Refinement and Extension of COSMO-RS-Trained Fragment Contribution Models for Predicting Partition Properties of C10–20 Chlorinated Paraffin Congeners

COSMO-RS-trained fragment contribution models (FCMs) to predict partition properties of chlorinated paraffin (CP) congeners were refined and extended. The improvement includes (i) the use of an improved conformer generation method for COSMO-RS, (ii) extension of training and validation sets for FCMs up to C₂₀ congeners covering short-chain (SCCPs), medium-chain (MCCPs) and long-chain CPs (LCCPs), and (iii) more realistic simulation of industrial CP mixture compositions by using a stochastic algorithm. Extension of the training set markedly improved the accuracy of model predictions for MCCPs and LCCPs, as compared to the previous study. The predicted values of the log octanol/water partition coefficients (<i>K</i>_ow) for CP mixtures agreed well with experimentally determined values from the literature. Using the established FCMs, this study provided a set of quantum chemically based predictions for 193 congener groups (C_10–20, Cl_0–21) regarding <i>K</i>_ow, air/water (<i>K</i>_aw), and octanol/air (<i>K</i>_oa) partition coefficients, subcooled liquid vapor pressure (VP) and aqueous solubility (<i>S</i>_w) in a temperature range of 5–45 °C as well as the respective enthalpy and internal energy changes.<br><br>This is a preprint version and has not yet been peer reviewed.

Refinement and Extension of COSMO-RS-Trained Fragment Contribution Models for Predicting Partition Properties of C10–20 Chlorinated Paraffin Congeners

COSMO-RS-trained fragment contribution models (FCMs) to predict partition properties of chlorinated paraffin (CP) congeners were refined and extended. The improvement includes (i) the use of an improved conformer generation method for COSMO-RS, (ii) extension of training and validation sets for FCMs up to C₂₀ congeners covering short-chain (SCCPs), medium-chain (MCCPs) and long-chain CPs (LCCPs), and (iii) more realistic simulation of industrial CP mixture compositions by using a stochastic algorithm. Extension of the training set markedly improved the accuracy of model predictions for MCCPs and LCCPs, as compared to the previous study. The predicted values of the log octanol/water partition coefficients (<i>K</i>_ow) for CP mixtures agreed well with experimentally determined values from the literature. Using the established FCMs, this study provided a set of quantum chemically based predictions for 193 congener groups (C_10–20, Cl_0–21) regarding <i>K</i>_ow, air/water (<i>K</i>_aw), and octanol/air (<i>K</i>_oa) partition coefficients, subcooled liquid vapor pressure (VP) and aqueous solubility (<i>S</i>_w) in a temperature range of 5–45 °C as well as the respective enthalpy and internal energy changes.<br><br>This is a preprint version and has not yet been peer reviewed.

BCL::Conf – Improved Open-Source Knowledge-Based Conformation Sampling using the Crystallographic Open Database

<div>This paper describes recent improvements made to the BCL::Conf rotamer generation algorithm and comparison of its performance against other freely available and commercial conformer generation software. We demonstrate that BCL::Conf, with the use of rotamers derived from the COD, more effectively recovers crystallographic ligand-binding conformations seen in the PDB than other commercial and freely available software. BCL::Conf is now distributed with the COD-derived rotamer library, free for academic use. The BCL can be downloaded at <a href="http://meilerlab.org/index.php/bclcommons/show/b_apps_id/1">http://meilerlab.org/ bclcommons</a> for Windows, Linux, or Apple operating systems.<br></div>

BCL::Conf – Improved Open-Source Knowledge-Based Conformation Sampling using the Crystallographic Open Database

<div>This paper describes recent improvements made to the BCL::Conf rotamer generation algorithm and comparison of its performance against other freely available and commercial conformer generation software. We demonstrate that BCL::Conf, with the use of rotamers derived from the COD, more effectively recovers crystallographic ligand-binding conformations seen in the PDB than other commercial and freely available software. BCL::Conf is now distributed with the COD-derived rotamer library, free for academic use. The BCL can be downloaded at <a href="http://meilerlab.org/index.php/bclcommons/show/b_apps_id/1">http://meilerlab.org/ bclcommons</a> for Windows, Linux, or Apple operating systems.<br></div>

BOKEI: Bayesian optimization using knowledge of correlated torsions and expected improvement for conformer generation

A key challenge in conformer sampling is finding low-energy conformations using a small number of energy evaluations. By extracting patterns of correlated torsions, we improve the efficiency of Bayesian Optimization in finding optimal conformations.

A Practical Perspective: The Effect of Ligand Conformers on the Negative Image-Based Screening

Negative image-based (NIB) screening is a rigid molecular docking methodology that can also be employed in docking rescoring. During the NIB screening, a negative image is generated based on the target protein’s ligand-binding cavity by inverting its shape and electrostatics. The resulting NIB model is a drug-like entity or pseudo-ligand that is compared directly against ligand 3D conformers, as is done with a template compound in the ligand-based screening. This cavity-based rigid docking has been demonstrated to work with genuine drug targets in both benchmark testing and drug candidate/lead discovery. Firstly, the study explores in-depth the applicability of different ligand 3D conformer generation software for acquiring the best NIB screening results using cyclooxygenase-2 (COX-2) as the example system. Secondly, the entire NIB workflow from the protein structure preparation, model build-up, and ligand conformer generation to the similarity comparison is performed for COX-2. Accordingly, hands-on instructions are provided on how to employ the NIB methodology from start to finish, both with the rigid docking and docking rescoring using noncommercial software. The practical aspects of the NIB methodology, especially the effect of ligand conformers, are discussed thoroughly, thus, making the methodology accessible for new users.