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Design of in situ dispersible and calcium cross-linked alginate pellets as intestinal-specific drug carrier by melt pelletization technique

Nurulaini H, Wong TW

J Pharm Sci, 2011 Jun;100(6):2248-57.
PMID: 21213311 DOI: 10.1002/jps.22459

Conventional alginate pellets underwent rapid drug dissolution and loss of multiparticulate characteristics such as aggregation in acidic medium, thereby promoting oral dose dumping. This study aimed to design sustained-release dispersible alginate pellets through rapid in situ matrix dispersion and cross-linking by calcium salts during dissolution. Pellets made of alginate and calcium salts were prepared using a solvent-free melt pelletization technique that prevented reaction between processing materials during agglomeration and allowed such a reaction to occur only in dissolution phase. Drug release was remarkably retarded in acidic medium when pellets were formulated with water-soluble calcium acetate instead of acid-soluble calcium carbonate. Different from calcium salt-free and calcium carbonate-loaded matrices that aggregated or underwent gradual erosion, rapid in situ solvation of calcium acetate in pellets during dissolution resulted in burst of gas bubbles, fast pellet breakup, and dispersion. The dispersed fragments, though exhibiting a larger specific surface area for drug dissolution than intact matrix, were rapidly cross-linked by Ca(2+) from calcium acetate and had drug release retarded till a change in medium pH from 1.2 to 6.8. Being dispersible and pH-dependent in drug dissolution, these pellets are useful as multiparticulate intestinal-specific drug carrier without exhibiting dose dumping tendency of a "single-unit-like" system via pellet aggregation.

Matched MeSH terms: Drug Design*
Synthesis of Apoptotic New Quinazolinone-Based Compound and Identification of its Underlying Mitochondrial Signalling Pathway in Breast Cancer Cells

Zahedifard M, Faraj FL, Paydar M, Looi CY, Hasandarvish P, Hajrezaie M, et al.

Curr Pharm Des, 2015;21(23):3417-26.
PMID: 25808938

The anti-carcinogenic effect of the new quinazolinone compound, named MMD, was tested on MCF-7 human breast cancer cell line. The synthesis of quinazolinone-based compounds attracted strong attention over the past few decades as an alternative mean to produce analogues of natural products. Quinazolinone compounds sharing the main principal core structures are currently introduced in the clinical trials and pharmaceutical markets as anti-cancer agents. Thus, it is of high clinical interest to identify a new drug that could be used to control the growth and expansion of cancer cells. Quinazolinone is a metabolite derivative resulting from the conjugation of 2-aminobenzoyhydrazide and 5-methoxy-2- hydroxybenzaldehyde based on condensation reactions. In the present study, we analysed the influence of MMD on breast cancer adenoma cell morphology, cell cycle arrest, DNA fragmentation, cytochrome c release and caspases activity. MCF-7 is a type of cell line representing the breast cancer adenoma cells that can be expanded and differentiated in culture. Using different in vitro strategies and specific antibodies, we demonstrate a novel role for MMD in the inhibition of cell proliferation and initiation of the programmed cell death. MMD was found to increase cytochrome c release from the mitochondria to the cytosol and this effect was enhanced over time with effective IC50 value of 5.85 ± 0.71 μg/mL detected in a 72-hours treatment. Additionally, MMD induced cell cycle arrest at G0/G1 phase and caused DNA fragmentation with obvious activation of caspase-9 and caspases-3/7. Our results demonstrate a novel role of MMD as an anti-proliferative agent and imply the involvement of mitochondrial intrinsic pathway in the observed apoptosis.

