Journal of Biomolecular Structure & Dynamics最新文献

The re-emergence of the monkeypox virus (MPXV) in 2022 has become a global issue. The virus was first found in Denmark in 1958. The first human MPXV disease was reported in 1980 in Congo, caused by a rare zoonotic virus belonging to the genus Orthopoxvirus and the family Poxviridae. Like SARS-CoV, there are no specific drugs to treat this infection. Taking cues from the successful implementation of drug repositioning for the Covid-19 pandemic using in silico drug discovery. We employed structure-based drug design in the study to repurpose the existing drug and natural product derivatives libraries against MPXV. The E8 protein was chosen as a therapeutic target because it is a surface membrane protein involved in viral entry and adhesion to the host cell surface membrane. Our study was bifurcated into the following steps; determining and analyzing the structure of the E8, followed by structure-based virtual screening of different datasets (natural products obtained from bacteria and fungi and FDA-approved drugs) to identify the hits. Based on the best binding affinities and protein-ligand interactions, we further proceeded for molecular dynamic (MD) studies of the identified hits, which revealed Gabosine D (docking score = -8.469 kcal/mol, MM/GBSA dG bind = -41.6729 kcal/mol) and Edoxudine (docking score = -6.372 kcal/mol, MM/GBSA dG bind = -35.8291 kcal/mol) as the best lead molecules. MD simulation for 100 ns was performed in triplicate, and post MM/GBSA analysis was conducted, which proves the stability of the identified leads. In addition, their ADME profiles also confirmed their suitability as therapeutic options for the treatment of monkeypox.Communicated by Ramaswamy H. Sarma.

Thymidylate synthase (TS) is a crucial target of cancer drug discovery and is mainly involved in the De novo synthesis of the DNA precursor thymine. In the present study, to generate reliable models and identify a few promising molecules, we combined QSAR modelling with the pharmacophore hypothesis-generating technique. Input molecules were clustered on their similarity, and a cluster of 74 molecules with a pyrimidine moiety was chosen as the set for 3D-QSAR and pharmacophore modelling. Atom-based and field-based 3D-QSAR models were generated and statistically validated with R² > 0.90 and Q² > 0.75. The common pharmacophore hypothesis(CPH) generation identified the best six-point model ADHRRR. Using these best models, a library of FDA-approved drugs was screened for activity and filtered via molecular docking, ADME profiling, and molecular dynamics simulations. The top ten promising TS-inhibiting candidates were identified, and their chemical features profitable for TS inhibitors were explored.Communicated by Ramaswamy H. Sarma.

In this work, a new Cu(II)-based complex as a chemotherapeutic drug agent, formulated as[Cu(DCA)₄(H₂O)₂]⋅4H₂O⋅4MeOH, (DCA = 3,4-dimethoxycinnamic acid), namely 1 was successfully synthesized utilizing DCA as a ligand to arrest fibrillation in Human lysozyme. The 1 was thoroughly characterized by single crystal X-ray diffraction (SC-XRD), spectroscopic (UV-Vis and FTIR) techniques, PXRD, and TGA analysis. Its crystal structure reveals a paddle wheel network around central copper metal ions. The Cu(II) metal ions exhibit a distorted square pyramidal configuration. The fluorescence titration studies showed moderate binding interaction of 1 with HuL with Ka of 6.3x10⁵ M^-1 at pH-2, 25 °C due to its interaction withAsp53, Tyr63, Val110, and Ala111 as shown by docking and simulation studies. 1suppresses the HuL fibrillation in a concentration-dependent manner, as demonstrated by ThT assay. At 200 µM concentration, it leads to the formation of smaller species of the protein in comparison to the control sample, as suggested by Light Scattering studies. The species formed are less hydrophobic and retain their native α-helix structure compared to the control samples, which are hydrophobic and form β-sheet rich amyloids as shown by ANS hydrophobicity assay and CD spectroscopy, respectively. Furthermore, morphological analysis of the species by AFM has demonstrated that, unlike mature amyloid fibrils in the control sample, HuL forms small-size aggregates in the presence of 1 under similar fibrillation conditions. It can be concluded that 1 effectively suppresses HuL fibrillation due to moderate binding to the protein.Communicated by Ramaswamy H. Sarma.

