Ously, no predictive QSAR models against IP3 R antagonists were reported
Ously, no predictive QSAR models against IP3 R antagonists were reported due to the availability of restricted and structurally diverse datasets. Hence, inside the present study, alignment-independent molecular descriptors according to molecular interaction fields (MIFs) were used to probe the 3D structural characteristics of IP3 R antagonists. Additionally, a grid-independent molecular descriptor (GRIND) model was developed to evaluate the proposed pharmacophore model and to establish a binding hypothesis of antagonists with IP3 R. General, this study may possibly add value to recognize the important pharmacophoric features and their mutual distances and to design and style new potent ligands needed for IP3 R inhibition. two. Final results 2.1. Preliminary Information Analysis and Template Choice Overall, the dataset of 40 competitive NF-κB Inhibitor MedChemExpress compounds exhibiting 0.0029 to 20,000 half-maximal inhibitory concentration (IC50 ) against IP3 R was chosen from the ChEMBL database [40] and literature. Based upon a common scaffold, the dataset was divided into four classes (Table 1). Class A consisted of inositol derivatives, where phosphate groups with distinctive stereochemistry are attached at positions R1R6 . Similarly, Class B consistedInt. J. Mol. Sci. 2021, 22,3 ofof NMDA Receptor Modulator custom synthesis cyclic oxaquinolizidine derivatives normally called xestospongins, whereas, Class C was composed of biphenyl derivatives, exactly where phosphate groups are attached at unique positions of the biphenyl ring (Table 1). Nonetheless, Class M consisted of structurally diverse compounds. The chemical structures of Class M are illustrated in Figure 1.Figure 1. Chemical structure with the compounds in Class M with inhibitory potency (IC50 ) and lipophilic efficiency (LipE) values.Int. J. Mol. Sci. 2021, 22,four 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(1,2,4,five)P4 scyllo-Ins(1,two,4,five)P4 DL-scyllo-Ins(1,two,four)P3 Ins(1,three,4,five)P4 D-chiro-Ins(1,three,four,six)P4 Ins(1,4,5,6)P4 Ins(1,four,5)P3 Ins(1,5,6)P3 Ins(three,four,5,six)P4 Ins(3,4,five)P3 Ins(4,5,six)P3 Ins(4, 5)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.six 1.8 1.three 2.5 0.7 0.two two.2 0.four 1.three 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.five -6.4 -7.five -7.5 -7.7 -6.four -6.two -7.7 -6.six -6.9 -5.-7.two -7.two -5.7 -6.5 -6.7 -8.5 -5.eight -5.eight -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-1.3 -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 ( ) six.60 five.01 five.86 six.40 2.53 0.logP 5.7 6.eight six.five six.three 7.3 7.clogP four.7 7.two six.8 6.eight eight.1 eight.pIC50 5.two five.3 5.two 5.two five.six six.LipE 0.Ref. [44] [45] [46].