Matched MeSH terms: Drug Design*
Design, Synthesis and Therapeutic Potential of Some 6, 6'-(1,4- phenylene)bis(4-(4-bromophenyl)pyrimidin-2-amine)analogues

Kumar S, Narasimhan B, Lim SM, Ramasamy K, Mani V, Shah SAA

Mini Rev Med Chem, 2019;19(7):609-621.
PMID: 30526456 DOI: 10.2174/1389557519666181210162413

BACKGROUND: A series of 6, 6'-(1,4-phenylene)bis(4-(4-bromophenyl)pyrimidin-2-amine) derivatives has been synthesized by Claisen-Schmidt condensation and its chemical structures was confirmed by FT-IR, 1H/13C-NMR spectral and elemental analyses. The molecular docking study was carried out to find the interaction between active bis-pyrimidine compounds with CDK-8 protein. The in vitro antimicrobial potential of the synthesized compounds was determined against Gram-positive and Gram-negative bacterial species as well fungal species by tube dilution technique. Antimicrobial results indicated that compound 11y was found to be most potent one against E. coli (MICec = 0.67 µmol/mL) and C. albicans (MICca = 0.17 µmol/mL) and its activity was comparable to norfloxacin (MIC = 0.47 µmol/mL) and fluconazole (MIC = 0.50 µmol/mL), respectively.
CONCLUSION: Anticancer screening of the synthesized compounds using Sulforhodamine B (SRB) assay demonstrated that compounds 2y (IC50 = 0.01 µmol/mL) and 4y (IC50= 0.02 µmol/mL) have high antiproliferative potential against human colorectal carcinoma cancer cell line than the reference drug (5- fluorouracil) and these compounds also showed best dock score with better potency within the ATP binding pocket and may also be used lead for rational drug designing.

Matched MeSH terms: Drug Design*
Design, Synthesis, SAR Study, Antimicrobial and Anticancer Evaluation of Novel 2-Mercaptobenzimidazole Azomethine Derivatives

Tahlan S, Narasimhan B, Lim SM, Ramasamy K, Mani V, Shah SAA

Mini Rev Med Chem, 2020;20(15):1559-1571.
PMID: 30179132 DOI: 10.2174/1389557518666180903151849

BACKGROUND: Various analogues of benzimidazole are found to be biologically and therapeutically potent against several ailments. Benzimidazole when attached with heterocyclic rings has shown wide range of potential activities. So, from the above provided facts, we altered benzimidazole derivatives so that more potent antagonists could be developed. In the search for a new category of antimicrobial and anticancer agents, novel azomethine of 2-mercaptobenzimidazole derived from 3-(2- (1H-benzo[d]imidazol-2-ylthio)acetamido)benzohydrazide were synthesized.
RESULTS AND DISCUSSION: The synthesized analogues were characterized by FT-IR, 1H/13C-NMR and MS studies as well C, H, N analysis. All synthesized compounds were evaluated for in vitro antibacterial activity against Gram-positive (B. subtilis), Gram-negative (E. coli, P. aeruginosa, K. pneumoniae and S. typhi) strains and in vitro antifungal activity against C. albicans and A. niger strains by serial dilution method, the minimum inhibitory concentration (MIC) described in μM/ml. The in vitro anticancer activity of synthesized compounds was determined against human colorectal carcinoma cell line (HCT- 116) using 5-fluorouracil as standard drug.
CONCLUSION: In general, most of the synthesized derivatives exhibited significant antimicrobial and anticancer activities. Compounds 8, 10, 15, 16, 17, 20 and 22 showed significant antimicrobial activity towards tested bacterial and fungal strains and compound 26 exhibited significant anticancer activity.

Matched MeSH terms: Drug Design*
Fulltext Protective Immunity against SARS Subunit Vaccine Candidates Based on Spike Protein: Lessons for Coronavirus Vaccine Development

