Ligand‐based Modeling for the Prediction of Pharmacophore Features for Multi‐targeted Inhibition of the Arachidonic Acid Cascade

Abstract

The single-target drugs against the arachidonic acid inflammatory pathway are associated with serious side effects, hence, as a first step towards multi-target drugs, we have studied the pharmacophoric features common to the inhibitors of 5-lipoxygenase-activating protein (FLAP), microsomal prostaglandin E-synthase 1 (mPGES-1) and leukotriene A4 hydrolase (LTA4H). FLAP and mPGES-1 shared subfamily-specific positions (SSPs) and four mPGES-1 inhibitors binding to them mapped onto the pharmacophore derived from FLAP inhibitors (Ph-FLAP). The reactions of mPGES-1 and LTA4H had high structural similarity. The pharmacophore derived from two substrate mimic inhibitors of LTA4H (Ph-LTA4H) also mapped onto three mPGES-1 inhibitors. Screening of in-house database for Ph-FLAP and Ph-LTA4H identified one compound, C1. It inhibited the production of the mPGES-1 product, prostaglandin E2 (PGE2) by 97.8±1.6 % at 50 μM in HeLa cells and can be a starting point for designing molecules inhibiting all three targets simultaneously.

Catalytic Functionalization of Metallocarbenes Derived from α‐Diazocarbonyl Compounds and Their Precursors

“…In this personal account, our efforts in the utilization of Nsulfonyl-1,2,3-triazoles as the precursor of rhodium imino carbene, in the presence of rhodium catalyst and their transformations have been discussed. Particularly, electrophilic rhodium imino carbenes reacts with various nucleophiles, such as O, N, S and C based nucleophiles, for the functionalization and transannulation reactions to construct synthetically valuable intermediates and heterocyclic compounds and biologically active molecules [37] in a single step. Similar reactivity has also been observed with metal (Pd, Cu, and Rh)-carbenes derived from diazocarbonyl compounds.…”

Bioinformatic analysis of subfamily-specific regions in 3D-structures of homologs to study functional diversity and conformational plasticity in protein superfamilies

“…Interest in the analysis of functionally important specific positions is a long-standing trend in computational biology: the concept was introduced in late 1990s [9] , [10] , the first systematic approach to identify such positions/residues in protein sequences was published in 2002 [11] , followed by a variety of improvements to increase the accuracy of predictions and facilitate the ease-of-use in the daily routine [3] , [5] , [7] , [12] , [13] . In particular, the original Zebra/Zebra2 approach [14] to identify SSPs/SDPs in multiple sequence alignments was recognized as a tool [15] , [16] to help studying structure–function relationship in protein superfamilies [17] , [18] , [19] , and used to assist experimental design of improved enzymes [20] and ligand binding specificity [21] .…”

CASBench: A Benchmarking Set of Proteins with Annotated Catalytic and Allosteric Sites in Their Structures

“…The anticipation of the discovery of a new regulatory mechanism in proteins currently considered as non-allosteric has generated intense attention to the field, driven by a fundamental interest in establishing new ways of regulating proteins/ enzymes, and the prospects for creating novel allosteric drugs having a lower toxicity due to higher binding selectivity [4, 23-26]. In recent years, a number of computational methods have been developed to search for new regulatory sites in protein structures, as well as complementary selective ligands that can influence the functional activity upon binding to the biopolymer [9]: using geometric [27-30], energy-based [31, 32] or bioinformatic criteria [13, 33, 34, 35], training sets of experimentally annotated sites [36, 37], and high-throughput virtual screening procedures [38, 39]. The currently available computer programs usually predict multiple sites in the structure of a selected protein (tens or even hundreds, depending on the globule size and the selected parameters).…”