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Investigating the binding preferences of small molecule inhibitors of human protein arginine methyltransferase 1 using molecular modelling

Hong W, Li J, Laughton CA, Yap LF, Paterson IC, Wang H

J Mol Graph Model, 2014 Jun;51:193-202.
PMID: 24937176 DOI: 10.1016/j.jmgm.2014.05.010

Protein arginine methyltransferases (PRMTs) catalyse the methylation of arginine residues of target proteins. PRMTs utilise S-adenosyl methionine (SAM) as the methyl group donor, leading to S-adenosyl homocysteine (SAH) and monomethylarginine (mMA). A combination of homology modelling, molecular docking, Active Site Pressurisation, molecular dynamic simulations and MM-PBSA free energy calculations is used to investigate the binding poses of three PRMT1 inhibitors (ligands 1-3), which target both SAM and substrate arginine binding sites by containing a guanidine group joined by short linkers with the SAM derivative. It was assumed initially that the adenine moieties of the inhibitors would bind in sub-site 1 (PHE44, GLU137, VAL136 and GLU108), the guanidine side chain would occupy sub-site 2 (GLU 161, TYR160, TYR156 and TRP302), with the amino acid side chain occupying sub-site 3 (GLU152, ARG62, GLY86 and ASP84; pose 1). However, the SAH homocysteine moiety does not fully occupy sub-site 3, suggesting another binding pose may exist (pose 2), whereby the adenine moiety binds in sub-site 1, the guanidine side chain occupies sub-site 3, and the amino acid side chain occupies sub-site 2. Our results indicate that ligand 1 (pose 1 or 2), ligand 2 (pose 2) and ligand 3 (pose 1) are the predominant binding poses and we demonstrate for the first time that sub-site 3 contains a large space that could be exploited in the future to develop novel inhibitors with higher binding affinities.
Development of small molecule inhibitors targeting TGF-β ligand and receptor: Structures, mechanism, preclinical studies and clinical usage

Wang H, Chen M, Sang X, You X, Wang Y, Paterson IC, et al.

Eur J Med Chem, 2020 Apr 01;191:112154.
PMID: 32092587 DOI: 10.1016/j.ejmech.2020.112154

Transforming growth factor-β (TGF-β) is a member of a superfamily of pleiotropic proteins that regulate multiple cellular processes such as growth, development and differentiation. Following binding to type I and II TGF-β serine/threonine kinase receptors, TGF-β activates downstream signaling cascades involving both SMAD-dependent and -independent pathways. Aberrant TGF-β signaling is associated with a variety of diseases, such as fibrosis, cardiovascular disease and cancer. Hence, the TGF-β signaling pathway is recognized as a potential drug target. Various organic molecules have been designed and developed as TGF-β signaling pathway inhibitors and they function by either down-regulating the expression of TGF-β or by inhibiting the kinase activities of the TGF-β receptors. In this review, we discuss the current status of research regarding organic molecules as TGF-β inhibitors, focusing on the biological functions and the binding poses of compounds that are in the market or in the clinical or pre-clinical phases of development.
Crustal fluid and ash alteration impacts on the biosphere of Shikoku Basin sediments, Nankai Trough, Japan

Torres ME, Cox T, Hong WL, McManus J, Sample JC, Destrigneville C, et al.

Geobiology, 2015 Nov;13(6):562-80.
PMID: 26081483 DOI: 10.1111/gbi.12146

We present data from sediment cores collected from IODP Site C0012 in the Shikoku Basin. Our site lies at the Nankai Trough, just prior to subduction of the 19 Ma Philippine Sea plate. Our data indicate that the sedimentary package is undergoing multiple routes of electron transport and that these differing pathways for oxidant supply generate a complex array of metabolic routes and microbial communities involved in carbon cycling. Numerical simulations matched to pore water data document that Ca(2+) and Cl(1-) are largely supplied via diffusion from a high-salinity (44.5 psu) basement fluid, which supports the presence of halophile Archean communities within the deep sedimentary package that are not observed in shallow sediments. Sulfate supply from basement supports anaerobic oxidation of methane (AOM) at a rate of ~0.2 pmol cm(-3) day(-1) at ~400 mbsf. We also note the disappearance of δ-Proteobacteria at 434 mbsf, coincident with the maximum in methane concentration, and their reappearance at 463 mbsf, coinciding with the observed deeper increase in sulfate concentration toward the basement. We did not, however, find ANME representatives in any of the samples analyzed (from 340 to 463 mbsf). The lack of ANME may be due to an overshadowing effect from the more dominant archaeal phylotypes or may indicate involvement of unknown groups of archaea in AOM (i.e., unclassified Euryarchaeota). In addition to the supply of sulfate from a basement aquifer, the deep biosphere at this site is also influenced by an elevated supply of reactive iron (up to 143 μmol g(-1)) and manganese (up to 20 μmol g(-1)). The effect of these metal oxides on the sulfur cycle is inferred from an accompanying sulfur isotope fractionation much smaller than expected from traditional sulfate-reducing pathways. The detection of the manganese- and iron-reducer γ-Proteobacteria Alteromonas at 367 mbsf is consistent with these geochemical inferences.
Synthesis and biological evaluation of indole core-based derivatives with potent antibacterial activity against resistant bacterial pathogens

Hong W, Li J, Chang Z, Tan X, Yang H, Ouyang Y, et al.