Khalaj-Hedayati A

J Immunol Res, 2020;2020:7201752.
PMID: 32695833 DOI: 10.1155/2020/7201752

The recent outbreak of the novel coronavirus disease, COVID-19, has highlighted the threat that highly pathogenic coronaviruses have on global health security and the imminent need to design an effective vaccine for prevention purposes. Although several attempts have been made to develop vaccines against human coronavirus infections since the emergence of Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) in 2003, there is no available licensed vaccine yet. A better understanding of previous coronavirus vaccine studies may help to design a vaccine for the newly emerged virus, SARS-CoV-2, that may also cover other pathogenic coronaviruses as a potentially universal vaccine. In general, coronavirus spike protein is the major antigen for the vaccine design as it can induce neutralizing antibodies and protective immunity. By considering the high genetic similarity between SARS-CoV and SARS-CoV-2, here, protective immunity against SARS-CoV spike subunit vaccine candidates in animal models has been reviewed to gain advances that can facilitate coronavirus vaccine development in the near future.

Matched MeSH terms: Drug Design*
Fulltext Development of MTH1-Binding Nucleotide Analogs Based on 7,8-Dihalogenated 7-Deaza-dG Derivatives

Shi H, Ishikawa R, Heh CH, Sasaki S, Taniguchi Y

Int J Mol Sci, 2021 Jan 28;22(3).
PMID: 33525366 DOI: 10.3390/ijms22031274

MTH1 is an enzyme that hydrolyzes 8-oxo-dGTP, which is an oxidatively damaged nucleobase, into 8-oxo-dGMP in nucleotide pools to prevent its mis-incorporation into genomic DNA. Selective and potent MTH1-binding molecules have potential as biological tools and drug candidates. We recently developed 8-halogenated 7-deaza-dGTP as an 8-oxo-dGTP mimic and found that it was not hydrolyzed, but inhibited enzyme activity. To further increase MTH1 binding, we herein designed and synthesized 7,8-dihalogenated 7-deaza-dG derivatives. We successfully synthesized multiple derivatives, including substituted nucleosides and nucleotides, using 7-deaza-dG as a starting material. Evaluations of the inhibition of MTH1 activity revealed the strong inhibitory effects on enzyme activity of the 7,8-dihalogenated 7-deaza-dG derivatives, particularly 7,8-dibromo 7-daza-dGTP. Based on the results obtained on kinetic parameters and from computational docking simulating studies, these nucleotide analogs interacted with the active site of MTH1 and competitively inhibited the substrate 8-oxodGTP. Therefore, novel properties of repair enzymes in cells may be elucidated using new compounds.

Matched MeSH terms: Drug Design*
2-Mercaptobenzimidazole Schiff Bases: Design, Synthesis, Antimicrobial Studies and Anticancer Activity on HCT-116 Cell Line

Tahlan S, Narasimhan B, Lim SM, Ramasamy K, Mani V, Shah SAA

Mini Rev Med Chem, 2019;19(13):1080-1092.
PMID: 30306865 DOI: 10.2174/1389557518666181009151008

BACKGROUND: Increased rate of mortality due to the development of resistance to currently available antimicrobial and anticancer agents initiated the need to develop new chemical entities for the treatment of microbial infections and cancer.
OBJECTIVE: The present study was aimed to synthesize and evaluate antimicrobial and anticancer activities of Schiff bases of 2-mercaptobenzimidazole.
METHODS: The Schiff bases of 2-mercaptobenzimidazole were synthesized from 4-(2-(1H-benzo[d]- imidazol-2-ylthio)acetamido)benzohydrazide. The synthesized compounds were evaluated for antimicrobial and anticancer activities by tube dilution method and Sulforhodamine-B (SRB) assay, respectively.
RESULTS: Compounds 8 (MICpa, an = 2.41, 1.20 µM/ml), 10 (MICse, sa = 2.50 µM/ml), 20 (MICec = 2.34 µM/ml) and 25 (MICca = 1.46 µM/ml) showed significant antimicrobial activity against tested bacterial and fungal strains and compounds 20 (IC50 = 8 µg/ml) and 23 (IC50 = 7 µg/ml) exhibited significant anticancer activity.
CONCLUSION: In general, the synthesized derivatives exhibited moderate antimicrobial and anticancer activities. Compounds 8 and 25 having high antifungal potential among the synthesized compounds may be taken as lead molecules for the development of novel antifungal agents.

