Recently several molecular mechanics models of halogen bonding have been published. They describe the electrostatic potential anisotropy near the heavy halogen atom (known as a σ-hole) in different ways, ranging from an all-atom multipole expansion to a single positive extra-point charge. However, the question of a reasonable balance between the accuracy and the simplicity of the model remains open. In this work, we introduce the simplistic RESPQ electrostatics model built on the RESP charges complemented with fixed atomic quadrupoles. We show that it: (1) correctly describes the MEP anisotropy of aromatic halogen atoms, (2) improves the description of the halogen-water interaction energies in both halogen and hydrogen bonding cases, (3) provides an excellent estimation of solvation free energy differences of aromatic halogens, and (4) is compatible (with the help of multipole charge cluster approximation) with contemporary molecular modeling packages.

Nowadays, as computing has become much more available, a fresh momentum has been observed in the field of re-visioning and re-parameterizing the usual tools, as well as estimating for the incorporation of new qualitative capabilities, aimed at making more accurate and reliable predictions in drug discovery processes. Inspired by the success of modelling the electrostatic part of the halogen bonding (XB) by means of the distributed multipole expansion, a study is presented which attempts to extend this approach to a tougher case of σ-hole interaction: sulphur-based chalcogen bonding. To that end, 11 anisotropic models have been derived and tested for their performance in the reproduction of reference ab initio molecular electrostatic potential. A careful examination resulted in three models which have been selected for further examination as a part of the molecular mechanics force field (GAFF). The combined force field was used to estimate inter- and intra-molecular interactions for the molecular systems, capable of differentiating the binding from the σ-hole and other directions. The anisotropic models proposed were generally able to correct the wrong predictions of the sulphur models based only on isotropic charges and, thus, are a promising direction for further development of the refined electrostatics force fields.

Halogen bonding is electrostatic attraction between halogen atoms in an organic molecule and Lewis bases. It is important to consider halogen bonding during molecular docking and virtual screening, in particular, at early stages of drug development. A new scoring function AutoDock-XB, which takes into account halogen bonding by means of the quadrupole correction, has been constructed. The function has been tested for a series of phosphodiesterase-5 inhibitors.

Halogen bonding (XB) is a new promising interaction pattern in medicinal chemistry. It has predominantly electrostatic nature – high electrostatic potential anisotropy. However to fully unleash the potential of XB in rational drug design fast and robust empirical methods of XB description should be developed. Current approaches rely heavily on ab initio calculation for each molecule studied. Thus fast prediction of electrostatic parameters for description of XB for arbitrary organic molecules is of paramount importance to promptly establish QSAR/QSPR, virtual screening and molecular docking pipelines suitable for today′s agile development requirements. The two most promising approaches to describe anisotropic electrostatic models – the extra point (EP) charge model and the multipole expansion (ME) model – were studied on their ability (1) to describe ab initio molecular electrostatic potential (MEP) and (2) to produce parameters that can be predicted for each molecule empirically rather than estimated via ab initio calculations. The reference ab initio MEP was calculated for a set of 730 substituted halobenzenes. Parameters for anisotropic electrostatics of both empirical models (EP and ME) studied were extracted from ab initio MEP. The FreeWilson and Hansch type QSPR models relating XB parameters with aromatic substituents were built and analyzed, providing the guidelines for further development.

Recently, the phenomenon of favorable interaction between heavy halogen atom (Cl, Br, I) and Lewis bases was rediscovered. It is called halogen bonding (XB) and attracts much attention [1,2] for several reasons. First, it is found in many different systems such as organic crystals, liquid crystals, polymers, biological macromolecules and their complexes. Second, the interaction energy is comparable to traditional hydrogen bonding energies. Third, it is able to form directional interactions in hydrophobic environment and complement [2] identified previously and widely used interaction patterns, such as hydrogen bonding, electrostatic interactions, dispersion interactions, hydrophobic interactions, aromatic stacking. At last, XB contradicts traditional conception of halogen in molecule being only a Lewis base. Although the nature of XB is still under investigation, the main hypothesis states that electrostatic interaction is the main factor determining its energetics [3]. Despite several models for empirical description of XB were reported earlier, none became a scheme of common choice, due to lack of systematic investigation comparing different approaches. Moreover, development of fast empirical models capable of reliable description of XB is of crucial significance to progress in its better understanding and its successful application.

O. Titov V. Palyulin N. Zefirov PERSPECTIVES OF DIRECT MODELING OF HALOGEN BONDING IN EARLY DRUG DISCOVERY Chair of Medicinal Chemistry, Department of Chemistry, Lomonosov Moscow State University, Leninskie Gory, Moscow, Russia shulga@qsar.chem.msu.ru Halogen bonding (XB), defined as attractive interaction between a heavy halogen atom in a molecule and an electron rich donor, has received considerable attention recently [1] as a new promising interaction pattern (such as e.g. hydrogen bonding, hydrophobic interactions, pi-pi stacking, etc.) that could be used rationally in early stages of drug discovery [2]. XB uniquely combines hydrophobic properties and directional electrostatic interactions. Moreover, halogen atoms are abundant in drugs and drug candidates [3], therefore the route to additional optimization of a molecule is open. Despite its potential usefulness, XB description in computer-aided tools used in the early drug discovery has not reached the level ensuring their comprehensive utilization. As of today only a few molecular mechanics descriptions of XB were reported, as well as a few attempts to incorporate XB explicitly in scoring functions used for molecular docking and virtual screening. Thus, XB interactions are not properly represented in the current tools for early stages of computer aided drug discovery. We observe the perspectives and means for incorporation of XB description at different levels of approximation consistent with the approaches proved to be fruitful in drug discovery and, hence, incorporated in a series of tools used in drug discovery practice. The spectrum of levels of XB description should span from the force field to empirical scoring functions. Starting from the nature of the XB interactions – high molecular electrostatic potential anisotropy – we have compared and optimized earlier two approaches to incorporate XB in a force field modeling [4,5]. Our current focus is on the explicit incorporation of the XB description in the current scoring functions used for molecular docking and virtual screening studies. The main challenge is to quickly (avoiding quantum chemical calculation) assign proper values of anisotropic electrostatic parameters to a molecule belonging to a broad and diverse space of pharmaceutically relevant compounds. On the route to build an empirical scheme to assign the electrostatic XB parameters for diverse organic molecules we investigated the extent and the nature of dependence of those parameters on the substitution pattern on an archetypal set of monoand di-substituted phenyl halides. Since the relative importance of resonance and inductive effects were estimated, our current aim is to check the findings within the molecular docking environment.