Long-time scale simulations means we can now see how our small molecules change the conformation of proteins upon binding.
Advent of computing power have given rise to a new set of tools: GPUs alone represent a 100x increase in speed (FGPA's and ASICs are magnitudes faster as well).
Detailed Quantum Mechanical methods gives us capability to model sub-atomic particles, allowing us to accurately model metal interactions.
Silicon Therapeutics is an integrated computational drug discovery company using rigorous physics-based simulations to significantly accelerate the drug discovery process. We are building our company around a core platform that leverages quantum mechanics and molecular dynamics, which we are deploying on massive computational resources, including internal clusters and the cloud to attack previously undruggable targets highly implicated in a number of human diseases.
STX was founded on the premise that ultimately, "...everything that is living can be understood in terms of the jiggling and wiggling of atoms" (Richard Feynman). while we are a long way off from rigorously simulating cells, organs, and organisms, with current state-of-the-art approaches we can accurately simulate proteins and protein-ligand binding. Using all-atom simulations with explicit waters and an accurate representation of molecules in the system, we can predict relative binding energies to on-targets and off-targets, allowing for in
silico affinity and selectivity profiling much more rapidly and efficiently than experimental approaches. Tightly coupling these simulations experimental synthesis and assays allows us to shorten the time between design cycles and increase the fraction of desirable compounds made. This gives STX a significant advantage both in the accuracy with which it can solve extremely difficult biochemical problems and in the speed.
Our scientific leadership team has published seminal papers in the field of computer-aided drug design related to the above topics, with an emphasis on rigorous all-atom simulations to compute binding affinity, selectivity, water thermodynamics, and virtual screening. The below publications highlight our work and approach.
Accurate and reliable prediction of relative ligand binding potency in prospective drug discovery by way of modern free-energy calculation protocol and force field
--L Wang et al., J. Am.
Chem. Soc., 137 (7), 2695-2703, 2015
Accurate binding free energy predictions in fragment optimization.
--TB Steinbrecher, et al., J.
Chem. Inf. Model., 55 (11), 2411-2420, 2015
Predicting binding affinities for GPCR ligands using free-energy perturbation.
-- EB Lenselink, et al.,
ACS Omega, 1 (2), 293-304, 2016
Relative Binding Free Energy Calculations Apllied to Protein Homology Models.
--D Cappel, ML Hall, EB Lenselink, T Beuming, J Qi, J Bradner, W Sherman,
J. Chem. Inf. Model., 56 (12), 2388-2400, 2016
Differential water thermodynamics determine PI3K-Beta/Delta selectivity for solvent-exposed ligan modifications.
--D Robinson, et al.,
J. Chem. Inf. Model., 56 (5), 886-894, 2016
Mechanism of the hydrophobic effect in the bio-molecular recognition of aryl-sulfonamides by carbonic anhydrase
--PW Snyder, et al.,
Proc. Nat. Acad. Sci., 108 (44), 17889-17894, 2011
Water networks contribute to enthalpy.entropy compensation in protein-ligand binding.
--B Breiten, et al.
J. Am. Chem. Soc., 135 (41), 15579-15584, 2013
RInteractions between Hofmeister anions and the binding pocket of a protein.
-- JM Fox, et al.,
J. Am. Chem. Soc., 137 (11), 3859-3866 2015
Thermodynamic analysis of water molecules at the surface of proteins and applications to bind site prediction and characterization.
-- T Beuming, Y Che, R Abel, B Kim, V Shanmugasundaram, W Sherman,
Prot. Struct. Funct, Bioinf., 80 (3), 871-883, 2012
High-energy water sites determine peptide binding affinity and specificity of PDZ domains.
-- T Beuming, R Farid, W Sherman,
Prot. Sci., 18 (8), 1609-1619, 2009
Hydration site thermodynamics explain SARs for triazolypurines analogues binding to the A2A receptor.
-- C Higgs, T Beuming, W Sherman,
ACS Med. Chem. Lett., 1 (4), 160-164, 2010
Novel method for probing the specificity binding profile of ligands: applications to HIV Protease.
-- W Sherman, B Tidor,
Chem. Bio. Drug Des., 71 (5), 387-407, 2006
Rational approaches to improving selectivity in drug design.
-- DJ Huggins, W Sherman, B Tidor,
J. Med. Chem., 55(4), 1424-1444, 2012
Understanding kinase selectivity through energetic analysis of binding site waters.
-- DD Robinson, W Sherman, R Farid,
ChemMedChem, 5 (4), 618-627, 2010
Solvation Free Energy Calculations
Prediction of absolute solvation free energies using molecular dynamics free energy perturbation and the OPLS force field.
--D Shivakumar, J Williams, Y Wu, W Damm, J Shelley, W Sherman,
J. Chem. Theory Comput., 6 (5), 1509-1519, 2010
Improving the prediction of absolute solvation free energies using the next generation OPLS force field.
-- D Shivakumar, E Harder, W Damm, RA Friesnerm, W Sherman,
J. Chem. Theory Comput., 8 (8), 2553-2558, 2012
Virtual Screening and Drug Design
Generation of receptor structural ensembles for virtual screening using binding site shape analysis and clustering.
-- DJ Osguthorpe, W Sherman, AT Hagler,
Chem. Bio. Drug Des., 80 (2), 182-193, 2012
Exploring protein flexibility: incorporating structural ensembles from crystal structures and simulation into virtual screening protocols.
-- DJ Osguthorpe, W Sherman, AT Hagler,
J. Phys. Chem. B, 116 (23), 6952-6959, 2012
Boosting virtual screening enrichment with data fusion: coalescing hits from two-dimensional fingerprints, shape, and docking.
-- GM Sastry, VSS Inakollu, W Sherman,
J. Chem. Inf. Model., 53 (7), 1531-1542. 2013
Selecting an optimal number of binding site waters to improve virtual screening enrichments against the adenosine A2A receptor.
-- EB Lenselink, T Beuming, W Sherman, HWT van Vlikmen, AP Ijzerman,
J. Chem. Inf. Model., 54 (6), 1737-1746, 2014
Discovery of furan carboxylate derivatives as novel inhibitors of ATP-citrate lyase via virtual high-throughput screening.
--Jernigan FE, Hanai J, Sukhatme VP, Sun L, Bioorg. Med. Chem. Lett. 27 (4), 929-935, 2017
Design and synthesis of emodin derivatives as novel inhibitors of ATP-citrate lyase.
--Koerner SK, Hanai J, Bai S, Jernigan FE, Oki M, Komaba C, Shuto E, Sukhatme VP, Sun L, Eur. J. Med. Chem. 126, 920-928, 2017
Glycopeptide analogues of PSGL-1 inhibit P-selectin in vitro and in vivo.
---Krishnamurthy VR, et al. Nat. Commun. 6, 6387, 2015
Ganetespib, a unique triazolone-containing Hsp90 inhibitor, exhibits potent antitumor activity and a superior safety profile for cancer therapy.
--Ying W, et al. Mol. Cancer Ther. 11, 475, 2012.