Synthesis, molecular docking, and in vitro activity of a novel angiotensin-converting enzyme 2 inhibitor, LMS1007: a potential molecule in Covid-19 and cancer treatments

Abstract

Angiotensin-converting enzyme 2 (ACE2) is a validated commonly studied in the pathology of several diseases, including novel coronavirus and breast cancer. Herein, we report the synthesis, molecular docking, and validation of a novel ACE2 inhibitor that was previously discovered by our team based on diverse scaffolds of other ACE2 inhibitors and carnosine. The synthesized 4-subsitituted imidazole compound, namely, LMS1007, was characterized through ¹H-NMR, LC-MS, and SFC. LMS1007 was then tested in vitro with ACE2 and viral spike protein-ACE2 inhibitor kits and was found to be approximately 100 times more potent as an ACE2 inhibitor than carnosine. However, it was less potent than the standard ACE2 inhibitor. In the same concentration range of the standard drug for ACE2 inhibition, LMS1007 demonstrated similar inhibitory effects on the interaction of the viral spike protein with ACE2. LMS1007 had an inhibitory concentration of 50% (IC₅₀) at a concentration of 2.3 mM in all kits. LMS1007, similar to carnosine in breast cancer cell lines, exhibited potential inhibitory effects on the ACE2-mediated host uptake of Covid-19. Thus, a thorough review and discussion are provided on the role of ACE2 as an attractive target for the development of new drugs for Covid-19 treatment.

Fig. 1. Structures of (A) Carnosine, (B) ORE1001, and (C) LMS1007.

Fig. 2. (A) The ACE2 (solid blue colour) interacts with spike protein (red), and the three active spheres are assigned. (B) ACE2 receptor with its three active sites assigned at the interface.

Fig. 3. The spike receptor with its three active sites assigned to the interface.

Fig. 4. (A) 3D view of compound LMS1023SSS bound in its active site with a surrounding surface showing the H-donor (purple) and H-acceptor areas (green). (B) 2D view of LMS1023SSS within the active site, showing its interactions with the amino acids at the ACE2 surface. (C) 3D view of compound LMS004RS bound in its active site with a surrounding surface showing the H-donor (purple) and H-acceptor areas (green). (D) 2D view of LMS1004RS within the active site, showing its interactions with the amino acids at the spike surface.

Fig. 5. The total synthesis of LMS1007.

Scheme 1. The total synthesis of LMS1007.

Fig. 6. Mean inhibition% of ACE2 at concentrations ranging from 0.23 μM to 23 mM for LMS1007 and from 6.25 nm to 50 nM for the standard kit inhibitor.