Matched MeSH terms: Drug Design*
Current approaches in antiviral drug discovery against the Flaviviridae family

Baharuddin A, Hassan AA, Sheng GC, Nasir SB, Othman S, Yusof R, et al.

Curr Pharm Des, 2014;20(21):3428-44.
PMID: 24001228

Viruses belonging to the Flaviviridae family primarily spread through arthropod vectors, and are the major causes of illness and death around the globe. The Flaviviridae family consists of 3 genera which include the Flavivirus genus (type species, yellow fever virus) as the largest genus, the Hepacivirus (type species, hepatitis C virus) and the Pestivirus (type species, bovine virus diarrhea). The flaviviruses (Flavivirus genus) are small RNA viruses transmitted by mosquitoes and ticks that take over host cell machinery in order to propagate. However, hepaciviruses and pestiviruses are not antropod-borne. Despite the extensive research and public health concern associated with flavivirus diseases, to date, there is no specific treatment available for any flavivirus infections, though commercially available vaccines for yellow fever, Japanese encephalitis and tick-born encephalitis exist. Due to the global threat of viral pandemics, there is an urgent need for new drugs. In many countries, patients with severe cases of flavivirus infections are treated only by supportive care, which includes intravenous fluids, hospitalization, respiratory support, and prevention of secondary infections. This review discusses the strategies used towards the discovery of antiviral drugs, focusing on rational drug design against Dengue virus (DENV), West Nile virus (WNV), Japanese encephalitis virus (JEV), Yellow Fever virus (YFV) and Hepatitis C virus (HCV). Only modified peptidic, nonpeptidic, natural compounds and fragment-based inhibitors (typically of mass less than 300 Da) against structural and non-structural proteins are discussed.

Matched MeSH terms: Drug Design
Fragment-based molecular design of new competitive dengue Den2 Ns2b/Ns3 inhibitors from the components of fingerroot (Boesenbergia rotunda)

Frimayanti N, Zain SM, Lee VS, Wahab HA, Yusof R, Abd Rahman N

In Silico Biol. (Gedrukt), 2011;11(1-2):29-37.
PMID: 22475750 DOI: 10.3233/ISB-2012-0442

Publication year=2011-2012

Matched MeSH terms: Drug Design
Eimeria tenella glucose-6-phosphate isomerase: molecular characterization and assessment as a target for anti-coccidial control

Loo SS, Blake DP, Mohd-Adnan A, Mohamed R, Wan KL

Parasitology, 2010 Jul;137(8):1169-77.
PMID: 20233491 DOI: 10.1017/S0031182010000119

Limitations with current chemotherapeutic and vaccinal control of coccidiosis caused by Eimeria species continue to prompt development of novel controls, including the identification of new drug targets. Glucose-6-phosphate isomerase (G6-PI) has been proposed as a valid drug target for many protozoa, although polymorphism revealed by electrophoretic enzyme mobility has raised doubts for Eimeria. In this study we identified and sequenced the Eimeria tenella G6-PI orthologue (EtG6-PI) from the reference Houghton strain and confirmed its position within the prevailing taxonomic hierarchy, branching with the Apicomplexa and Plantae, distinct from the Animalia including the host, Gallus gallus. Comparison of the deduced 1647 bp EtG6-PI coding sequence with the 9016 bp genomic locus revealed 15 exons, all of which obey the intron-AG-/exon/-GT-intron splicing rule. Comparison with the Weybridge and Wisconsin strains revealed the presence of 33 single nucleotide polymorphisms (SNPs) and 14 insertion/deletion sites. Three SNPs were exonic and all yielded non-synonymous substitutions. Preliminary structural predictions suggest little association between the coding SNPs and key G6-PI catalytic residues or residues thought to be involved in the coordination of the G6-PI's substrate phosphate group. Thus, the significant polymorphism from its host orthologue and minimal intra-specific polymorphism suggest G6-PI remains a valid anti-coccidial drug target.

