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1.
Pathog Dis ; 812023 Jan 17.
Article in English | MEDLINE | ID: mdl-37852672

ABSTRACT

The rapid occurrence of gonococcal resistance to all classes of antibiotics could lead to untreatable gonorrhea. Thus, development of novel anti-Neisseria gonorrhoeae drugs is urgently needed. Neisseria gonorrhoeae FA1090 is the most used in gonococcal infection mouse models because of its natural resistance to streptomycin. Streptomycin inhibits the urogenital commensal flora that permits gonococcal colonization. However, this strain is drug-susceptible and cannot be used to investigate the efficacy of novel agents against multidrug-resistant N. gonorrhoeae. Hence, to test the in vivo efficacy of new therapeutics against N. gonorrhoeae resistant to the frontline antibiotics, azithromycin, or ceftriaxone, we constructed streptomycin-resistant mutants of N. gonorrhoeae CDC-181 (azithromycin-resistant) and WHO-X (ceftriaxone-resistant). We identified the inoculum size needed to successfully colonize mice. Both mutants, CDC-181-rpsLA128G and WHO-X-rpsLA128G, colonized the genital tract of mice for 14 days with 100% colonization observed for at least 7 days. CDC-181-rpsLA128G demonstrated better colonization of the murine genital tract compared to WHO-X-rpsLA128G. Lower inoculum of WHO-X-rpsLA128G (105 and 106 CFU) colonized mice better than higher inoculum. Overall, our results indicate that CDC-181-rpsLA128G and WHO-X-rpsLA128G can colonize the lower genital tract of mice and are suitable to be used in mouse models to investigate the efficacy of antigonococcal agents.


Subject(s)
Gonorrhea , Neisseria gonorrhoeae , Animals , Mice , Female , Ceftriaxone , Azithromycin/pharmacology , Microbial Sensitivity Tests , Anti-Bacterial Agents/pharmacology , Anti-Bacterial Agents/therapeutic use , Gonorrhea/drug therapy , Gonorrhea/epidemiology , Streptomycin , Disease Models, Animal
2.
J Biomol Struct Dyn ; : 1-19, 2023 Jun 01.
Article in English | MEDLINE | ID: mdl-37261796

ABSTRACT

Dipeptidyl peptidase-4 (DPP4) inhibitors are a potent therapeutic treatment for type 2 diabetes mellitus (T2DM). There is a family of compounds used as DPP4 inhibitors (DPP4Is) called gliptins. They bind tightly to DPP4 to form an inactive protein-ligand complex. However, there remains a need to identify novel DPP4Is that are more efficacious and safer due to the increasing prevalence of T2DM and the undesirable side effects of gliptins. To identify potential DPP4Is, we screened over 1800 novel compounds in a comparative study with gliptins. We performed dual-factor molecular docking to assess the binding affinity of the compounds to DPP4 and found four compounds with a higher binding affinity to DPP4 than currently used gliptins. The newly identified compounds interacted with the dyad glutamate (GLU205 and GLU206) and tyrosine (TYR662 and TYR666) residues in DPP4's active site. We performed molecular dynamics simulations to determine the stability of the protein-ligand complexes formed by the compounds and DPP4. Furthermore, we examined the toxicity and pharmacological profile of the compounds. The compounds are drug-like, easy to synthesize, and relatively less toxic than gliptins. Collectively, our results suggest that the novel compounds are potential DPP4Is and should be considered for further studies to develop novel antidiabetics.Communicated by Ramaswamy H. Sarma.

3.
J Biomol Struct Dyn ; 41(20): 10388-10395, 2023 12.
Article in English | MEDLINE | ID: mdl-36524470

ABSTRACT

Diabetes mellitus (DM) is a group of metabolic disorders characterised by chronic hyperglycaemia. DM is currently one of the top ten causes of death in humans. Chronic hyperglycaemia in DM leads to long-term damage and failure of different organs in the body. Type 2 DM (T2D) is the most common DM form, characterised by peripheral insulin resistance, relative insulin deficiency, impaired hepatic glucose production regulation and pancreatic ß cell dysfunction. The human pancreatic α-amylase (HPA) inhibitor is currently one of the most effective methods developed to inhibit hyperglycaemia in T2D patients. However, the current standard drug available, acarbose, has been associated with severe side effects following prolonged use in patients. Therefore, an alternative drug capable of effectively inhibiting HPA with minimal side effects is required. Based on our previous study, we further explored the therapeutic potential of quercetin and ombuin via molecular dynamics (MD) simulation. The Desmond Simulation Package was used to run 100-ns MD simulations to examine the steady nature and conformational stability of the ligand-HPA complexes. Post-simulation molecular mechanics-generalised born surface area (MM-GBSA) analysis of HPA's binding free energy with quercetin and ombuin was explored. The lead compounds' drug-likeness, absorption, distribution, metabolism and elimination properties were also studied using the SwissADME tool. These results indicate that quercetin and ombuin have great potential as anti-DM drugs with more favourable properties than acarbose.Communicated by Ramaswamy H. Sarma.


