Advancements in Cancer Therapeutics

2021 ◽  
pp. 89-115
Author(s):  
Serda Kecel Gunduz ◽  
Bilge Bicak ◽  
Aysen E. Ozel
Keyword(s):  
Protein Design ◽  
Complex Structure ◽  
Cancer Therapeutics ◽  
New Drugs ◽  
In Vivo Studies ◽  
Drug Induced ◽  
Dimensional Simulation ◽  
Dynamics And Function

In this chapter, computational approaches for the discovery of new drugs that are useful for diagnosis and treatment of disease will be described in three parts. MD technique uniquely supports protein design attempts by giving information about protein dynamics associated with atomic-level descriptions of the relationship between dynamics and function. The purpose of molecular docking is to provide an estimate of the ligand-receptor complex structure using computational methods. By this estimation, the mechanism of drug binding and action are described by determining the three-dimensional simulation of drug and drug-induced macrostructure. ADME characteristics are physicochemically significant descriptors and pharmacokinetically relevant properties used to design more effective drugs and new analogs. As a result, in-silico calculations can provide robust preliminary information as to drug activity and mechanism in the drug production process, as well as in vitro and in vivo studies.

scholarly journals Can We Panelize Seizure?

2020 ◽  
Author(s):  
Ruth Roberts ◽  
Simon Authier ◽  
R Daniel Mellon ◽  
Michael Morton ◽  
Ikuro Suzuki ◽  
...  
Keyword(s):  
Ion Channel ◽  
New Drugs ◽  
Detection Methods ◽  
In Vivo Studies ◽  
Design Stage ◽  
Early Screening ◽  
Drug Induced ◽  
Abnormal Movements

Abstract Seizure liability remains a significant cause of attrition in drug discovery and development, leading to loss of competitiveness, delays, and increased costs. Current detection methods rely on observations made in in vivo studies intended to support clinical trials, such as tremors or other abnormal movements. These signs could be missed or misinterpreted; thus, definitive confirmation of drug-induced seizure requires a follow-up electroencephalogram study. There has been progress in in vivo detection of seizure using automated video systems that record and analyze animal movements. Nonetheless, it would be preferable to have earlier prediction of seizurogenic risk that could be used to eliminate liabilities early in discovery while there are options for medicinal chemists making potential new drugs. Attrition due to cardiac adverse events has benefited from routine early screening; could we reduce attrition due to seizure using a similar approach? Specifically, microelectrode arrays could be used to detect potential seizurogenic signals in stem-cell-derived neurons. In addition, there is clear evidence implicating neuronal voltage-gated and ligand-gated ion channels, GPCRs and transporters in seizure. Interactions with surrounding glial cells during states of stress or inflammation can also modulate ion channel function in neurons, adding to the challenge of seizure prediction. It is timely to evaluate the opportunity to develop an in vitro assessment of seizure linked to a panel of ion channel assays that predict seizure, with the aim of influencing structure-activity relationship at the design stage and eliminating compounds predicted to be associated with pro-seizurogenic state.

Subcellular Organelle Targeting of Mitochondria Using Nanomedicines: Cancer Therapeutics and Theranostics Potential

2020 ◽  
Vol 10 (4) ◽  
pp. 358-390
Author(s):  
Revathi Paramasivam Oviya ◽  
Gopisetty Gopal
Keyword(s):  
Cancer Therapy ◽  
Cancer Cells ◽  
Complex Structure ◽  
Cancer Therapeutics ◽  
Recent Decade ◽  
Metabolic Reprogramming ◽  
In Vivo Studies ◽  
Drug Molecules

Nanomedicines are rapidly evolving in chemotherapy and image-guided theranostics for specific and controlled delivery of the target therapeutic molecule. Targeting the subcellular organelles of cancer cells has gained focus in the recent decade for precise targeting of cancer cells and the activation of specific cancer death pathways. This strategy also overcomes the limitations of conventional chemo and radiation therapies, such as non-specificity and toxicity to the surrounding healthy tissue. Diverse roles of mitochondria in cancer, including oxidative stress signaling, metabolic reprogramming, cell death evasion, and cell survival mechanism, make it a promising target for cancer therapy. However, targeting mitochondria is tedious due to its complex structure and strong negative membrane potential. Various studies have designed mitochondria specific inorganic-, polymer-, dendrimer-, peptide- and protein-based nanoformulations to overcome barriers in targeting mitochondria of cancer cells. In this review, we have summarized the recently developed mitochondria-targeted nanoformulations in the field of chemotherapy, imageguided phototherapy, and combinatorial therapies. These nanoformulations showed enhanced cell penetration and mitochondrial accumulation of the drug molecules. In vitro and in vivo studies have shown promising results and further pre-clinical and clinical studies are required to develop these nanoformulations as effective cancer therapy.