Matched MeSH terms: Drug Design
Ultrasound mediated efficient synthesis of new 4-oxoquinazolin-3(4H)-yl)furan-2-carboxamides as potent tyrosinase inhibitors: Mechanistic approach through chemoinformatics and molecular docking studies

Dige NC, Mahajan PG, Raza H, Hassan M, Vanjare BD, Hong H, et al.

Bioorg Chem, 2019 11;92:103201.
PMID: 31445195 DOI: 10.1016/j.bioorg.2019.103201

We have carried out the synthesis of new 4-oxoquinazolin-3(4H)-yl)furan-2-carboxamide derivatives by the reaction between isatoic anhydride, 2-furoic hydrazide and substituted salicylaldehydes in ethanol: water (5:5 v/v) solvent system using p-TSA as a catalyst under ultrasound irradiation at room temperature. The structures of newly synthesized compounds were confirmed through spectral techniques such as IR, 1H NMR, 13C NMR, and LCMS. The important features of this protocol include simple and easy workup procedure, reaction carried out at ambient temperature, use of ultrasound and high yield of oxoquinazolin-3(4H)-yl)furan-2-carboxamides in short reaction time. The synthesized compounds 4a-4j were screened against tyrosinase enzyme and all these compounds found to be potent inhibitors with much lower IC50 value of 0.028 ± 0.016 to 1.775 ± 0.947 µM than the standard kojic acid (16.832 ± 1.162 µM). The kinetics mechanism for compound 4e was analyzed by Lineweaver-Burk plots which revealed that compound inhibited tyrosinase non-competitively by forming an enzyme-inhibitor complex. Along with this all the synthesized compounds (4a-4j) were scanned for their DPPH free radical scavenging ability. The outputs received through in vitro and in silico analysis are coherent to the each other with good binding energy values (kcal/mol) posed by synthesized ligands.

Matched MeSH terms: Drug Design
Hendra and Nipah viruses: pathogenesis and therapeutics

Eaton BT, Broder CC, Wang LF

Curr Mol Med, 2005 Dec;5(8):805-16.
PMID: 16375714

Within the past decade a number of new zoonotic paramyxoviruses emerged from flying foxes to cause serious disease outbreaks in man and livestock. Hendra virus was the cause of fatal infections of horses and man in Australia in 1994, 1999 and 2004. Nipah virus caused encephalitis in humans both in Malaysia in 1998/99, following silent spread of the virus in the pig population, and in Bangladesh from 2001 to 2004 probably as a result of direct bat to human transmission and spread within the human population. Hendra and Nipah viruses are highly pathogenic in humans with case fatality rates of 40% to 70%. Their genetic constitution, virulence and wide host range make them unique paramyxoviruses and they have been given Biosecurity Level 4 status in a new genus Henipavirus within the family Paramyxoviridae. Recent studies on the virulence, host range and cell tropisms of henipaviruses provide insights into the unique biological properties of these emerging human pathogens and suggest approaches for vaccine development and therapeutic countermeasures.

Matched MeSH terms: Drug Design
Synthesis and biological activity of oxadiazole and triazolothiadiazole derivatives as tyrosinase inhibitors

Lam KW, Syahida A, Ul-Haq Z, Abdul Rahman MB, Lajis NH

Bioorg Med Chem Lett, 2010 Jun 15;20(12):3755-9.
PMID: 20493688 DOI: 10.1016/j.bmcl.2010.04.067

A series of 16 oxadiazole and triazolothiadiazole derivatives were designed, synthesized and evaluated as mushroom tyrosinase inhibitors. Five derivatives were found to display high inhibition on the tyrosinase activity ranging from 0.87 to 1.49 microM. Compound 5 exhibited highest tyrosinase inhibitory activity with an IC(50) value of 0.87+/-0.16 microM. The in silico protein-ligand docking using AUTODOCK 4.1 was successfully performed on compound 5 with significant binding energy value of -5.58 kcal/mol. The docking results also showed that the tyrosinase inhibition might be due to the metal chelating effect by the presence of thione functionality in compounds 1-5. Further studies revealed that the presence of hydrophobic group such as cycloamine derivatives played a major role in the inhibition. Piperazine moiety in compound 5 appeared to be involved in an extensive hydrophobic contact and a 2.9A hydrogen bonding with residue Glu 182 in the active site.

