Identification of selective mtb DHFR inhibitors by virtual screening and experimental approaches

2022 ◽  
Author(s):  
Juan He ◽  
Cong Li ◽  
Wei Hu ◽  
Chungen Li ◽  
Song Liu ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Experimental Approaches ◽  
Dhfr Inhibitors

scholarly journals Discovery of Amoebicidal Compounds by Combining Computational and Experimental Approaches

2020 ◽  
Author(s):  
Víctor Sebastián-Pérez ◽  
Ines Sifaoui ◽  
María Reyes-Batlle ◽  
Angélica Domínguez-De Barros ◽  
Atteneri López-Arencibia ◽  
...  
Keyword(s):  
Virtual Screening ◽  
Therapeutic Potential ◽  
Homology Model ◽  
Chemical Library ◽  
Granulomatous Amoebic Encephalitis ◽  
Screening Protocol ◽  
Recent Developments ◽  
Experimental Approaches ◽  
Lengthy Treatment

Pathogenic and opportunistic free-living amoebae such as Acanthamoeba spp. can cause keratitis (AK), which may ultimately lead to permanent visual impairment or blindness. Acanthamoeba can also cause a rare but usually fatal granulomatous amoebic encephalitis (GAE). Current therapeutic options for AK require a lengthy treatment with nonspecific drugs that often are associated with adverse effects. Recent developments in the field led us to target cAMP pathways, specifically phosphodiesterase. Guided by computational tools we targeted the Acanthamoeba phosphodiesterase, RegA. Computational studies led to the construction and validation of a homology model followed by a virtual screening protocol guided by induced-fit docking and chemical scaffold analysis using our MBC chemical library. Subsequently, 18 virtual screening hits were prioritized for further testing in vitro against A. castellanii, identifying amoebicidal hits containing piperidine and urea imidazole cores. Promising activities were confirmed in the resistant cyst form of the amoeba and in additional clinical Acanthamoeba strains, increasing their therapeutic potential. Mechanism of action studies revealed that these compounds produce apoptosis through ROS-mediated mitochondrial damage. These chemical families show promise for further optimization to produce effective anti-Acanthamoebal drugs.

Case studies on computer-based identification of natural products as lead molecules

2020 ◽  
Vol 5 (10) ◽  
Author(s):  
Conrad V. Simoben ◽  
Fidele Ntie-Kang ◽  
Dina Robaa ◽  
Wolfgang Sippl
Keyword(s):  
Natural Products ◽  
Virtual Screening ◽  
Experimental Validation ◽  
Chemical Space ◽  
Chemical Diversity ◽  
Computer Aided Drug Design ◽  
Drug Molecules ◽  
Success Stories ◽  
Computer Based ◽  
Experimental Approaches

AbstractThe development and application of computer-aided drug design/discovery (CADD) techniques (such as structured-base virtual screening, ligand-based virtual screening and neural networks approaches) are on the point of disintermediation in the pharmaceutical drug discovery processes. The application of these CADD methods are standing out positively as compared to other experimental approaches in the identification of hits. In order to venture into new chemical spaces, research groups are exploring natural products (NPs) for the search and identification of new hits and more efficient leads as well as the repurposing of approved NPs. The chemical space of NPs is continuously increasing as a result of millions of years of evolution of species and these data are mainly stored in the form of databases providing access to scientists around the world to conduct studies using them. Investigation of these NP databases with the help of CADD methodologies in combination with experimental validation techniques is essential to identify and propose new drug molecules. In this chapter, we highlight the importance of the chemical diversity of NPs as a source for potential drugs as well as some of the success stories of NP-derived candidates against important therapeutic targets. The focus is on studies that applied a healthy dose of the emerging CADD methodologies (structure-based, ligand-based and machine learning).

Learned Placebo Effects in the Immune System

2014 ◽  
Vol 222 (3) ◽  
pp. 148-153 ◽  
Author(s):  
Sabine Vits ◽  
Manfred Schedlowski
Keyword(s):  
Nervous System ◽  
Immune System ◽  
Associative Learning ◽  
Placebo Response ◽  
Immunosuppressive Drug ◽  
Immune Functions ◽  
Placebo Effects ◽  
New Therapeutic Approaches ◽  
Biological Variables ◽  
Experimental Approaches