scholarly journals Computational toxicology

2015 ◽  
Vol 34 (12) ◽  
pp. 1304-1309 ◽  
Author(s):  
RT Naven ◽  
S Louise-May
Keyword(s):  
Critical Role ◽  
Pharmaceutical Research ◽  
In Vitro Models ◽  
New Drugs ◽  
Data Sets ◽  
Predictive Toxicology ◽  
Drug Induced ◽  
Chemical Toxicology

Predictive toxicology plays a critical role in reducing the failure rate of new drugs in pharmaceutical research and development. Despite recent gains in our understanding of drug-induced toxicity, however, it is urgent that the utility and limitations of our current predictive tools be determined in order to identify gaps in our understanding of mechanistic and chemical toxicology. Using recently published computational regression analyses of in vitro and in vivo toxicology data, it will be demonstrated that significant gaps remain in early safety screening paradigms. More strategic analyses of these data sets will allow for a better understanding of their domain of applicability and help identify those compounds that cause significant in vivo toxicity but which are currently mis-predicted by in silico and in vitro models. These ‘outliers’ and falsely predicted compounds are metaphorical lighthouses that shine light on existing toxicological knowledge gaps, and it is essential that these compounds are investigated if attrition is to be reduced significantly in the future. As such, the modern computational toxicologist is more productively engaged in understanding these gaps and driving investigative toxicology towards addressing them.

scholarly journals Immune responses to azacytidine in animal models of inflammatory disorders: a systematic review

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Sija Landman ◽  
Chiel van der Horst ◽  
Piet E. J. van Erp ◽  
Irma Joosten ◽  
Rob de Vries ◽  
...  
Keyword(s):  
Animal Models ◽  
Risk Of Bias ◽  
New Drugs ◽  
In Vivo Studies ◽  
Common Mechanism ◽  
Solid Organ ◽  
Inflammatory Disorders ◽  
Organ Rejection

AbstractInflammatory disorders like diabetes, systemic lupus erythematodes, inflammatory lung diseases, rheumatoid arthritis and multiple sclerosis, but also rejection of transplanted organs and GvHD, form a major burden of disease. Current classes of immune suppressive drugs to treat these disorders are never curative and side effects are common. Therefore there is a need for new drugs with improved and more targeted modes of action. Potential candidates are the DNA methyl transferase inhibitor 5-azacytidine (Aza) and its derivative 5-aza 2′deoxycitidine (DAC). Aza and DAC have been tested in several pre-clinical in vivo studies. In order to obtain an overview of disorders for which Aza and/or DAC can be a potential treatment, and to find out where information is lacking, we systematically reviewed pre-clinical animal studies assessing Aza or DAC as a potential therapy for distinct inflammatory disorders. Also, study quality and risk of bias was systematically assessed. In the 35 identified studies, we show that both Aza and DAC do not only seem to be able to alleviate a number of inflammatory disorders, but also prevent solid organ rejection and GvHD in in vivo pre-clinical animal models. Aza/DAC are known to upregulate FOXP3, a master transcription factor for Treg, in vitro. Seventeen studies described the effect on Treg, of which 16 studies showed an increase in Treg. Increasing Treg therefore seems to be a common mechanism in preventing inflammatory disorders by Aza/DAC. We also found, however, that many essential methodological details were poorly reported leading to an unclear risk of bias. Therefore, reported effects might be an overestimation of the true effect.

scholarly journals Lysophosphatidic Acid Induces Ligamentum Flavum Hypertrophy Through the LPAR1/Akt Pathway

2018 ◽  
Vol 45 (4) ◽  
pp. 1472-1486 ◽  
Author(s):  
Tangjun Zhou ◽  
Lin Du ◽  
Chen Chen ◽  
Chen Han ◽  
Xunlin Li ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Lysophosphatidic Acid ◽  
Molecular Mechanisms ◽  
Ligamentum Flavum ◽  
Akt Signaling ◽  
New Drugs ◽  
In Vivo Studies ◽  
Akt Phosphorylation