HDAC3 is an emerging target for the identification and discovery of novel drug candidates against several disease conditions including cancer. Here, a fragment-based non-linear machine learning (ML) method along with chemical space exploration followed by a structure-based binding mode of interaction analysis study was carried out on some HDAC3 inhibitors to obtain the key structural features modulating HDAC3 inhibition. Both the ML and chemical space analysis identified several physicochemical and structural properties namely lipophilicity, polar and relative polar surface area, arylcarboxamide moiety, bulky fused aromatic group, n-alkyl, and cinnamoyl moieties, the higher number of oxygen atoms, π-electrons for the substituted tetrahydrofuronaphthodioxolone moiety favorable for higher HDAC3 inhibition. Moreover, hydrogen bond forming capabilities, the length and substitution position of the linker moiety, the importance of phenyl ring in the linker motif, the contribution of heterocyclic cap moieties for effective inhibitor binding at the HDAC3 catalytic site that correspondingly affects the HDAC3 inhibitory potency. Again, macrocyclic ring structure and cyclohexyl cap moiety are responsible for lower HDAC3 inhibition. The MD simulation study of selected compounds explained strong binding patterns at the HDAC3 active site as evidenced by the lower RMSD and RMSF values. Nevertheless, it also explained the importance of the crucial structural fragments derived from the fragment-based analysis during ligand-enzyme interactions. Therefore, the outcomes of this current structural analysis will be a useful tool for fragment-based drug discovery of effective HDAC3 inhibitors for clinical therapeutics in the future.Communicated by Ramaswamy H. Sarma.

Despite the recent advances in drug research, finding a safe, effective, and easy to use chemotherapy for human African trypanosomiasis (HAT) remains a challenging task. Trypanosomatids have developed resistance mechanisms towards melarsoprol (the current drug of choice), and the fact that it is poisonous is problematic. Therefore, a search for alternative therapeutics against the parasite is urgently needed. Natural products offer potential for drug discovery, but little or nothing is known about the target of inhibition or possible mode of inhibition. Therefore, this study aimed to use molecular docking and molecular dynamics simulations to evaluate 30 antitrypanosomal natural products as potential inhibitors of trypanothione reductase, a key protein necessary for the survival of the Trypanosoma brucei. The study also assessed the pharmacokinetic properties of the most promising compounds. Of the compounds evaluated, α-bisabolol, letestuianin C, waltherione, and mexicanin E were found to bind at the active site of TR and interact with Met115, Tyr112, and Trp23, which are essential for enzyme functioning. Molecular dynamic simulations revealed the sustained binding of α-bisabolol and letestuianin C throughout the simulation period, potentially obstructing the binding of the substrate (T[S]₂) and impeding catalysis. The binding of these compounds to TR led to the presence of solvent molecules in the enzyme's active site, and this could potentially lead to protein aggregation. Furthermore, α-bisabolol and letestuianin C exhibited promising safety profiles. Consequently, α-bisabolol and letestuianin C have been shown to be viable candidates for targeting trypanothione reductase in the fight against human African trypanosomiasis.Communicated by Ramaswamy H. Sarma.

Alzheimer's disease (AD) is among the highly prevalent neurodegenerative disorder of the aging brain and is allied with cognitive and behavioral abnormalities. Unfortunately, there is very limited drug discovery for the effective management of AD, and the clinically approved drugs have limited efficacy. Consequently, there is an immediate demand for the development of new compounds that have the ability to act as multitarget-directed ligands (MTDLs). As major pathological targets of the disease, the current study aimed to investigate lead natural bioactive compounds including apigenin, epigallocatechin-3-gallate, berberine, curcumin, genistein, luteolin, quercetin, resveratrol for their inhibitory potentials against β-amyloid cleaving enzyme-1 (BACE1) and monoamine oxidase-B (MAO-B) enzymes. The study compounds were docked against the target enzymes (MAO-B and BACE1) using MOE software and subsequent molecular dynamics simulations (MDS) studies. The molecular docking analysis revealed that these phytochemicals (MTDLs) showed good interactions with the target enzymes as compared to the reference inhibitors. Among these eight phytocompounds, the epigallocatechin-3-gallate compound was an active inhibitor against both drug targets, with the highest docking scores and good interactions with the active residues of the enzymes. Furthermore, the docking result of the active one inhibitor in complex with the target enzymes (epigallocatechin-3-gallate/BACE1, epigallocatechin-3-gallate/MAO-B, reference/BACE1 and reference/MAO-B) were further validated by MDS. According to the findings of our study, epigallocatechin-3-gallate has the potential to be a candidate for use in the treatment of neurological illnesses like AD. This compound has MTDL potential and may be exploited to create new compounds with disease-modifying features.Communicated by Ramaswamy H. Sarma.

