Quantum Mechanical-Cluster Approach to Solve the Bioisosteric Replacement Problem in Drug Design

Abstract

Bioisosteres are molecules that differ in substituents but still have very similar shapes. Bioisosteric replacements are ubiquitous in modern drug design, where they are used to alter metabolism, change bioavailability, or modify activity of the lead compound. Prediction of relative affinities of bioisosteres with computational methods is a long-standing task; however, the very shape closeness makes bioisosteric substitutions almost intractable for computational methods, which use standard force fields. Here, we design a quantum mechanical (QM)-cluster approach based on the GFN2-xTB semi-empirical quantum-chemical method and apply it to a set of H → F bioisosteric replacements. The proposed methodology enables advanced prediction of biological activity change upon bioisosteric substitution of −H with −F, with the standard deviation of 0.60 kcal/mol, surpassing the ChemPLP scoring function (0.83 kcal/ mol), and making QM-based ΔΔG estimation comparable to ∼0.42 kcal/mol standard deviation of in vitro experiment. The speed of the method and lack of tunable parameters makes it affordable in current drug research.

Imidazole-4-N-acetamide Derivatives as a Novel Scaffold for Selective Targeting of Cyclin Dependent Kinases

“…Addressing the problem of extensive sampling of multiple local minima, we used a comprehensive workflow for preparing starting target-ligand complexes based on molecular docking, structural filtration, and QM. We used the semi-empirical QM cluster approach [29] to optimize alternative ligand conformations in different local energy minima identified by molecular docking. For each local minimum of the ligand conformation, we used the optimized structures for MD simulations and NEQ.…”

“…The resulting conformations were in agreement with the structures of known CDK2 inhibitors that have similar scaffolds (Supplementary Materials, Section S1.2.1). We used the QM cluster approach based on the GFN2-xTB semi-empirical method to optimize target-ligand complexes and estimate the binding energy [29] (Supplementary Materials, Section S1.2.2).…”

Untitled

“…Bioisosters were compounds that have the same biological activities and are used for modification of potency, efficacy, bioactivitites, pharmacokinetics and toxicological properties [15][16] . They can be classified as classical and nonclassical bioisosteres.…”

Modelagem molecular de inibidores covalentes reversíveis de cisteíno proteases

“…This type of methodology tends to be faster than QM/MM simulations and has been successfully applied to describe enzymatic catalysis reactions. 147,[149][150][151][152] However, its use for the development of new inhibitors is still in its early stages and has rarely been employed for this purpose.…”