Ously, no predictive QSAR models against IP3 R antagonists have been reported
Ously, no predictive QSAR models against IP3 R antagonists had been reported on account of the availability of limited and structurally diverse datasets. As a result, inside the present study, alignment-independent molecular descriptors determined by molecular interaction fields (MIFs) have been utilized to probe the 3D structural attributes of IP3 R antagonists. In addition, a grid-independent molecular descriptor (GRIND) model was developed to evaluate the proposed pharmacophore model and to establish a binding μ Opioid Receptor/MOR Inhibitor Purity & Documentation hypothesis of antagonists with IP3 R. Overall, this study may add worth to recognize the essential pharmacophoric characteristics and their mutual distances and to design new potent ligands expected for IP3 R inhibition. 2. Results 2.1. Preliminary Data Evaluation and Template Selection All round, the dataset of 40 competitive compounds exhibiting 0.0029 to 20,000 half-maximal inhibitory concentration (IC50 ) against IP3 R was selected from the ChEMBL database [40] and literature. Based upon a widespread scaffold, the dataset was divided into four classes (Table 1). Class A consisted of inositol derivatives, where phosphate groups with distinct stereochemistry are attached at positions R1R6 . Similarly, Class B consistedInt. J. Mol. Sci. 2021, 22,three ofof cyclic oxaquinolizidine derivatives generally referred to as xestospongins, whereas, Class C was composed of biphenyl derivatives, where phosphate groups are attached at TrkC Activator MedChemExpress unique positions from the biphenyl ring (Table 1). On the other hand, Class M consisted of structurally diverse compounds. The chemical structures of Class M are illustrated in Figure 1.Figure 1. Chemical structure of your compounds in Class M with inhibitory potency (IC50 ) and lipophilic efficiency (LipE) values.Int. J. Mol. Sci. 2021, 22,4 ofTable 1. Ligand dataset of IP3 R displaying calculated log p values and LipE values.Inositol Phosphate (IP) (Class A)Comp. No. A1 A2 A3 A4 A5 A6 A7 A8 A9 A10 A11 AR1 PO3 -2 PO3 PO3 PO3 PO3 PO3 PO3 PO-2 -2 -2 -2 -2 -2 -R2 PO3 -2 PO3 PO-2 -R3 OH OH OH PO3 PO-2 -R4 PO3 -2 PO3 PO3 PO3 PO3 PO3 PO3 PO-2 -2 -2 -2 -2 -R5 PO3 -2 PO3 PO3 PO3 PO3 PO3 PO-R6 OH OH OH OH PO3 PO3 PO3 PO-2 -Conformation R,S,S,S,S,S S,S,S,R,R,R S,S,R,R,R,R R,S,S,S,S,S R,S,R,S,S,R R,S,S,R,R,S R,R,S,R,R,S R,R,S,R,R,S S,R,R,S,R,S S,S,R,R,S,S R,S,S,S,R,S R,R,S,S,R,SKey Name DL-Ins(1,2,four,5)P4 scyllo-Ins(1,two,4,5)P4 DL-scyllo-Ins(1,2,4)P3 Ins(1,3,four,5)P4 D-chiro-Ins(1,three,four,six)P4 Ins(1,4,5,6)P4 Ins(1,four,five)P3 Ins(1,five,6)P3 Ins(3,four,five,6)P4 Ins(three,4,five)P3 Ins(four,5,six)P3 Ins(four, five)PIC50 ( ) 0.03 0.02 0.05 0.01 0.17 0.43 three.01 0.04 0.62 0.01 93.0 20.logPclogPpIC50 1.6 1.8 1.3 two.5 0.7 0.2 2.two 0.four 1.3 1.LipE 14.eight 15.1 13.1 15.1 13.4 14.9 14.1 13.1 13.4 13.9 9.eight 9.Ref. [41] [42] [41] [42] [42] [41] [42] [42] [41] [41] [43] [43]-7.5 -7.5 -6.four -7.5 -7.5 -7.7 -6.four -6.two -7.7 -6.6 -6.9 -5.-7.two -7.2 -5.7 -6.5 -6.7 -8.five -5.8 -5.8 -7.two -5.7 -5.8 -4.OH-OH OH OH OH OH OH OH OH OHOH-2 -2 -2 -OH OH OH PO-OH-2 -OH-OH OH OH OHPO3 -2 OH OHPO3 -2 PO3 -2 PO3 -PO3 -2 PO3 -2 PO3 -OH PO3 -2 OH-1.three -0.Int. J. Mol. Sci. 2021, 22,5 ofTable 1. Cont.Xestospongins (Xe) (Class B)Comp. No. B1 B2 B3 B4 B5 BR1 OH OH OH — — –R4 — — — OH — –R5 OH — — — — –R8 — CH3 — — — –Conformation R,R,S,R,R,S S,S,R,S,R,R,R S,S,R,R,S,R S,S,R,R,S,S,R S,S,R,S,S,R R,S,R,R,S,RKey Name Araguspongine C Xestospongin B Demethylated Xestospongin B 7-(OH)-XeA Xestospongin A Araguspongine BIC50 ( ) 6.60 five.01 5.86 six.40 2.53 0.logP five.7 six.8 six.5 six.three 7.3 7.clogP 4.7 7.two 6.eight 6.eight 8.1 eight.pIC50 5.two 5.3 5.2 five.two five.six six.LipE 0.Ref. [44] [45] [46].
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