Explicit treatment of active-site waters enhances quantum mechanical/implicit solvent scoring: Inhibition of CDK2 by new pyrazolo[1,5-a]pyrimidines

Abstract

We present comprehensive testing of solvent representation in quantum mechanics (QM)-based scoring of protein-ligand affinities. To this aim, we prepared 21 new inhibitors of cyclin-dependent kinase 2 (CDK2) with the pyrazolo[1,5-a]pyrimidine core, whose activities spanned three orders of magnitude. The crystal structure of a potent inhibitor bound to the active CDK2/cyclin A complex revealed that the biphenyl substituent at position 5 of the pyrazolo[1,5-a]pyrimidine scaffold was located in a previously unexplored pocket and that six water molecules resided in the active site. Using molecular dynamics, protein-ligand interactions and active-site water H-bond networks as well as thermodynamics were probed. Thereafter, all the inhibitors were scored by the QM approach utilizing the COSMO implicit solvent model. Such a standard treatment failed to produce a correlation with the experiment (R = 0.49). However, the addition of the active-site waters resulted in significant improvement (R = 0.68). The activities of the compounds could thus be interpreted by taking into account their specific noncovalent interactions with CDK2 and the active-site waters. In summary, using a combination of several experimental and theoretical approaches we demonstrate that the inclusion of explicit solvent effects enhance QM/COSMO scoring to produce a reliable structure-activity relationship with physical insights. More generally, this approach is envisioned to contribute to increased accuracy of the computational design of novel inhibitors.

Ranking Power of the SQM/COSMO Scoring Function on Carbonic Anhydrase II–Inhibitor Complexes

“…These results may be due in part to the relatively well‐conserved geometry of the CAII binding site. Obtaining correlation without considering explicit waters does not contradict previous findings that waters are important in P–L binding . Rather, it demonstrates that the implicit COSMO model can capture some of these effects in some P–L systems.…”

“…Obtaining correlation withoutc onsidering explicit waters does not contradict previous findings that waters are important in P-L binding. [9,15,34] Rather,i td emonstrates that the im-plicit COSMO model can captures ome of these effects in some P-Ls ystems. The correlation of the classical SFs remained low.I nterestingly,t he "single protein conformation" approximation improved the DOCK 6r esults.…”

“…P‐L complexes are optimized in an aqueous environment prior to scoring. The full SQM‐based SF has already been successfully applied for analysis of small molecule series inhibiting various enzyme classes (oxidoreductases, proteases, and kinases) …”

“…[13,14] P-L complexes are optimized in an aqueous environment prior to scoring.T he full SQM-based SF has already been successfully appliedf or analysiso fs mall molecule series inhibiting various enzyme classes (oxidoreductases, proteases,and kinases). [9,[13][14][15] We have recently simplified and accelerated the SQM-based SF by employing only the two dominant terms, DE int and DDG solv ,a nd neglecting SQM optimization. [6] This novel Accurate predictiono fp rotein-ligand binding affinitiesi se ssentialf or hit-to-lead optimizationa nd virtual screening.…”

Using the Semiempirical Quantum Mechanics in Improving the Molecular Docking: A Case Study with CDK2

“…[12,[18][19][20] Many studies on various biomolecular complexes have shown that the use of the SQM methods through each of the methodologies has led to more accurate estimation of complex geometry and binding energy and consequently has increased the docking accuracy. [9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] In this study, a post-docking optimization with the different popular corrected SQM Hamiltonians has been performed for the docking results of a series of human cyclin-dependent kinase 2 (CDK2). The CDK2 is a serine/ threonine-protein kinase that is activated by binding to a regulatory cyclin protein for the cell cycle progression and transcription.…”