Compared with traditional non-covalent inhibitors, covalent inhibitors can achieve higher binding affinity and longer residence time. These characteristics can benefit lower doses, dosing frequency and systemic exposure of drugs. Therefore, many pharmaceutical companies have initiated drug development programs for covalent inhibitors of various enzymes. Once the ligand is docked into the binding site, the warhead will form a covalent bond with nearby amino acid residues. By designing inhibitors with covalent bonds only forming on non-catalytic residues with poor conservation, the target selectivity can be maximized.

The binding process of covalent inhibitors and proteins is divided into two steps:

• The reversible initial non-covalent complex EI is formed.
• The initial complex EI further transitions to the covalent bond complex E-I.

The enzymatic activity of covalent inhibitors is expressed by the second-order rate constant k_inact/K_i. K_inact reflects the rate of formation of covalent bonds, while K_i reflects the stability of the initial complex EI formed through non-covalent interactions.

Method

The first step can be simulated by structure-based methods (such as molecular docking);
The second step involves the formation and breaking of the bond, which needs to be simulated by the QM method.

Overall solutions

• Optimize the structure of the reactant molecules involved in the transition state.
• Optimize the initial guess of the transition state structure.
• Check whether the optimized structure is the required transition state structure.
• Free energy extraction.
• Result analysis.

Calculate the reaction rate constant

Next, we introduce how to calculate the reaction rate constant. In the transition state theory, the Eyring formula gives the expression of the reaction rate constant:

Where k(T) refers to the reaction rate constant at temperature T, kB is Boltzmann's constant, h is Planck's constant, c0 is the standard concentration (usually taken as 1), R is the ideal gas constant, and ΔG is Calculated activation energy barrier for the reaction.

Our services

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• QM/MM Computing Service
• Molecular Electrostatic Potential (MEP) calculation
• Natural Bond Orbit Analysis (NBO) Service
• Calculation Service of Chemical Isomers

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