Associative learning processes are one of the major neuropsychological mechanisms steering the placebo response in different physiological systems and end organ functions. Learned placebo effects on immune functions are based on the bidirectional communication between the central nervous system (CNS) and the peripheral immune system. Based on this “hardware,” experimental evidence in animals and humans showed that humoral and cellular immune functions can be affected by behavioral conditioning processes. We will first highlight and summarize data documenting the variety of experimental approaches conditioning protocols employed, affecting different immunological functions by associative learning. Taking a well-established paradigm employing a conditioned taste aversion model in rats with the immunosuppressive drug cyclosporine A (CsA) as an unconditioned stimulus (US) as an example, we will then summarize the efferent and afferent communication pathways as well as central processes activated during a learned immunosuppression. In addition, the potential clinical relevance of learned placebo effects on the outcome of immune-related diseases has been demonstrated in a number of different clinical conditions in rodents. More importantly, the learned immunosuppression is not restricted to experimental animals but can be also induced in humans. These data so far show that (i) behavioral conditioned immunosuppression is not limited to a single event but can be reproduced over time, (ii) immunosuppression cannot be induced by mere expectation, (iii) psychological and biological variables can be identified as predictors for this learned immunosuppression. Together with experimental approaches employing a placebo-controlled dose reduction these data provide a basis for new therapeutic approaches to the treatment of diseases where a suppression of immune functions is required via modulation of nervous system-immune system communication by learned placebo effects.

EXPERIMENTAL APPROACHES TO INVESTIGATING LIQUEFIED LPG SPRAY CHARACTERISTICS

2010 ◽  
Vol 20 (6) ◽  
pp. 553-564 ◽  
Author(s):  
Kwan-Soo Lee ◽  
Ki-Hyung Lee ◽  
Ki-Bum Kim ◽  
Yung-Jin Kim
Keyword(s):  
Spray Characteristics ◽  
Experimental Approaches

Ability of Naphthoquinondiazide Photoresists to Exothermic Decomposition

2020 ◽  
pp. 90-96
Author(s):  
A.N. Shushpanov ◽  
◽  
A.Ya. Vasin ◽  
V.M. Raykova ◽  
G.G. Gadzhiev ◽  
...  
Keyword(s):  
Convective Heat Exchange ◽  
Inert Atmosphere ◽  
Necessary Condition ◽  
Critical Temperatures ◽  
Good Convergence ◽  
Measuring Devices ◽  
Explosive Transformation ◽  
Exothermic Decomposition ◽  
Experimental Approaches ◽  
Experimental Values

The article considers two intermediate products of positive photoresists (1,2-naphthoquinonediazide-(2)-5-sulfonic acid of monosodium salt — Dye M and 1,2-naphthoquinonediazide-(2)-5-sulfochloride — Dye N2) from the standpoint of the tendency to explosive transformation. The experimental values of flash points determined on the OTP setup were 130 °C for Dye M and 95 °C for Dye N2. These values are close to the temperatures of the beginning of intensive exothermic decomposition (132 and 111 °C, respectively) obtained by thermogravimetric analysis. In addition, this analysis showed the presence of exothermic peaks in the studied samples both in the air and in an inert atmosphere of helium, which is a necessary condition for the manifestation of a tendency to explosive transformation. To confirm the possibility of explosive transformation, the flash points of substances were also determined by the calculation method according to the formula, which is a consequence of the problem of thermal explosion during convective heat exchange with the environment, and gave a result close to the experimental one (the values were 138 and 105 °C, respectively). For this calculation the following was used: the kinetic parameters determined by the Kissinger method, the values of the density of substances determined on an automatic pycnometer, as well as the values of the heat of explosive transformation obtained with the help of the Real computer thermodynamic program. The research results confirming the tendency of the investigated compounds to explosive transformation, as well as the critical temperatures, exceeding which is unacceptable, were transferred to the production of FGUP GNTs NIOPIK to create a safe technological process, safe storage and transportation conditions. Considering the accuracy of the measuring devices, the process temperature should not exceed 125 °C for Dye M and 90 °C for Dye N2. The conducted studies and calculations show that the computational and experimental approaches have good convergence, give values in a close temperature range, and increase the reliability of the obtained results.

Experimental approaches to the target editing of the CFTR gene using CRISPR-Cas9

2018 ◽  
pp. 14-20
Author(s):  
S.A. Smirnikhina ◽  
◽  
A.A. Anuchina ◽  
K.S. Kochergin-Nikitsky ◽  
E.P. Adilgereeva ◽  
...  
Keyword(s):  
Cftr Gene ◽  
Experimental Approaches
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