Developing force field parameters on-the-fly: H-TEQ

    The pharmaceutical industry, in the recent past, has benefitted from the improved efficiency in the drug discovery process through the use of virtual high-throughput screening (vHTS) employing in silico docking methodologies. This has successfully led to and allowed an enrichment of active compounds for subsequent synthetic or biological testing efforts. Unfortunately however, many scoring functions used in docking uses molecular mechanics (MM), which are fast, but less accurate compared to QM-based methodologies. The draw-backs of MM methods comes from the low accuracy of torsion terms as well as nonbonded interactions (ie. electrostatics, van der Waals, hydrogen bonding, pi-pi stacking interactions).
    For torsions, the errors mainly come from the assumption that energy barriers of a previously QM-parametrized molecule could be transferred and applied to another molecule despite having different chemical environments. In fact, transferring parameters between different torsions has been the only viable strategy until recently due to the prohibitive expense associated with having to perform QM-calculations for each molecule during the vHTS.
    To combat this issue, our group has developed and published, thus far, a series of four papers on a conceptually novel Force Field, which are atom-type intendent to predict the torsion energy of small molecules called H-TEQ. This Force Field is developed based on quantifying organic chemistry principles. With this new Force Field, vHTS could now be performed quickly and accurately. We are also expanding our development into other interactions in force fields (ie. nonbonded interactions).
Keywords : · Force fields · Hyperconjugation · Molecular mechanics · Torsional profile
Key people involved in the project: Jerome Genzling (graduate student), Chris Sitko (graduate student), Wanlei Wei (PhD '20), Zhaomin Liu (PhD '17), Stephen Jones Barigye (PDF '16-'18), Candide Champion (MSc '19), Moeed Shahamat (PDF '15)
Key publications related to the project : here