Mechanistic Modeling of Monoglyceride Lipase Covalent Modification Elucidates the Role of Leaving Group Expulsion and Discriminates Inhibitors with High and Low Potency

Abstract

Inhibition of monoglyceride lipase (MGL), also known as monoacylglycerol lipase (MAGL), has emerged as a promising approach for treating neurological diseases. To gain useful insights in the design of agents with balanced potency and reactivity, we investigated the mechanism of MGL carbamoylation by the reference triazole urea SAR629 (IC 50 = 0.2 nM) and two recently described inhibitors featuring a pyrazole (IC 50 = 1800 nM) or a 4-cyanopyrazole (IC 50 = 8 nM) leaving group (LG), using a hybrid quantum mechanics/molecular mechanics (QM/MM) approach. Opposite to what was found for substrate 2-arachidonoyl- sn -glycerol (2-AG), covalent modification of MGL by azole ureas is controlled by LG expulsion. Simulations indicated that changes in the electronic structure of the LG greatly affect reaction energetics with triazole and 4-cyanopyrazole inhibitors following a more accessible carbamoylation path compared to the unsubstituted pyrazole derivative. The computational protocol provided reaction barriers able to discriminate between MGL inhibitors with different potencies. These results highlight how QM/MM simulations can contribute to elucidating structure–activity relationships and provide insights for the design of covalent inhibitors.

Dynamics Playing a Key Role in the Covalent Binding of Inhibitors to Focal Adhesion Kinase

“…The use of computational simulations to investigate medicinal chemistry problem has significantly increased and has been instrumental in advancing the development of covalent inhibitors. − For example, quantum mechanics (QM)-based methods have been employed to analyze the covalent binding mechanism of ibrutinib, a drug approved for the treatment of B-cell cancers, to Bruton’s tyrosine kinase (BTK). , Additionally, Callegari et al applied QM/MM MD to investigate the covalent binding process of osimertinib to EGFR, providing insights into resistance mechanisms associated with the L718Q mutation. Furthermore, Arafet et al utilized QM/MM and path collective variables (PCVs) to identify chemical determinants for designing new CKIs targeting the EGFR C797S mutation, aiming to overcome resistance .…”

Mechanistic Modeling of Lys745 Sulfonylation in EGFR C797S Reveals Chemical Determinants for Inhibitor Activity and Discriminates Reversible from Irreversible Agents

“…In the present work, we applied a hybrid quantum mechanics/molecular mechanics (QM/MM) approach, , coupled with the path collective variables (PCVs) method, to investigate at the atomic level the mechanism of Lys745 sulfonylation in EGFR L858R/T790M/C797S . Computational strategies of this kind have allowed to clarify mechanisms of action of enzymes , and relevant covalent inhibitors. − …”

“…Computational strategies of this kind have allowed to clarify mechanisms of action of enzymes 30 , 31 and relevant covalent inhibitors. 32 − 34 …”

Landscape of In Silico Tools for Modeling Covalent Modification of Proteins: A Review on Computational Covalent Drug Discovery

“…Nevertheless, within the capacity of this review, it will be impossible to discuss all of the outstanding contributions in this research area. Thus, we refer the reader to a detailed list of references here. − Our review here starts with a brief discussion on the kinetics of covalent inhibition. It is then followed by discussion on different investigations classified based on the methods/approach considered (e.g., “reports focusing on p K a ’s of reacting amino acid residues”, “reports focusing on QM treatment of covalent fragment-adducts”, “reports focusing on determining the binding poses”, “reports focusing on the evaluation of binding free energies”, “reports focusing on determining the catalytic mechanism”, and “reports focusing on machine learning/artificial intelligence driven methodologies”).…”