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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].
ChIP-seq analysis
Published in Altuna Akalin, Computational Genomics with R, 2020
Explore the co-localization of CTCF and ZNF143. Where are the co-bound regions located? Which sequence motifs do they contain? Download the ChIA-pet data for the GM12878 cell line, and look at the 3D interaction between different classes of binding sites. [Difficulty: Advanced]
Associated Methods
Published in Lars-Inge Larsson, Immunocytochemistry: Theory and Practice, 2020
Thus, with all of these approaches, knowledge of the biological activity of the receptor probe and kinetic data need to be presented if claims of receptor detection are to be made. In the absence of these data, the use of the term “binding site” instead of “receptor” is more appropriate. “Binding sites” may include receptors, but also encompass a vast array of other molecules as discussed above.
Design, synthesis, and biological evaluation of new thieno[2,3-d] pyrimidine derivatives as targeted therapy for PI3K with molecular modelling study
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2022
Fatma M. Elmenier, Deena S. Lasheen, Khaled A. M. Abouzid
The common pharmacophoric features of several potent PI3K inhibitors (Figure 3) are summarised as follows: the morpholine ring is crucial for binding to Val amino acid (Val851, Val848, and Val882 in PI3Kα, PI3Kβ, and PI3Kγ, respectively) at hinge region (colored red). The central core can be a heterocycle (either fused or single) having an aryl substituent at meta-position to morpholine moiety (colored violet and green). HB donor/acceptor group should be present on the aryl substituent preferably at 3 positions to maintain the same HBs with key amino acids (Tyr, Asp and/or Lys) at affinity region (Tyr836, Asp810 or Lys802 for PI3Kα) (Tyr833, Asp807 for PI3Kβ) (Tyr867, Asp841 and Lys833 for PI3Kγ) (colored blue). Some derivatives are extended towards the solvent-exposed area in PI3K binding site. Hence, form additional interactions with surrounding amino acids or improve the pharmacokinetics of the designed compounds (colored orange). Although the most important regions in the binding site can be described as 4 main regions (hinge region, specificity region, affinity region, and non-conserved region), there are still unclear key aspects to inhibitor selectivity such as the exact contribution of the specificity pocket, the way by which hinge and affinity binding motifs affects selectivity, and the influence of conserved regions. In general, isoform selectivity and inhibitor binding result from a complex combination of interactions throughout the binding site, affected by protein and inhibitor conformational flexibility27.
The discovery of berberine erythrocyte-hemoglobin self-assembly delivery system: a neglected carrier underlying its pharmacokinetics
Published in Drug Delivery, 2022
Qiuxia Yu, Minhua Li, Hanbin Chen, Lieqiang Xu, Juanjuan Cheng, Guoshu Lin, Yuhong Liu, Ziren Su, Xiaobo Yang, Yucui Li, Jiannan Chen, Jianhui Xie
It is well-known that the pharmacological effect of a drug is dependent on both its pharmacokinetic and pharmacodynamic properties, which are largely influenced by the reversible binding of the drug to proteins in the blood (Schmidt et al., 2010; Borkar et al., 2015). The primary binding sites of drugs in erythrocytes are associated with Hb, proteins, or plasma membrane. Hb is the major (soluble) protein and makes up 97% of the erythrocyte’s dry weight. In addition to carrying O2 and CO2, Hb also has important physiological functions, such as storing endogenous metabolites and exogenous small molecules (Wang et al., 2007). And it is reported that Hb in blood plasma is naturally scavenged by monocytes and macrophages and is subsequently denatured in the lysosome, making it a natural drug carrier to target monocytes and macrophages (Zhang and Palmer, 2011; Singhal et al., 2017). In our work, the blood routine examination showed that the counts of WBC and PLT in blood did not fluctuate obviously, while the contents of erythrocyte and Hb were significantly reduced (p < .01 or p < .05) post intravenous administration of BBR, which might indicate the interaction of erythrocyte and Hb with BBR. Besides, Hb tended to accumulate in the liver, which was similar to the biodistribution of BBR (Ship et al., 2005; Tan et al., 2013), presumptively ascribed to the recognition and phagocytosis of BBR-loaded erythrocyte by the reticuloendothelial system of the liver. However, further endeavors are merited to provide definite insight.
Anti-COVID-19 and antidiabetic activities of new oleanane and ursane-type triterpenoids from Salvia grossheimii: an in-silico approach
Published in Journal of Receptors and Signal Transduction, 2022
Somayeh Zare, Somayeh Pirhadi, Hesham R. El Seedi, Amir Reza Jassbi
The oleanane-type 2 was the most potent one in the list, with an affinity of −9.39 kcal/mol. The 3 D interaction pattern of 2 is shown in Figure 4(a). Docking analysis showed that in 2, two stabilizing H-bonds were observed between GAA residues Phe525 and Asn525 with the hydroxyl substituent of C-3. Further stabilizing interactions with the enzyme surface provided several hydrophobic contacts of residues surrounding 2 in the binding site. They include pi-alkyl and alkyl-alkyl of methyl substitutes interactions. Pi-alkyl interactions were between residues Phe525 and Trp481 and Me-26, Phe649, Trp481 and Me-28, and Trp376 and Me-29 and ring E. Alkyl-alkyl interactions were between residues Leu677, Leu678, and Me29, Leu678 and Me-30, and Ala555 and Me-23. The 3 D interaction pattern of 6 was illustrated in Figure4(b). Docking interaction analysis of the ursane-type 6, as the second potent compound against GAA, showed three stabilizing H-bonds between C-2 acetoxy with Arg600, C-11 hydroxyl with Asp282, and C-20 hydroxyl with Arg281. The pi-sigma, pi-alkyl, and alkyl-alkyl hydrophobic interactions are among several contacts that strengthened the binding of 6 in the binding site of the enzyme, similar to those seen in 2. Pi-sigma interactions were between residues Trp376 and the methyl of acetoxy group at C-3, and Phe525 and Me-27. Pi-alkyl interactions with residues of the binding site included Trp376 with Me-23, Phe525 with ring D, and Trp481 with Me-23, Me-27, and ring B. The hydrophobic alkyl-alkyl interactions were seen from Leu650 to Me-24, and Ala555 to Me-29 and Me-30.