Subject(s)
Diabetes Mellitus, Type 2 , Hyperglycemia , Humans , Acarbose , Molecular Dynamics Simulation , Quercetin/pharmacology , Pancreatic alpha-Amylases , Diabetes Mellitus, Type 2/drug therapy , Molecular Docking Simulation
4.
J Biochem Mol Toxicol ; 36(11): e23179, 2022 Nov.
Article in English | MEDLINE | ID: mdl-35906875

ABSTRACT

This study investigated the protective effect of quercetin against cyclophosphamide-induced immunosuppressive indoleamine 2,3-dioxygenase (IDO) via the mechanism of oxidative-inflammatory stress and behavioral indices. Cyclophosphamide (CYP) was administered to male Wister rats at a dose of 100 mg/kg with or without quercetin 50 mg/kg every other day for 7 days. Experimental techniques including western blotting, immunohistochemistry analysis, and inflammatory and oxidative stress marker assays were carried out. We also conducted behavioral analyses such as open field, tail suspension, and Y-maze tests for cognitive assessment. The results indicated that quercetin attenuated oxidative-inflammatory stress induced by CYP in the hippocampus and cerebral cortex of male Wister rats by augmenting the activities of antioxidant enzymes and suppressing lipid peroxidation as well as inflammatory mediators such as interleukin-6 and interferon-γ. Concomitantly, quercetin partially prevented the alteration in brain tissue histological architecture and mitigated the activities of IDO/tryptophan 2,3-dioxygenase (TDO) and protein expression of IDO1. This was corroborated by the IDO-quercetin model obtained in silico, revealing a favorable inhibitory interaction between quercetin and the enzyme. Finally, the results of behavioral tests suggested that quercetin significantly prevented the depressive-like posture of the CYP-treated rats. Our study for the first time revealed that quercetin ameliorates the effect of CYP-instigated IDO/TDO activities in the cerebral cortex and hippocampus via restoration of antioxidant enzymes and preventing oxidative-inflammatory stress.


Subject(s)
Indoleamine-Pyrrole 2,3,-Dioxygenase , Quercetin , Animals , Rats , Male , Quercetin/pharmacology , Indoleamine-Pyrrole 2,3,-Dioxygenase/metabolism , Indoleamine-Pyrrole 2,3,-Dioxygenase/pharmacology , Antioxidants/pharmacology , Antioxidants/metabolism , Rats, Wistar , Hippocampus/metabolism , Cyclophosphamide/toxicity , Cerebral Cortex/metabolism
5.
J Biomol Struct Dyn ; 40(4): 1801-1812, 2022 03.
Article in English | MEDLINE | ID: mdl-33054572

ABSTRACT

Type II Diabetes Mellitus (DM) is caused by insulin resistance in peripheral tissue and impaired insulin secretion through a dysfunction of the pancreatic ß-cell. Acarbose is an anti-DM drug, it is effective but its continuous use may lead to undesirable side effects. Hence, the development of novel drugs from natural source that have both anti-diabetic and anti-oxidant activities, with little or no side effect during long-term use is of great importance. To investigate the anti-DM and anti-oxidant phyto-constituents of Chromoleana odorata, e-pharmacophore model was generated using human pancreatic α-amylase (HPA) standard inhibitor, Acarbose to map important pharmacophoric features of HPA, and used to screen several phyto-constituents of C. odorata to match at least 4 sites of the generated hypothesis. Glide and Induced Fit Docking followed by Prime MM-GBSA calculation, drug-likeness and ADME studies were employed for high fitness (>1.0) compounds retrieved from e-pharmacophore screening process. The drug-likeness properties of the lead compounds, Quercetin and Ombuin were analyzed taking into account the Lipinski's and Veber's rules. Further, machine-learning approach was used to generate QSAR model. The computed model, kpls_desc_19 was used to predict the bioactivity (pIC50) of Quercetin and Ombuin. Phyto-constituents of C. odorata; Quercetin and Ombuin have shown better and promising results when compared to that of the standard, acarbose. Based on the present study, orally delivered Quercetin and Ombuin from C. odorata are relatively better inhibitor of HPA, thus they can be a useful therapeutic candidate in the management/treatment of DM when compared to acarbose.Communicated by Ramaswamy H. Sarma.


Subject(s)
Chromolaena , Diabetes Mellitus, Type 2 , Pancreatic alpha-Amylases/antagonists & inhibitors , Phytochemicals/pharmacology , Acarbose/pharmacology , Chromolaena/chemistry , Diabetes Mellitus, Type 2/drug therapy , Humans , Molecular Docking Simulation
6.
Recent Pat Anticancer Drug Discov ; 16(2): 273-284, 2021.
Article in English | MEDLINE | ID: mdl-33563181

