Complementary Approaches to Existing Target Based Drug Discovery for Identifying Novel Drug Targets

Vasaikar, Suhas; Bhatia, Pradeep Kumar; Bhatia, P. G.; Yaiw, Koon-Chu

doi:10.3390/biomedicines4040027

Cited by 27 publications

(16 citation statements)

References 86 publications

(106 reference statements)

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“…Multi-target drug discovery represents an innovative approach of medicinal chemistry to overcome a crisis in drug design, reflected in the small number of newly approved drugs. This approach is based on the concepts of privileged scaffolds, polypharmacology, and multifactorial diseases [ 7 , 8 , 9 , 10 , 11 , 12 ]. Thus, multi-target drugs can be designed for the simultaneous treatment of, for example, autoimmune, inflammatory, and invasive diseases.…”

Section: Introductionmentioning

confidence: 99%

Biological Activities and ADMET-Related Properties of Novel Set of Cinnamanilides

et al. 2020

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A series of nineteen novel ring-substituted N-arylcinnamanilides was synthesized and characterized. All investigated compounds were tested against Staphylococcus aureus as the reference strain, two clinical isolates of methicillin-resistant S. aureus (MRSA), and Mycobacterium tuberculosis. (2E)-N-[3-Fluoro-4-(trifluoromethyl)phenyl]-3-phenylprop-2-enamide showed even better activity (minimum inhibitory concentration (MIC) 25.9 and 12.9 µM) against MRSA isolates than the commonly used ampicillin (MIC 45.8 µM). The screening of the cell viability was performed using THP1-Blue™ NF-κB cells and, except for (2E)-N-(4-bromo-3-chlorophenyl)- 3-phenylprop-2-enamide (IC50 6.5 µM), none of the discussed compounds showed any significant cytotoxic effect up to 20 μM. Moreover, all compounds were tested for their anti-inflammatory potential; several compounds attenuated the lipopolysaccharide-induced NF-κB activation and were more potent than the parental cinnamic acid. The lipophilicity values were specified experimentally as well. In addition, in silico approximation of the lipophilicity values was performed employing a set of free/commercial clogP estimators, corrected afterwards by the corresponding pKa calculated at physiological pH and subsequently cross-compared with the experimental parameters. The similarity-driven property space evaluation of structural analogs was carried out using the principal component analysis, Tanimoto metrics, and Kohonen mapping.

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Section: Introductionmentioning

confidence: 99%

Biological Activities and ADMET-Related Properties of Novel Set of Cinnamanilides

et al. 2020

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“…Another approach, which is based on the so-called multi-target agents, aims to develop drugs with dual anti-inflammatory and antimicrobial activity [ 32 ]. This approach is based on the concepts of privileged scaffolding, polypharmacology, and multifactorial diseases [ 33 , 34 , 35 , 36 , 37 , 38 , 39 ]. Thus, multi-target drugs can be designed for the simultaneous treatment of, for example, autoimmune, inflammatory, and invasive diseases.…”

Section: Drugs With Anti-inflammatory Effectmentioning

confidence: 99%

Chronic Inflammatory Diseases, Anti-Inflammatory Agents and Their Delivery Nanosystems

Plachá

Jampílek

2021

Pharmaceutics

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Inflammatory diseases, whether caused by excessive stress on certain tissues/parts of the body or arising from infections accompanying autoimmune or secondary diseases, have become a problem, especially in the Western world today. Whether these are inflammations of visceral organs, joints, bones, or the like, they are always a physiological reaction of the body, which always tries to eradicate noxious agents and restore tissue homeostasis. Unfortunately, this often results in damage, often irreversible, to the affected tissues. Nevertheless, these inflammatory reactions of the body are the results of excessive stress, strain, and the generally unhealthy environment, in which the people of Western civilization live. The pathophysiology and pathobiochemistry of inflammatory/autoimmune processes are being studied in deep detail, and pharmaceutical companies are constantly developing new drugs that modulate/suppress inflammatory responses and endogenous pro-inflammatory agents. In addition to new specifically targeted drugs for a variety of pro-inflammatory agents, a strategy can be found for the use of older drugs, which are formulated into special nanodrug delivery systems with targeted distribution and often modified release. This contribution summarizes the current state of research and development of nanoformulated anti-inflammatory agents from both conventional drug classes and experimental drugs or dietary supplements used to alleviate inflammatory reactions.

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“…Target‐based drug discovery has generally been accepted as the preferred method to discover new chemical entities and develop corresponding therapeutic compounds . The rational drug design is usually based on the well‐defined 3D structure of globular proteins; however, targeting disordered proteins is a challenging task, since these proteins exist in a highly flexible state and form a dynamic structural ensemble without a well‐defined 3D structure.…”

Section: Druggability Of Intrinsically Disordered Proteinsmentioning

confidence: 99%

Pharmacological targeting of α‐synuclein and TPPP/p25 in Parkinson's disease: challenges and opportunities in a Nutshell

Oláh

Ovádi

2019

FEBS Letters

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With the aging of population, neurological disorders, and especially disorders involving defects in protein conformation (also known as proteopathies) pose a serious socio‐economic problem. So far there is no effective treatment for most proteopathies, including Parkinson's disease (PD). The mechanism underlying PD pathogenesis is largely unknown, and the hallmark proteins, α‐synuclein (SYN) and tubulin polymerization promoting protein (TPPP/p25) are challenging drug targets. These proteins are intrinsically disordered with high conformational plasticity, and have diverse physiological and pathological functions. In the healthy brain, SYN and TPPP/p25 occur in neurons and oligodendrocytes, respectively; however, in PD and multiple system atrophy, they are co‐enriched and co‐localized in both cell types, thereby marking pathogenesis. Although large inclusions appear at a late disease stage, small, soluble assemblies of SYN promoted by TPPP/p25 are pathogenic. In the light of these issues, we established a new innovative strategy for the validation of a specific drug target based upon the identification of contact surfaces of the pathological SYN‐TPPP/p25 complex that may lead to the development of peptidomimetic foldamers suitable for pharmaceutical intervention.

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Complementary Approaches to Existing Target Based Drug Discovery for Identifying Novel Drug Targets

Cited by 27 publications

References 86 publications

Biological Activities and ADMET-Related Properties of Novel Set of Cinnamanilides

Biological Activities and ADMET-Related Properties of Novel Set of Cinnamanilides

Chronic Inflammatory Diseases, Anti-Inflammatory Agents and Their Delivery Nanosystems

Pharmacological targeting of α‐synuclein and TPPP/p25 in Parkinson's disease: challenges and opportunities in a Nutshell

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