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Contributors to Cancer Susceptibility, Development and Treatment: Cyclic Nucleotides, Steroids and Autophagy Modulators

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Journal of Biosciences and Medicines 2022年第2期10卷 65-86页

作者： wynford robert williams Faculty of Life Sciences & Education University of South Wales Cardiff UK

Cell autophagy and apoptosis processes are of interest in drug development and contribute to the chemotherapy outcomes of patients receiving cancer treatment. The functional roles of cyclic nucleotides in cells include maintenance of metabolic homeostasis. cGMP and steroid compounds participate in apoptotic and autophagic events, and modulate the function of multi-drug resistance proteins. Endogenous steroid and cyclic nucleotide ratios change with ageing and this may initiate detrimental changes in cell function. This study uses a computational chemistry approach to investigate molecular similarity within chemotherapeutic and steroid compound structures. Modulators of autophagy/apoptosis and endogenous steroid structures all demonstrate molecular similarity to the structure of cGMP. Relative molecular similarity within these structures facilitates additive and synergistic treatment effects. Endogenous steroids are natural modulators of autophagy and apoptosis;concentration changes consequently have the potential to impact cancer risks.

关键词： Apoptosis Chemotherapy Molecular Similarity Breast Cancer Prostate Cancer

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Journal of Biosciences and Medicines 2022年第5期10卷 86-94页

作者： wynford robert williams Faculty of Life Sciences & Education University of South Wales Cardiff UK

Tumor promoters, apoptosis and autophagy modulators, chemotherapy drugs, and endogenous steroids demonstrate molecular similarity relative to cyclic nucleotide structure. This study explores relative molecular similarity within established human carcinogen structures using computational chemistry software. Molecular structures of conventional carcinogenic drugs and industrial agents demonstrate molecular similarity with a focus on the guanine base and nucleotide cyclized ring. Structures of volatile and gaseous anesthetic carcinogens do not conform to conventional 3-point pharmacophore-based fits characteristic of receptor-binding drugs. The results of this study provide some insight into how carcinogen structures may interact with endogenous compounds to disrupt cyclic nucleotide-driven homeostatic mechanisms.

关键词： Anesthetics Cancer Carcinogens Guanosine Cyclic Monophosphate Molecular Similarity

Relative Molecular Similarity in Compound Structures Modulating Neurodegenerative Apoptosis

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Journal of Biosciences and Medicines 2023年第2期11卷 105-123页

作者： wynford robert williams Faculty of Life Sciences & Education University of South Wales Cardiff UK

Neurodegeneration is attributable to metabolic disturbances in the various cell types responsible for this condition, in respect of glucose utilisation and dysfunctional mitochondrial oxidative mechanisms. The properties of neurotoxins and antagonists that limit their action are well documented in disease models, whereas effective therapy is very limited. Cell apoptosis, a general marker of neurodegeneration, is also of therapeutic interest in the treatment of cancer. cGMP nucleotide influences apoptosis and has a role in maintaining equilibrium within cell redox parameters. The chemical structure of cGMP provides a comparative template for demonstrating relative molecular similarity within the structures of natural and synthetic compounds influencing tumour cell apoptosis. The present study uses computational software to investigate molecular similarity within the structures of cGMP and compounds that modulate cell apoptosis in experimental models of diabetic peripheral neuropathy (DPN), Parkinson’s and multiple sclerosis. Differential molecular similarity demonstrated in neurotoxin and antagonist structures implicate metabolite impairment of cGMP signaling function as a common mechanism in the initial phases of these neurodegenerative conditions.

关键词： Apoptosis cGMP Neurodegeneration Neurotoxins Molecular Similarity

Cytotoxicity of Cholesterol Oxides and the Consequences of Relative Molecular Similarity to cGMP Nucleotide

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Journal of Biosciences and Medicines 2023年第11期11卷 190-207页

作者： wynford robert williams Faculty of Life Sciences & Education University of South Wales Cardiff UK

Cholesterol and cholesterol oxides impact on the functional properties of cells, in respect of the intracellular and extracellular distribution of compounds across cell membranes, carcinogenesis and drug resistance. Abnormal levels of cholesterol oxides and steroids in cancerous tissues promote interest in steroid receptor cross-talk during cell-signalling and the steroid metabolome of cancer patients. The research literature links the cytotoxic properties of oxysterols to interference with the NO/cGMP pathway. cGMP participates in cell-signalling and has a molecular structure that relates to cancer-inducing and cancer-preventing agents. This study uses a molecular modelling approach to compare the structures of cholesterol oxides to cGMP. Cholesterol and cholesterol oxide structures fit to a cGMP structural template in several ways, some of which are replicated by corticosteroids and gonadal steroid hormones. The results of this study support the concept that cholesterol oxides modulate cell apoptosis and autophagy via the NO/cGMP pathway and in conjunction with steroid hormones participate in modulating regulation of cell function by cGMP.

关键词： Cholesterol Oxides cGMP Oxysterols Molecular Similarity Apoptosis Autophagy Cancer

Cyclic Nucleotide Structural Differentiation of Compounds Modulating Apoptosis and Drug Resistance

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Journal of Biosciences and Medicines 2021年第8期9卷 10-28页

作者： wynford robert williams Faculty of Life Sciences & Education University of South Wales Cardiff UK

Carcinogenesis is associated with malfunction in the cGMP-mediated regulation of cytosolic Ca2+ and reactive oxygen species. Chemotherapy resistant cancer cells are re-sensitised to apoptosis by the action of a substantial number of natural compounds on cell membrane multidrug resistant proteins. Chemical structures of pro-apoptotic and anti-apoptotic compounds demonstrate relative molecular similarity to cGMP. This study uses a computational chemistry program to investigate molecular similarity within cGMP and chemo-preventative structures. Chemotherapeutic drugs and resistance modulators provide multiple fits to a nucleotide template that differ in their relationship to the cyclised ring of cGMP. The alternative fits of drug and modulator structures may relate to the development and unblocking of apoptosis and drug resistance.

关键词： Cancer Chemotherapy Guanosine Cyclic Monophosphate Molecular Similarity Multidrug Resistance