The human gastric pathogen Helicobacter pylori chronically affects the gastric mucosal layer of approximately half of world's population. The emergence of resistant strains urges the need for identification of novel and selective drug against new molecular targets. A ubiquitous enzyme, Deoxyuridine 5'-triphosphate nucleotidohydrolase (dUTPase), is considered as first line of defense against uracil mis-incorporation into DNA, and essential for genome integrity. Lack of dUTPase triggers an elevated recombination frequency, DNA breaks and ultimately cell death. Hence, dUTPase can be considered as a promising target for development of novel lead inhibitor compounds in H. pylori treatment. Herein, we report the generation of three-dimensional model of the target protein using comparative modelling and its validation. To identify dUTPase inhibitors, a high throughput virtual screening approach utilizing Knowledge-based inhibitors and DrugBank database was implemented. Top ranked compounds were scrutinized based on investigations of the protein-ligand interaction fingerprints, molecular interaction maps and binding affinities and the drug potentiality. The best ligands were studied further for complex stability and intermolecular interaction profiling with respect to time under 100 ns classical molecular dynamic stimulation, establishing significant stability in dynamic states as observed from RMSD and RMSF parameters and interactions with the catalytic site residues. The binding free energy calculation computed using MM-GBSA method from the MD simulation trajectories demonstrated that our molecules possess strong binding affinity towards the Helicobacter pylori dUTPase protein. We conclude that our proposed molecules may be potential lead molecules for effective inhibition against the H. pylori dUTPase protein subject to experimental validation.Communicated by Ramaswamy H. Sarma.

Prolyl specific oligopeptidase (POP), is one of the highly expressed enzymes in the brain and is a prime target to treat disorders related to the central nervous system. Here, we describe the structure-based design of the tacrine derivatives, selective, and brain-permeable POP inhibitors. These compounds inactivate POP in-vitro specifically and sustainably at very low concentrations (nano molar). Among this series, compound 6b (IC₅₀ = 0.81 ± 0.04 µM) exhibited most potent inhibition. Furthermore, kinetic study revealed that these molecules target active site of POP which is further confirmed by in-silico molecular interaction analysis. The computational docking results indicates that the compounds are well fitted in the active site with high binding score (i.e., > -7 to > -4 kcal/mol) where Trp595, Arg643, Tyr473, and Ser554 plays important role in binding with the active compounds. The molecular dynamic simulation of most active compounds (6a, 6b, 6d, and 6f) displayed higher free energy binding, when compared to the standard drug in MM-PBSA based binding free energy calculation. In addition, the predicted pharmacokinetic profile suggests that these compounds can serve as excellent inhibitors upon additional optimization which makes them prime choice for further investigation.Communicated by Ramaswamy H. Sarma.

Elevated levels of alkaline phosphatase (ALP) in the tumor microenvironment (TME) are a hallmark of cancer progression and thus inhibition of ALP could serve as an effective approach against cancer. Herein, we developed a novel prodrug approach to tackle cancer that bears self-inhibiting alkaline phosphatase-responsiveness properties that can enhance at the same time the solubility of the parent compound. To probe this novel concept, we selected apigenin as the cytotoxic agent since we first unveiled, that it directly interacts and inhibits ALP activity. Consequently, we rationally designed and synthesized, using a self-immolative linker, an ALP responsive apigenin-based phosphate prodrug, phospho-apigenin. Phospho-apigenin markedly increased the stability of the parent compound apigenin. Furthermore, the prodrug exhibited enhanced antiproliferative effect in malignant cells with elevated ALP levels, compared to apigenin. This recorded potency of the developed prodrug was further confirmed in vivo where phospho-apigenin significantly suppressed by 52.8% the growth of PC-3 xenograft tumors.Communicated by Ramaswamy H. Sarma.

The β-lactamase of Pseudomonas aeruginosa is known to degrade β-lactam antibiotics such as penicillins, cephalosporins, monobactams, and carbapenems. With the discovery of an extended-spectrum β-lactamase in a clinical isolate of P. aeruginosa, the bacterium has become multi-drug resistant. In this study, we aim to identify new β-lactamase inhibitors by virtually screening a total of 43 phytocompounds from two Indian medicinal plants. In the molecular docking studies, pinocembrin-7-O-β-D-glucopyranoside (P7G) (-9.6 kcal/mol) from Acacia pennata and ellagic acid (EA) (-9.2 kcal/mol) from Bridelia retusa had lower binding energy than moxalactam (-8.4 kcal/mol). P7G and EA formed 5 (Ser62, Asn125, Asn163, Thr209, and Ser230) and 4 (Lys65, Ser123, Asn125, and Glu159) conventional hydrogens bonds with the active site residues. 100 ns MD simulations revealed that moxalactam and P7G (but not EA) were able to form a stable complex. The binding free energy calculations further revealed that P7G (-59.6526 kcal/mol) formed the most stable complex with β-lactamase when compared to moxalactam (-46.5669 kcal/mol) and EA (-28.4505 kcal/mol). The HOMO-LUMO and other DFT parameters support the stability and chemical reactivity of P7G at the active site of β-lactamase. P7G passed all the toxicity tests and bioavailability tests indicating that it possesses drug-likeness. Among the studied compounds, we identified P7G of A. pennata as the most promising phytocompound to combat antibiotic resistance by potentially inhibiting the β-lactamase of P. aeruginosa.Communicated by Ramaswamy H. Sarma.