Background/Aims: Hypertrophic ligamentum flavum (LF) is a major cause of lumbar spinal stenosis. Our previous work showed that high levels of lysophosphatidic acid (LPA) expression are positively correlated with LF hypertrophy. This study aimed to further unveil how LPA regulates LF hypertrophy Methods: We studied LPAR1 expression in human LF cells using PCR and western blotting. Cell viability cell cycle, apoptosis rate and molecular mechanisms were assayed in LPAR1 knockdown or overexpression LF cells. LF hypertrophy and the molecular mechanism was confirmed in human samples and in in vivo studies. Results: The expression of LPA and its receptor LPAR1 is significantly higher in tissues or cells harvested from hypertrophic LF compared to healthy controls. Moreover, LPA promoted LF cell proliferation by interacting with LPAR1. This conclusion is supported by the fact that depletion or overexpression of LPAR1 changed the effect of LPA on LF cell proliferation. LPA also inhibits apoptosis in LF cells through the receptor LPAR1. Importantly, we demonstrated that the LPA-LPAR1 interaction initiated Akt phosphorylation and determined cell proliferation and apoptosis. Our in vitro findings were supported by our in vivo evidence that lyophilized LPA significantly induced LF hypertrophy via the LPAR1-Akt signaling pathway. More importantly, targeted inhibition of LPAR1 by Ki16425 with a gel sponge implant effectively reduced LPA-associated LF hypertrophy. Taken together, these data indicate that LPA binds to the receptor LPAR1 to induce LF cell proliferation and inhibit apoptosis by activating AKT signaling cascades. Targeting this signaling cascade with Ki16425 is a potential therapeutic strategy for preventing LF hypertrophy. Conclusion: LPA-LPAR1-Akt activation is positively correlated with the proliferation and survival of LF cells. LPAR1 could be a target for new drugs and the development of new therapeutic methods for treating LF hypertrophy.

Synthesis, biology, computational studies and in vitro controlled release of new isoniazid-based adamantane derivatives

2019 ◽  
Vol 11 (21) ◽  
pp. 2779-2802 ◽  
Author(s):  
Andria Papageorgiou ◽  
Angeliki-Sofia Foscolos ◽  
Ioannis P Papanastasiou ◽  
Marilena Vlachou ◽  
Angeliki Siamidi ◽  
...  
Keyword(s):  
Antitubercular Activity ◽  
New Drugs ◽  
In Vivo Studies ◽  
Adamantane Derivatives ◽  
Dissolution Profile ◽  
Pharmacological Test ◽  
Dynamics Simulations ◽  
Drug Resistant Strains

Aim: There is a necessity for new drugs to be more efficient than today's standard due to the emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb) Results/methodology: 12 new isoniazid-based adamantane derivatives were synthesized and tested for their antitubercular activity. The pharmacological test results and the aqueous dissolution profile of representative examples of the new molecules are in agreement with the computational results obtained from docking poses and molecular dynamics simulations on the tested compounds. Conclusion: Among their congeners, the adamantane isonicotinoyl hydrazones Ia and Ih exhibit the best antitubercular activity (MIC = 0.04 μg/ml) and the lowest cytotoxicity (selectivity index ≥2500). These results are useful for in future in vivo studies.

scholarly journals Morpholine derivatives as potential agents for neurological manifestations of nervous system diseases

2020 ◽  
Vol 2 (1) ◽  
pp. 16-35
Author(s):  
Veronika A. Prikhodko ◽  
Yuriy I. Sysoev ◽  
Sergey Okovityi
Keyword(s):  
Nervous System ◽  
Social Impact ◽  
Neurological Diseases ◽  
Clinical Manifestations ◽  
Biologically Active ◽  
New Drugs ◽  
In Vivo Studies ◽  
Morpholine Derivatives

Diseases of the nervous system, especially those of vascular, traumatic, and neurodegenerative nature, are characterized by high prevalence, disability and mortality rates, and therefore have a particularly big medical and social impact. Currently, pharmacotherapy options for these diseases are limited to a relatively small number of clinically proven drugs, which is largely due to the difficulties associated with the translation of preclinical studies results. This explains the essential importance of discovering and developing new drugs, both effective and safe, that could be used to reduce clinical manifestations of neurological disorders. The present review is aimed to give a detailed account of several biologically active derivatives of morpholine, a six-membered heterocyclic compound. As demonstrated by a number of in vitro and in vivo studies using cell and animal models, morpholine derivatives should be considered viable drug candidates for a broad range of neurological diseases.

scholarly journals Virtual Drug Repurposing Study Against SARS-CoV-2 TMPRSS2 Target

2020 ◽  
Author(s):  
Serdar Durdagi
Keyword(s):  
Clinical Investigation ◽  
Binding Free Energy ◽  
Drug Repurposing ◽  
Md Simulations ◽  
Positive Control ◽  
New Drugs ◽  
In Vivo Studies ◽  
Approved Drugs

