scholarly journals Selective Optimization of Side Activities (SOSA) as an Efficient Approach for Generation of New Leads from Old Drugs

2021 ◽  
pp. 287-297
Author(s):  
Preeti P. Mehta ◽  
Yogita Ozarde ◽  
Ranjit Gadhave ◽  
Arti Swami
Keyword(s):  
Structural Changes ◽  
Present Review ◽  
Secondary Effect ◽  
Pharmacokinetic Profiles ◽  
Promising Strategy ◽  
Primary Activity ◽  
Main Effect ◽  
Drug Discovery Program ◽  
Lead Generation ◽  
Old Drugs

The selective optimization of side activities (SOSA) approach appears to be a promising strategy for lead generation. In this approach old drugs are used to generate new hits or leads. The objective of SOSA is to prepare analogues of the hit molecule in order to transform the observed “side activity” into the main effect and to strongly reduce or abolish the initial pharmacological activity. The idea of taking a molecule with a primary activity in humans and then enhancing a secondary effect through structural changes describes the most common implementation of SOSA. An advantage to starting a drug discovery program with molecules that have already been tested in humans is that those molecules have already satisfied many safety criteria. Such molecules also likely have favourable pharmacokinetic profiles. In the present review different successful examples of SOSA switches are summarized. We hope that the present review will be useful for scientists working in the area of drug design and discovery.

scholarly journals Assays, Surrogates, and Alternative Technologies for a TB Lead Identification Program Targeting DNA Gyrase ATPase

2014 ◽  
Vol 20 (2) ◽  
pp. 265-274 ◽  
Author(s):  
Vaishali Humnabadkar ◽  
Prashanti Madhavapeddi ◽  
Halesha Basavarajappa ◽  
Md. Gulebahar Sheikh ◽  
Rajendra Rane ◽  
...  
Keyword(s):  
Mycobacterium Smegmatis ◽  
Specific Activity ◽  
Dna Gyrase ◽  
Enzyme Concentration ◽  
Alternative Technologies ◽  
Lead Identification ◽  
Drug Discovery Program ◽  
Lead Generation ◽  
Nanomolar Range

Mycobacterium tuberculosis (Mtb) DNA gyrase ATPase was the target of a tuberculosis drug discovery program. The low specific activity of the Mtb ATPase prompted the use of Mycobacterium smegmatis (Msm) enzyme as a surrogate for lead generation, since it had 20-fold higher activity. Addition of GyrA or DNA did not significantly increase the activity of the Msm GyrB ATPase, and an assay was developed using GyrB alone. Inhibition of the Msm ATPase correlated well with inhibition of Mtb DNA gyrase supercoiling across three chemical scaffolds, justifying its use. As the IC50 of compounds approached the enzyme concentration, surrogate assays were used to estimate potencies (e.g., the shift in thermal melt of Mtb GyrB, which correlated well with IC50s >10 nM). Analysis using the Morrison equation enabled determination of [Formula: see text]s in the sub-nanomolar range. Surface plasmon resonance was used to confirm these IC50s and measure the Kds of binding, but a fragment of Mtb GyrB had to be used. Across three scaffolds, the dissociation half life, t1/2, of the inhibitor-target complex was ≤8 min. This toolkit of assays was developed to track the potency of enzyme inhibition and guide the chemistry for progression of compounds in a lead identification program.

The structural carbohydrates and the in vitro digestibility of a ryegrass and a cocksfoot at two levels of nitrogenous fertilizer

1970 ◽  
Vol 74 (3) ◽  
pp. 457-462 ◽  
Author(s):  
R. Waite
Keyword(s):  
In Vitro Digestibility ◽  
Secondary Effect ◽  
Nitrogenous Fertilizer ◽  
Main Effect

SUMMARY‘Nitro-chalk” was applied to established swards of ryegrass S. 24 and cocksfoot S. 37 at the rate of 24 and 96 lb N/acre (27 and 107 kg N/ha) before growth commenced and after each cutting. The cuts were taken each time the grass reached a length of 10–11 in (8–9 in of cut herbage). The main effect was that the higher rate of fertilization allowed the grass to be harvested more frequently and this grass had lower pectin, cellulose and hemicellulose contents and a higher level of digestibility. A secondary effect was that the proportion of hemicellulose to cellulose was less in the more heavily fertilized grasses. The cocksfoot grasses at both levels of fertilizer were cut more frequently than the corresponding ryegrasses and were only slightly less digestible. There was some decline in the digestibility of the grasses from May to September which was associated with lengthening growth intervals and generally higher percentages of the structural constituents.

Edgeworth expansion of the distribution of Stein's statistic

1983 ◽  
Vol 93 (1) ◽  
pp. 163-175 ◽  
Author(s):  
Peter Hall
Keyword(s):  
Edgeworth Expansion ◽  
Exact Distribution ◽  
Double Sampling ◽  
Secondary Effect ◽  
Parent Population ◽  
Normal Parent ◽  
Main Effect

AbstractWe derive a two-term Edgeworth expansion for the distribution of Stein's double sampling statistic in the case of a non-normal parent population. The first term describes the main effect of skewness, while the second describes the main effect of kurtosis and the secondary effect of skewness. The remainder is shown to be uniformly negligible in comparison with these effects. Explicit conditions are given for the expansion to be valid. These conditions are considerably weaker than those which were imposed in an earlier derivation of the ‘exact’ distribution of Stein's statistic.

