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Herbal Drug Discovery Against Inflammation: From Traditional Wisdom to Modern Therapeutics
Published in Amit Baran Sharangi, K. V. Peter, Medicinal Plants, 2023
Shalini Dixit, Karuna Shanker, Madhumita Srivastava, Priyanka Maurya, Nupur Srivastava, Jyotshna, Dnyaneshwar U. Bawankule
Secondary metabolites are low molecular weight organic compounds produced in plants. The biosynthesis of secondary metabolites is restricted to the selected plant groups and is exhibiting a huge structural diversity. These secondary metabolites which are generally used for the self-defense of plants attracted natural products researchers around the globe. The structures provided a number of pharmacophores compatible with the receptor molecules in the body. A large number of secondary metabolites also qualify the criterion of Lipinski rule to be considered as a drug. As a result, a number of blockbuster molecules provided by the plants as well as the marine source in the area of drug discovery. These compounds are mainly classified as flavonoids, terpenes, glycosides, steroids, and alkaloids. In recent trends, these molecules correspond to valuable contribution in pharmaceutics, cosmetics, and fine chemicals and more recently in nutraceuticals as well (Pichersky and Gang, 2000). We summarized a small understanding of these beautiful defensive compounds in the plant kingdom. Natural products obtained from the plants are summarized in Table 3.2.
Computational Drug Discovery and Development Along With Their Applications in the Treatment of Women-Associated Cancers
Published in Shazia Rashid, Ankur Saxena, Sabia Rashid, Latest Advances in Diagnosis and Treatment of Women-Associated Cancers, 2022
Rahul Kumar, Rakesh Kumar, Harsh Goel, Somorjit Singh Ningombam, Pranay Tanwar
General structural characteristics of ligands can be attained utilizing pharmacophore modelling, which can be used to screen the molecules with these characteristics [39]. A pharmacophore model can be formed from a set of well-known ligands. Despite this, data concerning 3D protein structures or protein-ligand complexes coupled with information about active sites can also be utilized to model a pharmacophore. By examining the binding site, a potential interaction between the active compound and the protein can be understood and pharmacophore models can be established from data on target protein structure followed by virtual screening and lead optimization [40].
Drug Discovery: From Hits to Clinical Candidates
Published in Divya Vohora, The Third Histamine Receptor, 2008
Sylvain Celanire, Florence Lebon, Holger Stark
The difficulty for the realization is rising with the given numbering. Depending on the definition of the pharmacophore, some differences in the approaches may be claimed. The strategic orientation for such a directed compound design has to orientate on the complexity of the disease and the optimization of treatment. An integrated approach and an additional approach on imidazole-based dual H1R/H3R antagonists have been realized by 201 (pKi 7.1 [H1] and 7.1 [H3]) [260] and 202 (pKi 8.2 [hH1] and 7.8 [hH3]) [261, 262], whereas a nonimidazole compound by a linker approach is represented with 203 (pKi 7.3 [H1] and 10.6 [H3]) (Figure 5.37) [263].
Overcoming challenges in developing small molecule inhibitors for GPVI and CLEC-2
Published in Platelets, 2021
Foteini-Nafsika Damaskinaki, Luis A. Moran, Angel Garcia, Barrie Kellam, Steve P. Watson
Molecular modeling and virtual experimentation are powerful tools in screening and design of ligands with enhanced selectivity and physicochemical properties (Figure 6). The structure of a protein binding site can be obtained by x-ray crystallography, cryogenic electron microscopy (cryo-EM), multi-dimensional nuclear magnetic resonance (NMR) and molecular simulations (or homology modeling) [72]. Electron density mapping and quaternary structure visualization allows for exploration of both structural and thermodynamic properties of target receptors and are useful for identifying or revealing drug binding sites and exploring a drug’s mode of action. This can be supported by virtual screening searches of compound libraries of interest to identify possible drug candidates based on the protein binding sites or the pharmacophore being developed [73]. A pharmacophore is a group of the minimum structural or chemical characteristic to achieve target binding, based on knowledge of established ligands or a receptor cavity structure and amino acid content. de novo virtual drug design can take advantage of the pharmacophore to modify existing chemotypes to design small molecules with expected high affinity and optimized physicochemical properties [73]. Crystal structures for both GPVI and CLEC-2 are also available, both with and without a ligand, providing an opportunity for conducting virtual drug design.
Cytotoxic oxindole derivatives: in vitro EGFR inhibition, pharmacophore modeling, 3D-QSAR and molecular dynamics studies
Published in Journal of Receptors and Signal Transduction, 2019
Sasikala Maadwar, Rajitha Galla
By the allocation of activity threshold range whole data set was fractioned into active (pIC50>4.75) and inactive (pIC50<4.75). These ligands were internally validated through PHASE module to generate/identify series of common pharmacophore hypotheses [18,19]. A 3D pharmacophore model was developed using a set of pharmacophore features to generate sites for all the compounds, concurring with various chemical features that may make easy non-covalent binding among the ligand and its binding pocket. Distinctive six pharmacophore features are hydrogen bond acceptor (A), hydrogen bond donor (D), hydrophobic group (H), negatively ionizable (N), positively ionizable (P) and aromatic ring (R). Maximum of six and a minimum of five sites were selected in order to obtain an efficient pharmacophore model. Hypotheses were generated by a systematic variation of number of sites (nsites) and the number of matching active compounds (nact). With nact = nact – tot. Initially (nact - tot) is the total number of active compounds in the training set, nsites. The scoring protocol provides a ranking of different hypotheses to choose the most appropriate for further investigation.
COPD: preclinical models and emerging therapeutic targets
Published in Expert Opinion on Therapeutic Targets, 2019
Esther Barreiro, Xuejie Wang, Jun Tang
Nonselective inhibitors of BRD are currently being used for the treatment of cancer and metabolic and cardiovascular diseases [56,60]. Recently, more selective inhibitors of BRD4 that specifically target airway remodeling have been developed in which a pharmacophore model was used [56,60,61]. It should be mentioned that by definition a pharmacophore is a group of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with a specific biological target to trigger (or block) its biological response [62]. The purpose of those drugs is to decrease the levels of neutrophilic inflammation in the airways as well as to prevent the change of the epithelial cell state to avoid/reduce myofibroblast growth in response to viral and/or allergen exposures in patients.