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Ously, no predictive QSAR models against IP3 R antagonists had been reported
Ously, no predictive QSAR models against IP3 R antagonists have been reported on account of the availability of limited and structurally diverse datasets. Thus, in the present study, alignment-independent molecular descriptors based on molecular interaction fields (MIFs) have been employed to probe the 3D structural capabilities of IP3 R antagonists. Furthermore, a grid-independent molecular descriptor (GRIND) model was created to evaluate the proposed pharmacophore model and to establish a NPY Y1 receptor Antagonist drug binding hypothesis of antagonists with IP3 R. Overall, this study may possibly add worth to recognize the vital pharmacophoric features and their mutual distances and to design and style new potent ligands needed for IP3 R inhibition. two. Outcomes 2.1. Preliminary Data Analysis and Template Choice 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 prevalent scaffold, the dataset was divided into 4 classes (Table 1). Class A consisted of inositol derivatives, where phosphate groups with various 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 various positions of your biphenyl ring (Table 1). However, Class M consisted of structurally diverse compounds. The chemical structures of Class M are illustrated in Figure 1.Figure 1. Chemical structure of the 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 showing 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,two,four,five)P4 scyllo-Ins(1,2,four,five)P4 DL-scyllo-Ins(1,two,4)P3 Ins(1,3,four,5)P4 D-chiro-Ins(1,three,four,6)P4 Ins(1,four,five,6)P4 Ins(1,four,five)P3 Ins(1,5,6)P3 Ins(three,4,five,six)P4 Ins(3,4,five)P3 Ins(4,5,6)P3 Ins(four, five)PIC50 ( ) 0.03 0.02 0.05 0.01 0.17 0.43 3.01 0.04 0.62 0.01 93.0 20.logPclogPpIC50 1.six 1.8 1.three 2.five 0.7 0.2 2.2 0.4 1.3 1.LipE 14.eight 15.1 13.1 15.1 13.four 14.9 14.1 13.1 13.4 13.9 9.8 9.Ref. [41] [42] [41] [42] [42] [41] [42] [42] [41] [41] [43] [43]-7.5 -7.five -6.4 -7.five -7.5 -7.7 -6.four -6.2 -7.7 -6.6 -6.9 -5.-7.two -7.two -5.7 -6.five -6.7 -8.5 -5.8 -5.8 -7.2 -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 β adrenergic receptor Inhibitor Purity & Documentation Araguspongine C Xestospongin B Demethylated Xestospongin B 7-(OH)-XeA Xestospongin A Araguspongine BIC50 ( ) 6.60 5.01 five.86 six.40 2.53 0.logP 5.7 6.eight 6.5 six.three 7.3 7.clogP 4.7 7.2 6.8 6.eight 8.1 8.pIC50 five.two 5.three five.2 five.2 five.6 6.LipE 0.Ref. [44] [45] [46].