characterized by restricted residue flexibility and a reduction in exposure of residues to the solvent surface area. As a result of these structural alterations, crucial interactions of the mutant enzymes were inhibited, a phenomenon that results in a suppression of the production of oncogenic stimulator 2-HG. Findings therefore provide thorough structural and dynamic insights associated with the dual inhibitory activity of AG-881 towards glioma therapy.

17.
Cell Biochem Biophys ; 79(2): 175-187, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33792836

RESUMO

The recently emerged SARS-like coronavirus (SARS-CoV-2) has continued to spread rapidly among humans with alarming upsurges in global mortality rates. A major key to tackling this virus is to disrupt its RNA replication process as previously reported for Remdesivir (Rem-P3). In this study, we theorize, using computational simulations, novel mechanisms that may underlie the binding of Rem-P3 to SARS-CoV-2 RdRp-NSPs complex; a multimeric assembly that drives viral RNA replication in human hosts. Findings revealed that while ATP-binding stabilized the replicative tripartite, Rem-P3 disintegrated the RdRp-NSP complex, starting with the detachment of the NSP7-NSP8 heterodimer followed by minimal displacement of the second NSP8 subunit (NSP8II). More so, Rem-P3 interacted with a relatively higher affinity (ΔGbind) while inducing high perturbations across the RdRp-NSP domains. D452, T556, V557, S682, and D760 were identified for their crucial roles in stacking the cyano-adenosine and 3,4-dihydroxyoxolan rings of Rem-P3 while its flexible P3 tail extended towards the palm domain blocking D618 and K798; a residue-pair identified for essential roles in RNA replication. However, ATP folded away from D618 indicative of a more coordinated binding favorable for nucleotide polymerization. We believe findings from this study will significantly contribute to the structure-based design of novel disruptors of the SARS-CoV-2 RNA replicative machinery.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Antivirais/farmacologia , COVID-19/tratamento farmacológico , RNA-Polimerase RNA-Dependente de Coronavírus/antagonistas & inibidores , SARS-CoV-2/enzimologia , Monofosfato de Adenosina/farmacologia , Trifosfato de Adenosina/metabolismo , Alanina/farmacologia , COVID-19/metabolismo , RNA-Polimerase RNA-Dependente de Coronavírus/química , RNA-Polimerase RNA-Dependente de Coronavírus/metabolismo , Humanos , Simulação de Dinâmica Molecular , SARS-CoV-2/efeitos dos fármacos , Termodinâmica , Proteínas não Estruturais Virais/química , Proteínas não Estruturais Virais/metabolismo
18.
Protein J ; 40(2): 166-174, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33646477

RESUMO

Upregulation of Heme Oxygenase-1 (HO-1) has been widely implicated in cancer growth and chemoresistance. This explains the numerous drug discovery efforts aimed at mitigating its pro-carcinogenic roles till date. In a recent study, two selective azole-based HO-1 inhibitors (Cpd1 and Cpd2) were synthesized, which exhibited differential inhibitory potencies of ~200µm. Interestingly, variations in the affinities of these compounds were determined by their positioning across specific regions of the HO-1 binding domain, pin-pointing a pharmacological interrelationship that remains unresolved. Therefore, in this study, using molecular dynamics simulations and binding free energy calculations, we investigate how dynamical orientations of these compounds influence their binding affinities at the active HO-1 domain. Findings revealed favorable binding for the bromobenzene and imidazole substituents of Cpd1 at the western and eastern regions of the HO-1 active domain. The constituent hydroxyl group was coordinated by residues Asp140 and Arg136 over the simulation period. On the contrary, stable binding of the bromobenzene and imidazole substituents were negated by the optimal orientations of the benzyl substituent, which extended into the northeastern region. These were supported by the displacement of Asp140 and Arg136, crucial for hydrogen bond formation in Cpd1. Also, we observed that Cpd2 exhibited high deviations indicative of an unstable binding relative to Cpd1. This further supports the presumption that Cpd2 was systematically oriented away from the active HO-1 region, a phenomenon that was due to the optimal motions of the benzyl group at the northeastern regions. The highlight of our findings is that the benzyl substituent in Cpd2 elicited negative effects on HO-1, vis a vis, instability, displacement of crucial residues, and low binding energy when compared to Cpd1. Findings pave the way for future drug discovery efforts related to HO-1 inhibition in cancer therapy.


