Accurate conformation‐dependent molecular electrostatic potentials for high‐throughput in silico drug discovery

Abstract

The atom-centered partial charges-approximation is commonly used in current molecular modeling tools as a computationally inexpensive alternative to quantum mechanics for modeling electrostatics. Even today, the use of partial charges remains useful despite significant advances in improving the efficiency of ab initio methods. Here, we report on new parameters for the EEM and SFKEEM electronegativity equalization-based methods for rapidly determining partial charges that will accurately model the electrostatic potential of flexible molecules. The developed parameters cover most pharmaceutically relevant chemistries, and charges obtained using these parameters reproduce the B3LYP/cc-pVTZ reference electrostatic potential of a set of FDA-approved drug molecules at best to an average accuracy of 13 +/- 4 kJ mol(-1); thus, equipped with these parameters electronegativity equalization-based methods rival the current best non-quantum mechanical methods, such as AM1-BCC, in accuracy, yet incur a lower computational cost. Software implementations of EEM and SFKEEM, including the developed parameters, are included in the conformer-generation tool BALLOON, available free of charge at http://web.abo.fi/fak/mnf/bkf/research/johnson/software.php.

Can the electronegativity equalization method predict spectroscopic properties?

“…Over the past 27 years, EEM strongly influenced related areas, such as in-silico screening [6], chemical reactivity descriptors [7,8,9] and empirical models for molecular potential energy surfaces, hereafter referred to as (polarizable and possibly reactive) force fields [10,11,12,13,14,15,16]. Extensive calibration studies have demonstrated the accuracy of atomic charges and the parameter transferability of EEM [17,18,19,20,21,22,14,23] and its recent generalizations, the Split-Charge Equilibration (SQE) [15,24,25,26] and Atom-Condensed Kohn-Sham approximated to Second order (ACKS2) [16].…”

ACKS2: Atom-condensed Kohn-Sham DFT approximated to second order

“…After the introduction of EEM in the seminal paper of Mortier, 4 the model was extensively validated and applied to diverse chemical systems, including inorganic solids, 5-12 organic molecules, [13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29] biomolecular systems [30][31][32][33] and metal-organic frameworks. 34 These successes are the basis for the wide-spread adoption of EEM as a polarizable force field (PFF) used in high-throughput in-silico screening 35 and in molecular mechanics force fields. 9,13,15,20,21,[24][25][26]31,[36][37][38] Besides its practical utility, EEM is also of fundamental importance because it explains the molecular charge distribution with just a few simple equations and a set of transferable parameters.…”

Vascular endothelial growth factor receptor-2 (VEGFR-2) inhibitors: development and validation of predictive 3-D QSAR models through extensive ligand- and structure-based approaches

“…A total of 262 published compounds with known activities and unknown binding modes [15][16][17][18][19][45][46][47][48] (Supplementary Material Table SM-1) were collected. As an extension of previously reported applications [39,42,[45][46][47], in order to evaluate the 3-D QSAR model predictive abilities, either ligand-based (LB) or SB molecular alignments were ruled out by means of the programs Surflex-Sim [48], Omega/Rocs [49][50][51][52] and Balloon/ShaEP [53][54][55] for the LB and AutoDock4 [56], AutoDock Vina (herein just Vina), DOCK, Plants, ParaDocks and Surflex-Dock for the SB. Only the LB and SB best performing programs were then used to align the external test set compounds (see Test Set Selection section) and assess the 3-D QSAR models by means of pIC 50 predicted values (Fig.…”

“…To rule out LB molecular alignment 3 different LB programs (free for academia) were used: (1) Surflex-Sim [48]: an automatic flexible program which uses the principle of morphological similarity; (2) Omega/Rocs [49][50][51][52]: which generates (Omega) a multi-conformer database and performs a rigid shape-based superposition and scoring of molecules (Rocs), and (3) Balloon/ShaEP [53][54][55]: which, similarly to the previous, generates conformers (Balloon) and performs rigid-body superimposition (ShaEP). The LB alignment procedure assessment was conducted at different levels of difficulties:…”