Exercise-induced hemolysis is caused by protein modification and most evident during the early phase of an ultraendurance race

2007 ◽  
Vol 102 (2) ◽  
pp. 582-586 ◽  
Author(s):  
Ashril Yusof ◽  
Renate M. Leithauser ◽  
Heinz J. Roth ◽  
Holger Finkernagel ◽  
Michael T. Wilson ◽  
...  
Keyword(s):  
Erythrocyte Membrane ◽  
Cell Population ◽  
Early Phase ◽  
Plasma Proteins ◽  
Protein Modification ◽  
Structural Changes ◽  
Intravascular Hemolysis ◽  
Sodium Phosphate Buffer ◽  
Main Effect ◽  
Exercise Induced

Whether structural changes of the erythrocyte membrane increase the susceptibility to hemolysis particularly of the relatively older cell population during the early phase of a 216-km ultrarace was tested in six male runners (age 53.6 ± 10.4 yr, height 175.8 ± 11.1 cm, body mass 75.9 ± 8.4 kg). Erythrocyte membrane spectrins were lowest ( P < 0.001) after 42 km (75.59 ± 5.25% of prerace) and increased ( P < 0.001) toward 216 km (88.27 ± 3.37%). Susceptibility to osmotic hemolysis was highest ( P < 0.01) after 42 km (107.34 ± 3.02 mOsm sodium phosphate buffer) with almost identical ( P > 0.05) values prerace (97.98 ± 3.41 mOsm) and postrace (98.61 ± 3.26 mOsm). Haptoglobin indicated intravascular hemolysis of 9.27 × 109 cells/l ( P < 0.05) during the initial 84 km. Changes in hematocrit and plasma proteins indicated an estimated total net erythrocyte loss of 3.47 × 1011 cells/l ( P < 0.05) after 21 km. This was compensated by a gain in erythrocytes ( P < 0.05) of 3.31 × 1011 cells/l during the final 132 km. A main effect ( P < 0.05) on erythropoietin suggests increased erythropoiesis throughout the race. Exercise-induced hemolysis reflects alterations in erythrocyte membrane spectrins and occurs particularly in the early phase of an ultraendurance race because of a relative older cell population.

scholarly journals Anti-Angiogenic Therapy: Current Challenges and Future Perspectives

2021 ◽  
Vol 22 (7) ◽  
pp. 3765
Author(s):  
Filipa Lopes-Coelho ◽  
Filipa Martins ◽  
Sofia A. Pereira ◽  
Jacinta Serpa
Keyword(s):  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Immune Therapy ◽  
Vascular Endothelial ◽  
Future Perspectives ◽  
Angiogenic Therapy ◽  
Vegf Signaling ◽  
Promising Strategy ◽  
Endothelial Growth Factor ◽  
Old Drugs

Anti-angiogenic therapy is an old method to fight cancer that aims to abolish the nutrient and oxygen supply to the tumor cells through the decrease of the vascular network and the avoidance of new blood vessels formation. Most of the anti-angiogenic agents approved for cancer treatment rely on targeting vascular endothelial growth factor (VEGF) actions, as VEGF signaling is considered the main angiogenesis promotor. In addition to the control of angiogenesis, these drugs can potentiate immune therapy as VEGF also exhibits immunosuppressive functions. Despite the mechanistic rational that strongly supports the benefit of drugs to stop cancer progression, they revealed to be insufficient in most cases. We hypothesize that the rehabilitation of old drugs that interfere with mechanisms of angiogenesis related to tumor microenvironment might represent a promising strategy. In this review, we deepened research on the molecular mechanisms underlying anti-angiogenic strategies and their failure and went further into the alternative mechanisms that impact angiogenesis. We concluded that the combinatory targeting of alternative effectors of angiogenic pathways might be a putative solution for anti-angiogenic therapies.

scholarly journals Iso-Partricin, an Aromatic Analogue of Amphotericin B: How Shining Light on Old Drugs Might Help Create New Ones

Antibiotics ◽  
2021 ◽  
Vol 10 (9) ◽  
pp. 1102
Author(s):  
Paweł Szczeblewski ◽  
Justyna Górska ◽  
Witold Andrałojć ◽  
Patryk Janke ◽  
Karolina Wąsik ◽  
...  
Keyword(s):  
Antifungal Activity ◽  
Amphotericin B ◽  
Structural Changes ◽  
Macrolide Antibiotic ◽  
Selective Toxicity ◽  
Host System ◽  
Old Drugs ◽  
Photoisomerization Process

Partricin is a heptaene macrolide antibiotic complex that exhibits exceptional antifungal activity, yet poor selective toxicity, in the pathogen/host system. It consists of two compounds, namely partricin A and B, and both of these molecules incorporate two cis-type bonds within their heptaenic chromophores: 28Z and 30Z. In this contribution, we have proven that partricins are susceptible to a chromophore-straightening photoisomerization process. The occurring 28Z→28E and 30Z→30E switches are irreversible in given conditions, and they are the only structural changes observed during the experiment. The obtained all-trans partricin’s derivatives, namely iso-partricins A and B, exhibit very promising features, potentially resulting in the improvement of their selective toxicity.