Assuntos
Antineoplásicos , Inibidores Enzimáticos , Heme Oxigenase-1 , Imidazóis , Antineoplásicos/química , Antineoplásicos/metabolismo , Descoberta de Drogas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/metabolismo , Heme Oxigenase-1/química , Heme Oxigenase-1/metabolismo , Humanos , Imidazóis/química , Imidazóis/metabolismo , Simulação de Dinâmica Molecular , Termodinâmica
19.
Comput Biol Med ; 132: 104301, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33751994

RESUMO

Over the past two decades, covalent inhibitors have gained much interest and are living up to their reputation as a powerful tool in drug discovery. Covalent inhibitors possess several significant advantages, including increased biochemical efficiency, prolonged duration and the ability to target shallow, solvent-exposed substrate-binding domains. One of the enzymes that have been both covalently and non-covalently targeted is the heat shock protein 72 (HSP72). This elevated enzyme expression in cancer cells may be responsible for tumorigenesis and tumor progression by providing chemotherapy resistance. A critical gap remains in the molecular understanding of the structural mechanism's covalent and non-covalent binding to HSP72. In this study, we explore the most optimal binding mechanism in the inhibition of the HSP72. Based on the molecular dynamic analyses, it was evident that the non-covalent complex showed more stability than the covalent complex. The covalent ligand, however, was more able to induce and stabilize the sealed conformation of the HSP72-NBD ATP binding domain throughout the. Also, the non-covalent ligand does not induce any significant conformational change as it remained close to the shape of the unbound complex; and the affinity is only dependent on the multiple hydrogen bonds in contrast to the covalent ligand. This is supported by the secondary structure elements and principal component analysis that was more dominant in the covalently inhibited complex. Covalent bond induced the α-helices sealed conformation of the HSP72-NBD; based on our findings, this will prevent other small molecules from interacting at the ATP binding site domain. Moreover, inhibition of the ATP binding domain can directly affect the ATPs protein folding mechanism of the HSP72 enzyme. The essential dynamic analysis presented in this report compliments the binding mechanism of HSP72, establishing covalent inhibition as the preferred method of inhibiting the HSP72 protein. The findings from this study may assist in the design of more target-specific HSP72 covalent inhibitors exploring the surface-exposed lysine residues.


Assuntos
Simulação de Dinâmica Molecular , Neoplasias , Proteínas de Choque Térmico HSP72/metabolismo , Ligantes , Ligação Proteica , Domínios Proteicos , Estrutura Secundária de Proteína
20.
Artigo em Inglês | MEDLINE | ID: mdl-33749556

RESUMO

BACKGROUND: Fragment-based drug discovery in recent times has been explored in the design of highly potent therapeutics. METHODS: In this study, we explored the inhibitory dynamics of Compound 38 (Cpd38), a newly synthesized Bromodomain-containing protein 4 bromodomain 1 (BRD4-BD1) protein inhibitor derived from the synthetic coupling of Fragment 47 (Fgt47) into ABBV-075 scaffold. Using dynamic simulation methods, we unraveled the augmentative effects of chemical fragmentation on improved BRD4-BD1 inhibition. RESULTS: Findings from this study revealed that although Fgt47 exhibited a considerable ΔGbind, its incorporation into the difluoro-phenoxy pyridine scaffold (Cpd38) notably enhanced the binding affinity. Time-based analyses of interaction dynamics further revealed that the bulkiness of Cpd38 favored its interaction at the BRD4-BD1 active site relative to the fragment. Strikingly, when compared to Fgt47, Cpd38 demonstrated high mobility, which could have enabled it to bind optimally and complementarily with key residues of the active site such as Ile146, Asn140, Cys136, Tyr98, Leu94, Val87, Phe83 and Trp81. DISCUSSION: On the contrary, majority of these interactions were gradually lost in Fgt47 which could further indicate the essence of coupling it with the difluoro-phenoxy pyridine scaffold. Furthermore, Cpd38 had a more altering effect on BRD4-BDI relative to Fgt47 which could also be as a result of its higher inhibitory activity. CONCLUSION: Conclusively, the design of highly potent therapeutics could be facilitated by the incorporation of pharmacologically active small molecule fragments into the scaffold of existing drugs.

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