J Antibiot (Tokyo), 2017 Jul;70(7):832-844.
PMID: 28465626 DOI: 10.1038/ja.2017.55

The emergence of drug resistance in bacterial pathogens is a growing clinical problem that poses difficult challenges in patient management. To exacerbate this problem, there is currently a serious lack of antibacterial agents that are designed to target extremely drug-resistant bacterial strains. Here we describe the design, synthesis and antibacterial testing of a series of 40 novel indole core derivatives, which are predicated by molecular modeling to be potential glycosyltransferase inhibitors. Twenty of these derivatives were found to show in vitro inhibition of Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus. Four of these strains showed additional activity against Gram-negative bacteria, including extended-spectrum beta-lactamase producing Enterobacteriaceae, imipenem-resistant Klebsiella pneumoniae and multidrug-resistant Acinetobacter baumanii, and against Mycobacterium tuberculosis H37Ra. These four compounds are candidates for developing into broad-spectrum anti-infective agents.
Fulltext Synthesis of 2,4-Diaminopyrimidine Core-Based Derivatives and Biological Evaluation of Their Anti-Tubercular Activities

Ouyang Y, Yang H, Zhang P, Wang Y, Kaur S, Zhu X, et al.

Molecules, 2017 Sep 22;22(10).
PMID: 28937657 DOI: 10.3390/molecules22101592

Tuberculosis (TB) is a chronic, potentially fatal disease caused by Mycobacterium tuberculosis (Mtb). The dihyrofolate reductase in Mtb (mt-DHFR) is believed to be an important drug target in anti-TB drug development. This enzyme contains a glycerol (GOL) binding site, which is assumed to be a useful site to improve the selectivity towards human dihyrofolate reductase (h-DHFR). There have been previous attempts to design drugs targeting the GOL binding site, but the designed compounds contain a hydrophilic group, which may prevent the compounds from crossing the cell wall of Mtb to function at the whole cell level. In the current study, we designed and synthesized a series of mt-DHFR inhibitors that contain a 2,4-diaminopyrimidine core with side chains to occupy the glycerol binding site with proper hydrophilicity for cell entry, and tested their anti-tubercular activity against Mtb H37Ra. Among them, compound 16l showed a good anti-TB activity (MIC = 6.25 μg/mL) with a significant selectivity against vero cells. In the molecular simulations performed to understand the binding poses of the compounds, it was noticed that only side chains of a certain size can occupy the glycerol binding site. In summary, the novel synthesized compounds with appropriate side chains, hydrophobicity and selectivity could be important lead compounds for future optimization towards the development of future anti-TB drugs that can be used as monotherapy or in combination with other anti-TB drugs or antibiotics. These compounds can also provide much information for further studies on mt-DHFR. However, the enzyme target of the compounds still needs to be confirmed by pure mt-DHFR binding assays.
Knowledge, Attitude, Perception and Current Practices of Health Personnel in Managing Post-Stroke Delirium in a New Stroke Centre in Malaysia

Mohd Yosli HN, Hong W, Kazura K, Abdul Salim NH, Md Pauzi AL, Mat Din H, et al.

Malays J Med Sci, 2023 Aug;30(4):157-174.
PMID: 37655142 DOI: 10.21315/mjms2023.30.4.14

INTRODUCTION: Despite the high prevalence of post-stroke delirium in Malaysia, there are no studies on good practices related to its management. This study aimed to analyse the knowledge, attitude, perception, and factors associated with current practices related to delirium in acute stroke patients among health personnel at Hospital Sultan Abdul Aziz Shah (HSAAS) (formerly known as Hospital Pengajar Universiti Putra Malaysia).
METHODS: This cross-sectional study was conducted from 26 April 2021 to 9 May 2021 (17 weeks). All health personnel from various departments managing patients with acute stroke in our centre were invited to participate. An online questionnaire was disseminated to assess their knowledge, attitude, perception, and current practices concerning delirium. Multiple logistic regression was used to examine the association between the independent and dependent variables. The level of significance was set at P < 0.05.
RESULTS: The response rate was 22.49% (47 of 209 participants). More than half (61.7%, n = 29) had good current practices towards delirium in acute stroke patients. A significant association was found between knowledge and current practices related to delirium (P = 0.024). However, there was no significant association between current practices and sociodemographic factors (age, ethnicity, gender and job position), attitude, perceptions, screening barriers, or health service organisation.
CONCLUSION: Most respondents had good current practices and knowledge in managing post-stroke delirium. Therefore, upskilling health personnel for managing this illness is essential to ensure good post-stroke care and improve prognosis related to delirium.
Fulltext The identification of novel Mycobacterium tuberculosis DHFR inhibitors and the investigation of their binding preferences by using molecular modelling

Hong W, Wang Y, Chang Z, Yang Y, Pu J, Sun T, et al.