ABSTRACT

BACKGROUND: Breast Cancer (BC), a common fatal disease and the deadliest cancer next to lung cancer, is characterized by an abnormal growth of cells in the tissues of the breast. BC chemotherapy is marked by targeting the activities of some receptors such as Estrogen Receptor alpha (ER-α). At present, one of the most commonly used and approved marketed therapeutic drugs for BC is tamoxifen. Despite the short-term success of tamoxifen usage, its long time treatment has been associated with significant side effects. Therefore, there is a pressing need for the development of novel anti-estrogens for the prevention and treatment of BC. OBJECTIVE: In this study, we evaluate the inhibitory effect of Cannabis sativa phytoconstituents on ER-α. METHODS: Glide and induced fit docking followed by ADME, automated QSAR and binding free energy (Δ>Gbind) studies were used to evaluate anti-breast cancer and ER-α inhibitory activity of Cannabis sativa, which has been reported to be effective in inhibiting breast cancer cell proliferation. RESULTS: Phyto-constituents of Cannabis sativa possess lower docking scores and good ΔGbind when compared to that of tamoxifen. ADME and AutoQSAR studies revealed that our lead compounds demonstrated the properties required to make them promising therapeutic agents. CONCLUSION: The results of this study suggest that naringenin, dihydroresveratrol, baicalein, apigenin and cannabitriol could have relatively better inhibitory activity than tamoxifen and could be a better and patent therapeutic candidate in the treatment of BC. Further research such as in vivo and/or in vitro assays could be conducted to verify the ability of these compounds.


Subject(s)
Breast Neoplasms/drug therapy , Cannabis/chemistry , Estrogen Receptor alpha/antagonists & inhibitors , Plant Preparations/pharmacology , Estrogen Antagonists/chemistry , Estrogen Antagonists/pharmacology , Female , Humans , Molecular Docking Simulation , Patents as Topic , Plant Preparations/chemistry , Quantitative Structure-Activity Relationship , Tamoxifen/pharmacology
7.
Curr Drug Discov Technol ; 18(4): 554-569, 2021.
Article in English | MEDLINE | ID: mdl-32729419

ABSTRACT

BACKGROUND: In a bid to come up with effective compounds as inhibitors for antimalarial treatment, we built a library of 2,000 traditional Chinese medicine(TCM)-derived compounds retrieved from TCM Database@Taiwan. METHODS: The active sites of both the wild type and mutant Plasmodium falciparum dihydrofolatereductase (pfDHFR) were explored using computational tools. pfDHFR, one of the prime drug targets in the prevention of malaria infection induced by the female anopheles mosquito has continued to offer resistance to drugs (antifolates) due to mutation in some of the key amino acid residues crucial for its inhibition. RESULTS: We utilized virtual throughput screening and glide XP docking to screen the compounds, and 8 compounds were found to have promising docking scores with both the wild type and mutant pfDHFR. They were further subjected to Induce Fit Docking (IFD) to affirm their inhibitory potency. The ADME properties and biological activity spectrum of the compounds were also considered. The inhibition profile of the compounds revealed that a number of compounds formed intermolecular interactions with ASP54, ILE14, LEU164, SER108/ASN108, ARG122 and ASP58. Most of the compounds can be considered as drug candidates due to their antiprotozoal activities and accordance with the Lipinski's Rule of Five (ROF). CONCLUSION: The outcome of the present study should further be investigated to attest the efficacy of these compounds as better drug candidates than the antifolates.


Subject(s)
Antimalarials/pharmacology , Drugs, Chinese Herbal/pharmacology , Malaria, Falciparum/prevention & control , Plasmodium falciparum/drug effects , Protozoan Proteins/antagonists & inhibitors , Animals , Antimalarials/chemistry , Antimalarials/therapeutic use , Catalytic Domain/drug effects , Drug Design/methods , Drugs, Chinese Herbal/chemistry , Drugs, Chinese Herbal/therapeutic use , Humans , Malaria, Falciparum/parasitology , Molecular Docking Simulation , Plasmodium falciparum/enzymology , Plasmodium falciparum/genetics , Protozoan Proteins/genetics , Tetrahydrofolate Dehydrogenase/genetics
8.
Bioimpacts ; 10(4): 227-234, 2020.
Article in English | MEDLINE | ID: mdl-32983938

ABSTRACT

Introduction: Gout is a type of painful inflammation initiated by the interactions between monosodium urate crystals and connective tissue. Xanthine oxidase (XO) catalyzes the oxidation of hypoxanthine to xanthine, then to uric acid. The primary treatments for gout include XO inhibitors. At present, allopurinol is the most used XO inhibitor for the treatment of gout. However, it can cause adverse effects commonly known as allopurinol hypersensitivity syndrome, thereby limiting its usage. Consequently, it is necessary to develop potent and less toxic inhibitors of XO. Chromolaena odorata is one of such plants under investigation for its diverse health benefits. Methods: Phytochemicals of C. odorata were screened against XO receptor, using molecular docking. The top five hit compounds of glide docking yield flavones scaffold which were subjected to induced fit docking (IFD) and absorption, distribution, metabolism, and excretion (ADME) studies. Results: The result showed that flavones scaffold of C. odorata can bind with higher affinity and lower free energy values when compared to that of the standard, allopurinol. The IFD scores of the flavones scaffold range from -1525.25 to -1527.99 kcal/mol. Conclusion: Our results have shown that flavones scaffold might have the potential to act as an effective drug candidate when compared to allopurinol in treating and/or preventing gout and some inflammatory condition.

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