Development of a potent 2-oxoamide inhibitor of secreted phospholipase A2 guided by molecular docking calculations and molecular dynamics simulations

Abstract

Inhibition of group IIA secreted phospholipase A2 (GIIA sPLA2) has been an important objective for medicinal chemists. We have previously shown that inhibitors incorporating the 2-oxoamide functionality may inhibit human and mouse GIIA sPLA2s. Herein, the development of new potent inhibitors by molecular docking calculations using the structure of the known inhibitor 7 as scaffold, are described. Synthesis and biological evaluation of the new compounds revealed that the long chain 2-oxoamide based on (S)-valine GK241 led to improved activity (IC50 = 143 nM and 68 nM against human and mouse GIIA sPLA2, respectively). In addition, molecular dynamics simulations were employed to shed light on GK241 potent and selective inhibitory activity.

Small-molecule inhibitors as potential therapeutics and as tools to understand the role of phospholipases A2

“…4) exhibited high potency for inhibition of GIIA sPLA 2 (IC 50 143 nM and 68 nM against human and mouse GIIA sPLA 2 , respectively). The inhibitor was proven ten times more selective for GIIA than GV sPLA 2 and did not exhibit any appreciable inhibition against other human and mouse sPLA 2 enzymes [94]. Additionally, inhibitor 26 ( Fig.…”

“…Molecular docking calculations and MD simulations with AMBER led to the development of the more potent GIIA sPLA 2 inhibitor GK241 ( Fig. 10) [94,140]. Docking calculations have been also employed to simulate the interaction in GIVA cPLA 2 -2oxoamide inhibitor complexes [141].…”

2-Oxoamides based on dipeptides as selective calcium-independent phospholipase A 2 inhibitors

“…2-Hydroxy acids 8a and 8b were synthesized as described earlier 33 and the synthesis of 8c is depicted in Scheme 1. The key-intermediate was the cyanohydrin 6 , which was converted to carboxylic acid under hydrolytic conditions.…”

SAR study on inhibitors of GIIA secreted phospholipase A2 using machine learning methods

“…(Nicholls et al., ) Great efforts have been made to find new inhibitors of GIIA sPLA 2 by researchers. (Beaton et al., ; Boukli et al., ; Burke, Gregor, & Tramposch, ; Chen, Chang, Kim, & Park, ; De Rosa, Giordano et al., , De Rosa, Crispino et al., ; Dillard et al., ; Draheim et al., ; Giannini et al., ; Guerrero et al., ; Hagishita et al., ; Iwama, Segawa, Fujii, Ikeda, & Katsumura, ; Kley, Kiedrowski, Unger, & Massing, ; Lehr, Klimt, & Elfringhoff, ; LeMahieu et al., ; Lucas et al., ; Matsumoto et al., ; Meddad‐Belhabich et al., ; Meng, Liu, Zhai, & Lai, ; Mouchlis et al., ; Oslund et al., ; Oslund, Cermak, Verlinde, & Gelb, ; Dillard et al., ; Sawyer et al., ; Schädlich, Büchler, & Beger, ; Smart, Oslund, Walsh, & Gelb, ; Springer et al., ; Tanaka, Itazaki, & Yoshida, ; Tanaka, Matsutani, Matsumoto, & Yoshida, ; Teshirogi et al., ; Touaibia et al., ; Vasilakaki et al., ; Wei et al., ; Wright, Pinto, Sherk, Green, & Magolda, ; Wu et al., ; Ye et al., ; Zhou et al., ) Respectable compounds showed high inhibitory activity, and there was an inhibitor whose IC 50 reaches 4 nM. (Draheim et al., ; Sawyer et al., ) Some representative inhibitors of GIIA sPLA 2 are shown in Figure .…”

“…(Nicholls et al, 2014) Great efforts have been made to find new inhibitors of GIIA sPLA 2 by researchers. (Beaton et al, 1994;Boukli et al, 2008;Burke, Gregor, & Tramposch, 1995;Chen, Chang, Kim, & Park, 2006;De Rosa, Giordano et al, 1998, De Rosa, Crispino et al, 1998Dillard et al, 1996a;Draheim et al, 1996;Giannini et al, 2001;Guerrero et al, 2007;Hagishita et al, 1996;Iwama, Segawa, Fujii, Ikeda, & Katsumura, 1998;Kley, Kiedrowski, Unger, & Massing, 1999;Lehr, Klimt, & Elfringhoff, 2001;LeMahieu et al, 1993;Lucas et al, 2000;Matsumoto et al, 1995;Meddad-Belhabich et al, 2010;Meng, Liu, Zhai, & Lai, 2013;Mouchlis et al, 2011;Oslund, Cermak, Verlinde, & Gelb, 2008;Dillard et al, 1996b;Sawyer et al, 2005;Schädlich, Büchler, & Beger, 1987;Smart, Oslund, Walsh, & Gelb, 2006;Springer et al, 1996;Tanaka, Itazaki, & Yoshida, 1992;Tanaka, Matsutani, Matsumoto, & Yoshida, 1992;Teshirogi et al, 1996;Touaibia et al, 2007;Vasilakaki et al, 2016;Wei et al, 2008;Wright, Pinto, Sherk, Green, & Magolda, 1992;Wu et al, 2011;…”