Fine Structural Changes in the Microvasculature of the Mouse Pinna: Aging and Radiation Injury

1974 ◽  
Vol 32 ◽  
pp. 54-55
Author(s):  
S. Phyllis Steamer ◽  
Rosemarie L. Devine
Keyword(s):  
Structural Changes ◽  
Radiation Treatment ◽  
Arterial Stenosis ◽  
Ultrastructural Changes ◽  
Vascular Effects ◽  
Microvascular Changes ◽  
Surrounding Connective Tissue ◽  
Fission Neutrons ◽  
Total Body

The importance of radiation damage to the skin and its vasculature was recognized by the early radiologists. In more recent studies, vascular effects were shown to involve the endothelium as well as the surrounding connective tissue. Microvascular changes in the mouse pinna were studied in vivo and recorded photographically over a period of 12-18 months. Radiation treatment at 110 days of age was total body exposure to either 240 rad fission neutrons or 855 rad 60Co gamma rays. After in vivo observations in control and irradiated mice, animals were sacrificed for examination of changes in vascular fine structure. Vessels were selected from regions of specific interest that had been identified on photomicrographs. Prominent ultrastructural changes can be attributed to aging as well as to radiation treatment. Of principal concern were determinations of ultrastructural changes associated with venous dilatations, segmental arterial stenosis and tortuosities of both veins and arteries, effects that had been identified on the basis of light microscopic observations. Tortuosities and irregularly dilated vein segments were related to both aging and radiation changes but arterial stenosis was observed only in irradiated animals.

Evaluation of single-electron movies of glutamine synthetase molecules

1983 ◽  
Vol 41 ◽  
pp. 280-281
Author(s):  
W. Kunath ◽  
E. Zeitler ◽  
M. Kessel
Keyword(s):  
Electron Microscope ◽  
Glutamine Synthetase ◽  
Electron Irradiation ◽  
Structural Damage ◽  
Structural Changes ◽  
Single Electron ◽  
Continuous Series ◽  
Digital Recording ◽  
Recording Device ◽  
Low Exposure

The features of digital recording of a continuous series (movie) of singleelectron TV frames are reported. The technique is used to investigate structural changes in negatively stained glutamine synthetase molecules (GS) during electron irradiation and, as an ultimate goal, to look for the molecules' “undamaged” structure, say, after a 1 e/Å2 dose.The TV frame of fig. la shows an image of 5 glutamine synthetase molecules exposed to 1/150 e/Å2. Every single electron is recorded as a unit signal in a 256 ×256 field. The extremely low exposure of a single TV frame as dictated by the single-electron recording device including the electron microscope requires accumulation of 150 TV frames into one frame (fig. lb) thus achieving a reasonable compromise between the conflicting aspects of exposure time per frame of 3 sec. vs. object drift of less than 1 Å, and exposure per frame of 1 e/Å2 vs. rate of structural damage.

Fine Structural Changes in the Adenohypophyses of Rats Following Destruction of the Pituitary Stalk

1977 ◽  
Vol 35 ◽  
pp. 496-497
Author(s):  
K. Kovacs ◽  
E. Horvath ◽  
J. M. Bilbao ◽  
F. A. Laszlo ◽  
I. Domokos
Keyword(s):  
Structural Changes ◽  
Tissue Injury ◽  
Anterior Lobe ◽  
Uranyl Acetate ◽  
Male Rats ◽  
Pituitary Stalk ◽  
Sequence Of Events ◽  
Pituitary Glands ◽  
Electrolytic Lesions ◽  
Ultrathin Sections

Electrolytic lesions of the pituitary stalk in rats interrupt adenohypophysial blood flow and result in massive infarction of the anterior lobe. In order to obtain a deeper insight into the morphogenesis of tissue injury and to reveal the sequence of events, a fine structural investigation was undertaken on adenohypophyses of rats at various intervals following destruction of the pituitary stalk.The pituitary stalk was destroyed electrolytically, with a Horsley-Clarke apparatus on 27 male rats of the R-Amsterdam strain, weighing 180-200 g. Thirty minutes, 1,2,4,6 and 24 hours after surgery the animals were perfused with a glutaraldehyde-formalin solution. The skulls were then opened and the pituitary glands removed. The anterior lobes were fixed in glutaraldehyde-formalin solution, postfixed in osmium tetroxide and embedded in Durcupan. Ultrathin sections were stained with uranyl acetate and lead citrate and investigated with a Philips 300 electron microscope.

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