Matched MeSH terms: Drug Design
Quantitative Structure-Activity Relationship (QSAR) Studies for the Inhibition of MAOs

Ramesh M, Muthuraman A

Comb Chem High Throughput Screen, 2020;23(9):887-897.
PMID: 32208114 DOI: 10.2174/1386207323666200324173231

Monoamine oxidases are the crucial drug targets for the treatment of neurodegenerative disorders like depression, Parkinson's disease, and Alzheimer's disease. The enzymes catalyze the oxidative deamination of several monoamine containing neurotransmitters, i.e. serotonin (5-HT), melatonin, epinephrine, norepinephrine, phenylethylamine, benzylamine, dopamine, tyramine, etc. The oxidative reaction of monoamine oxidases results in the production of hydrogen peroxide that leads to the neurodegeneration process. Therefore, the inhibition of monoamine oxidases has shown a profound effect against neurodegenerative diseases. At present, the design and development of newer lead molecules for the inhibition of monoamine oxidases are under intensive research in the field of medicinal chemistry. Recently, the advancement in QSAR methodologies has shown considerable interest in the development of monoamine oxidase inhibitors. The present review describes the development of QSAR methodologies, and their role in the design of newer monoamine oxidase inhibitors. It will assist the medicinal chemist in the identification of selective and potent monoamine oxidase inhibitors from various chemical scaffolds.

Matched MeSH terms: Drug Design
Hybrid molecules based on 1,3,5-triazine as potential therapeutics: A focused review

Prasher P, Sharma M, Aljabali AAA, Gupta G, Negi P, Kapoor DN, et al.

Drug Dev Res, 2020 11;81(7):837-858.
PMID: 32579723 DOI: 10.1002/ddr.21704

Majority of the representative drugs customarily interact with multiple targets manifesting unintended side effects. In addition, drug resistance and over expression of the cellular efflux-pumps render certain classes of drugs ineffective. With only a few innovative formulations in development, it is necessary to identify pharmacophores and novel strategies for creating new drugs. The conjugation of dissimilar pharmacophoric moieties to design hybrid molecules with an attractive therapeutic profile is an emerging paradigm in the contemporary drug development regime. The recent decade witnessed the remarkable biological potential of 1,3,5-triazine framework in the development of various chemotherapeutics. The appending of the 1,3,5-triazine nucleus to biologically relevant moieties has delivered exciting results. The present review focuses on 1,3,5-triazine based hybrid molecules in the development of pharmaceuticals.

Matched MeSH terms: Drug Design
Molecular hybridization conceded exceptionally potent quinolinyl-oxadiazole hybrids through phenyl linked thiosemicarbazide antileishmanial scaffolds: In silico validation and SAR studies

Taha M, Ismail NH, Ali M, Rashid U, Imran S, Uddin N, et al.

Bioorg Chem, 2017 04;71:192-200.
PMID: 28228228 DOI: 10.1016/j.bioorg.2017.02.005

The high potential of quinoline containing natural products and their derivatives in medicinal chemistry led us to discover a novel series of compounds 6-23 based on the concept of molecular hybridization. Most of the synthesized analogues exhibited potent leishmanicidal potential. The most potent compound (23, IC50=0.10±0.001μM) among the series was found ∼70 times more lethal than the standard drug. The current series 6-23 conceded in the development of fourteen (14) extraordinarily active compounds against leishmaniasis. In silico analysis were also performed to probe the mode of action while all the compounds structure were established by NMR and Mass spectral analysis.