<p>Currently, the world suffers from a new coronavirus SARS-CoV-2 that causes COVID-19. Therefore, there is a need for the urgent development of novel drugs and vaccines for COVID-19. Since it can take years to develop new drugs against this disease, here we used a hybrid combined molecular modeling approach in virtual drug screening repurposing study to identify new compounds against this disease. One of the important SARS-CoV-2 targets namely type 2 transmembrane serine protease (TMPRSS2) was screened with NPC’s NIH small molecule library which includes approved drugs by FDA and compounds in clinical investigation. We used 6654 small molecules in molecular docking and top-50 docking scored compounds were initially used in short (10-ns) molecular dynamics (MD) simulations. Based on average MM/GBSA binding free energy results, long (100-ns) MD simulations were employed for the identified hits. Both binding energy results as well as crucial residues in ligand binding were also compared with a positive control TMPRSS2 inhibitor, Camostat mesylate. Based on these numerical calculations we proposed a compound (benzquercin) as strong TMPRSS2 inhibitor. If these results can be validated by in vitro and in vivo studies, benzquercin can be considered to be used as inhibitor of TMPRSS2 at the clinical studies.</p>

scholarly journals Simulations of Promising Indolizidine—α6-β2 Nicotinic Acetylcholine Receptor Complexes

2021 ◽  
Vol 22 (15) ◽  
pp. 7934
Author(s):  
Francis A. Acquah ◽  
Matthew Paramel ◽  
Adama Kuta ◽  
Syed R. Hussaini ◽  
David R. Wallace ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Nicotine Addiction ◽  
New Drugs ◽  
In Vivo Studies ◽  
Nicotinic Acetylcholine ◽  
Receptor Complexes

Smoking-cessation drugs bind many off-target nicotinic acetylcholine receptors (nAChRs) and cause severe side effects if they are based on nicotine. New drugs that bind only those receptors, such as α6β2* nAChR, implicated in nicotine addiction would avoid the off-target binding. Indolizidine (-)-237D (IND (-)-237D), a bicyclic alkaloid, has been shown to block α6β2* containing nAChRs and functionally inhibit the nicotine-evoked dopamine release. To improve the affinity of indolizidine (-)-237D for α6β2*, we built a library of 2226 analogs. We screened virtually the library against a homology model of α6β2 nAChR that we derived from the recent crystal structure of α4β2 nAChR. We also screened the crystal structure of α4β2 nAChR as a control on specificity. We ranked the compounds based on their predicted free energy of binding. We selected the top eight compounds bound in their best pose and subjected the complexes to 100 ns molecular dynamics simulations to assess the stability of the complexes. All eight analogs formed stable complexes for the duration of the simulations. The results from this work highlight nine distinct analogs of IND (-)-237D with high affinity towards α6β2* nAChR. These leads can be synthesized and tested in in vitro and in vivo studies as lead candidates for drugs to treat nicotine addiction.

scholarly journals Hexavalent bispecific antibodies represent a new class of anticancer therapeutics: 1. Properties of anti-CD20/CD22 antibodies in lymphoma

Blood ◽  
2009 ◽  
Vol 113 (24) ◽  
pp. 6161-6171 ◽  
Author(s):  
Edmund A. Rossi ◽  
David M. Goldenberg ◽  
Thomas M. Cardillo ◽  
Rhona Stein ◽  
Chien-Hsing Chang
Keyword(s):  
B Cells ◽  
Ex Vivo ◽  
Cancer Therapeutics ◽  
Bispecific Antibodies ◽  
In Vivo Studies ◽  
Lymphoma Cells ◽  
New Class ◽  
Anti Cd20

Abstract The dock and lock (DNL) method is a new technology for generating multivalent antibodies. Here, we report in vitro and in vivo characterizations of 20-22 and 22-20, a pair of humanized hexavalent anti-CD20/22 bispecific antibodies (bsAbs) derived from veltuzumab (v-mab) and epratuzumab (e-mab). The 22-20 was made by site-specific conjugation of e-mab to 4 Fabs of v-mab; 20-22 is of the opposite configuration, composing v-mab and 4 Fabs of e-mab. Each bsAb translocates both CD22 and CD20 into lipid rafts, induces apoptosis and growth inhibition without second-antibody crosslinking, and is significantly more potent in killing lymphoma cells in vitro than their parental antibodies. Although both bsAbs triggered antibody-dependent cellular toxicity, neither displayed complement-dependent cytotoxicity. Intriguingly, 22-20 and 20-22 killed human lymphoma cells in preference to normal B cells ex vivo, whereas the parental v-mab depleted malignant and normal B cells equally. In vivo studies in Daudi tumors revealed 20-22, despite having a shorter serum half-life, had antitumor efficacy comparable with equimolar v-mab; 22-20 was less potent than 20-22 but more effective than e-mab and control bsAbs. These results indicate multiple advantages of hexavalent anti-CD20/22 bsAbs over the individual parental antibodies and suggest that these may represent a new class of cancer therapeutics.

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