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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
Ligand binding sites can be predicted either by experimental studies or computational tools. However, binding site prediction tools often provide multiple binding sites, and users face challenges in opting the right active site. To overcome this limitation, MD simulation provides detailed information about their structural dynamics at an atomic level in a realistic time frame (Table 5.1) [41]. MD in association with other methods can be used to calculate the binding energy of top scored docking ligands and help in finding the most promising drug candidate. Based on the binding energies, ligands are preferred for further in vitro and in vivo validations [42].
Opioids Analgesics and Antagonists
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
R. Rachana, Tanya Gupta, Saumya Yadav, Manisha Singh
Further elaborating the process of developing of a new drug, we may have to target various signaling molecules and pathways while acting on the same receptor subtype. This strategy has been a very useful and crucial way of developing pathway specific ligands. Studying the pathways and the interactions between different targets and the drug molecules, ligand binding can be modified to show minimum side effects along with specific therapeutic applications thus, efficiency of the drug can be improved along with increasing the effectiveness of the therapy (Jamshidi et al., 2015).
Receptors for Neuropeptides: Receptor Isolation Studies and Molecular Biology
Published in Edwin E. Daniel, Neuropeptide Function in the Gastrointestinal Tract, 2019
Jean-Pierre Vincent, Patrick Kitabgi
From the amount of protein estimated by silver staining or amino acid analysis, binding capacities of the purified receptors were calculated to be between 5 and 20 nmol/mg protein (Table 5). These values are close to the theoretical binding capacities of pure receptors calculated on the basis of one ligand binding site per molecule of receptor. Therefore, it seems that the μ- and δ-opioid receptors as well as the high- and low-affinity neurotensin receptors have been purified to apparent homogeneity.
Pharmacoinformatics-based strategy in designing and profiling of some Pyrazole analogues as novel hepatitis C virus inhibitors with pharmacokinetic analysis
Published in Egyptian Journal of Basic and Applied Sciences, 2023
Stephen Ejeh, Adamu Uzairu, Gideon A. Shallangwa, Stephen E. Abechi, Muhammad Tukur Ibrahim
The reference receptor was uploaded into internal coordinate mechanics (ICM) software. The water molecules were removed from the binding pocket of the receptor and all hydrogen and HisProAsnGlnCys were optimized. Next, the receptor grid binding site map was created and extends an extra 4 Å in any direction as it defined the ligand binding pocket for docking at each site. The Monte Carlo algorithm of the ICM apps was employed to globally optimize a set of ligand internal coordinates in the space of the protein pocket’s grid potential maps. The ligand binding site is the center of a rectangular box with 0.5 Å grid spacing where the maps are derived. Ligand binding functions are graded based on how well the ligand binds to the complex binding site, and a user-defined subset of the highest-scoring poses is reranked utilizing the full ICM scoring tool [23,24].
A molecular perspective on identifying TRPV1 thermosensitive regions and disentangling polymodal activation
Published in Temperature, 2023
Dustin D. Luu, Aerial M. Owens, Mubark D. Mebrat, Wade D. Van Horn
In the concatemer and other studies, a Hill model of cooperativity can be used to assess the allosteric implications between multiple ligand-binding sites [189]. A Hill coefficient (Kd) for additional oxygen-binding molecules [190]. Highly positive cooperative events, like found in hemoglobin, will generally have minimal intermediate bound states with an “all or nothing” binding process. In the context of hemoglobin, which is exceptionally cooperative, it is typically found in either an unbound or fully bound state [191]. Conversely, negative cooperativity functions to decrease the affinity of ligand binding as more ligands bind the substrate. The outcomes of negative cooperativity are more populated and longer-lasting intermediate bound states [191]. A noncooperative process effectively has independent binding sites [191]. Analysis of the rTRPV1–CAP concatemer study identifies a Hill coefficient near unity, indicating that CAP activation is noncooperative. This appears to agree with the conclusion that CAP binding to a single subunit can fully open rTRPV1 [180]. In contrast, rTRPV1 concatemer proton activation exhibits positive cooperativity (4,180]. The reported differences in cooperativity between CAP and protons shines a light on mechanistically distinct TRPV1 activation modes and provide a vignette into the complexity of deciphering the polymodal crosstalk between activation modes.
The α9α10 nicotinic acetylcholine receptor: a compelling drug target for hearing loss?
Published in Expert Opinion on Therapeutic Targets, 2022
The market for a drug indicated for prevention of noise-induced, hidden hearing loss and presbycusis is huge and will grow further. In spite of the existence of such a huge market, compounds in pharma pipelines are scarce. Although a wide range of compounds with different cellular targets have been tested in animal models and some used in the clinics, their effectiveness is limited, and serendipitous discoveries of effective pharma treatments are lacking. In this regard, the α9α10 nAChR emerges as a new target to be investigated. The rationale behind this new avenue of research is that activation of the α9α10 nAChRs present in OHCs prevents noise-induced, hidden hearing loss and presbycusis. Two alternative compounds could be developed: agonists that bind to the orthosteric ligand binding site or positive allosteric modulators that enhance agonist activity. Compared to other nAChRs, very few agonists of α9α10 nAChRs have been described so far, and most classical nAChR agonists act as antagonists of this receptor [63]. The crystal structure of the α9 extracellular domain, together with molecular docking simulations and mutagenesis experiments, is beginning to decipher residues that impair agonist binding in α9α10 compared to other nAChRs [68,167,168]. In this regard, very recent discoveries shed light into novel α9α10 nAChR agonists [169].