Matched MeSH terms: Drug Design
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.

Matched MeSH terms: Drug Design
Novel furan-containing peptide-based inhibitors of protein arginine deiminase type IV (PAD4)

Teo CY, Tejo BA, Leow ATC, Salleh AB, Abdul Rahman MB

Chem Biol Drug Des, 2017 Dec;90(6):1134-1146.
PMID: 28581157 DOI: 10.1111/cbdd.13033

Protein arginine deiminase type IV (PAD4) is responsible for the posttranslational conversion of peptidylarginine to peptidylcitrulline. Citrullinated protein is the autoantigen in rheumatoid arthritis, and therefore, PAD4 is currently a promising therapeutic target for the disease. Recently, we reported the importance of the furan ring in the structure of PAD4 inhibitors. In this study, the furan ring was incorporated into peptides to act as the "warhead" of the inhibitors for PAD4. IC50 studies showed that the furan-containing peptide-based inhibitors were able to inhibit PAD4 to a better extent than the furan-containing small molecules that were previously reported. The best peptide-based inhibitor inhibited PAD4 reversibly and competitively with an IC50 value of 243.2 ± 2.4 μm. NMR spectroscopy and NMR-restrained molecular dynamic simulations revealed that the peptide-based inhibitor had a random structure. Molecular docking studies showed that the peptide-based inhibitor entered the binding site and interacted with the essential amino acids involved in the catalytic activity. The peptide-based inhibitor could be further developed into a therapeutic drug for rheumatoid arthritis.

Matched MeSH terms: Drug Design
Synthesis, in vitro and in silico studies of novel potent urease inhibitors: N-[4-({5-[(3-Un/substituted-anilino-3-oxopropyl)sulfanyl]-1,3,4-oxadiazol-2-yl}methyl)-1,3-thiazol-2-yl]benzamides

Abbasi MA, Hassan M, Aziz-Ur-Rehman, Siddiqui SZ, Raza H, Shah SAA, et al.

Bioorg Med Chem, 2018 07 30;26(13):3791-3804.
PMID: 29903414 DOI: 10.1016/j.bmc.2018.06.005

The present article describes the synthesis, in vitro urease inhibition and in silico molecular docking studies of a novel series of bi-heterocyclic bi-amides. The synthesis of title compounds was initiated by benzoylation, with benzoyl chloride (1), of the key starter ethyl 2-(2-amino-1,3-thiazol-4-yl)acetate (2) in weak basic aqueous medium followed by hydrazide formation, 4, and cyclization with CS2 to reach the parent bi-heterocyclic nucleophile, N-{4-[(5-sulfanyl-1,3,4-oxadiazol-2-yl)methyl]-1,3-thiazol-2-yl}benzamide (5). Various electrophiles, 8a-l, were synthesized by a two-step process and these were finally coupled with 5 to yield the targeted bi-heterocyclic bi-amide molecules, 9a-l. The structures of the newly synthesized products were corroborated by IR, 1H NMR, 13C NMR, EI-MS and elemental analysis. The in vitro screening of these molecules against urease explored that most of the compounds exhibit potent inhibitory potential against this enzyme. The compound 9j, with IC50 value of 2.58 ± 0.02 µM, exhibited most promising inhibitory activity among the series, relative to standard thiourea having IC50 value of 21.11 ± 0.12 µM. In silico studies fully augmented the experimental enzyme inhibition results. Chemo-informatics analysis showed that synthesized compounds (9a-l) mostly obeyed the Lipinski's rule. Molecular docking study suggested that ligand 9j exhibited good binding energy value (-7.10 kcal/mol) and binds within the active region of target protein. So, on the basis of present investigation, it was inferred that 9j may serve as a novel scaffold for designing more potent urease inhibitors.

Matched MeSH terms: Drug Design
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.

Matched MeSH terms: Drug Design

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