Sci Rep, 2015;5:15328.
PMID: 26471125 DOI: 10.1038/srep15328

It is an urgent need to develop new drugs for Mycobacterium tuberculosis (Mtb), and the enzyme, dihydrofolate reductase (DHFR) is a recognised drug target. The crystal structures of methotrexate binding to mt- and h-DHFR separately indicate that the glycerol (GOL) binding site is likely to be critical for the function of mt-DHFR selective inhibitors. We have used in silico methods to screen NCI small molecule database and a group of related compounds were obtained that inhibit mt-DHFR activity and showed bactericidal effects against a test Mtb strain. The binding poses were then analysed and the influence of GOL binding site was studied by using molecular modelling. By comparing the chemical structures, 4 compounds that might be able to occupy the GOL binding site were identified. However, these compounds contain large hydrophobic side chains. As the GOL binding site is more hydrophilic, molecular modelling indicated that these compounds were failed to occupy the GOL site. The most potent inhibitor (compound 6) demonstrated limited selectivity for mt-DHFR, but did contain a novel central core (7H-pyrrolo[3,2-f]quinazoline-1,3-diamine), which may significantly expand the chemical space of novel mt-DHFR inhibitors. Collectively, these observations will inform future medicinal chemistry efforts to improve the selectivity of compounds against mt-DHFR.
The development of a novel transforming growth factor-β (TGF-β) inhibitor that disrupts ligand-receptor interactions

Wu H, Sun Y, Wong WL, Cui J, Li J, You X, et al.

Eur J Med Chem, 2020 Mar 01;189:112042.
PMID: 31958737 DOI: 10.1016/j.ejmech.2020.112042

Transforming growth factor-β (TGF-β) plays an important role in regulating epithelial to mesenchymal transition (EMT) and the TGF-β signaling pathway is a potential target for therapeutic intervention in the development of many diseases, such as fibrosis and cancer. Most currently available inhibitors of TGF-β signaling function as TGF-β receptor I (TβR-I) kinase inhibitors, however, such kinase inhibitors often lack specificity. In the present study, we targeted the extracellular protein binding domain of the TGF-β receptor II (TβR-II) to interfere with the protein-protein interactions (PPIs) between TGF-β and its receptors. One compound, CJJ300, inhibited TGF-β signaling by disrupting the formation of the TGF-β-TβR-I-TβR-II signaling complex. Treatment of A549 cells with CJJ300 resulted in the inhibition of downstream signaling events such as the phosphorylation of key factors along the TGF-β pathway and the induction of EMT markers. Concomitant with these effects, CJJ300 significantly inhibited cell migration. The present study describes for the first time a designed molecule that can regulate TGF-β-induced signaling and EMT by interfering with the PPIs required for the formation of the TGF-β signaling complex. Therefore, CJJ300 can be an important lead compound with which to study TGF-β signaling and to design more potent TGF-β signaling antagonists.
The discovery of 1, 3-diamino-7H-pyrrol[3, 2-f]quinazoline compounds as potent antimicrobial antifolates

Li Y, Ouyang Y, Wu H, Wang P, Huang Y, Li X, et al.

Eur J Med Chem, 2022 Jan 15;228:113979.
PMID: 34802838 DOI: 10.1016/j.ejmech.2021.113979

The shortage of new antibiotics makes infections caused by gram-negative (G-) bacteria a significant clinical problem. The key enzymes involved in folate biosynthesis represent important targets for drug discovery, and new antifolates with novel mechanisms are urgently needed. By targeting to dihydrofolate reductase (DHFR), a series of 1,3-diamino-7H-pyrrol[3,2-f]quinazoline (PQZ) compounds were designed, and exhibited potent antibacterial activities in vitro, especially against multi-drug resistant G- strains. Multiple experiments indicated that PQZ compounds contain a different molecular mechanism against the typical DHFR inhibitor, trimethoprim (TMP), and the thymidylate synthase (TS) was identified as another potential but a relatively weak target. A significant synergism between the representative compound, OYYF-175, and sulfamethoxazole (SMZ) was observed with a strong cumulative and significantly bactericidal effect at extremely low concentrations (2 μg/mL for SMZ and 0.03 pg/mL for OYYF-175), which could be resulted from the simultaneous inhibition of dihydropteroate synthase (DHPS), DHFR and TS. PQZ compounds exhibited therapeutic effects in a mouse model of intraperitoneal infections caused by Escherichia coli (E. coli). The co-crystal structure of OYYF-175-DHFR was solved and the detailed interactions were provided. The inhibitors reported represent innovative chemical structures with novel molecular mechanism of action, which will benefit the generation of new, efficacious bactericidal compounds.