CpHMD
Constant pH Molecular Dynamics (CpHMD) for more accurate, holistic simulations
About CpHMD
Continuous constant pH (CpH) methods allow protonation states to respond to conformational dynamics and pH during molecular dynamics (MD) simulations. This delivers more accurate, holistic simulation information compared to conventional molecular dynamics methods, in which the protonation states are preassigned and fixed.
Applications
PROTAC Design: Scanning E3 Ligases
Proteolysis targeting chimeras (PROTACs) represent a new frontier in small-molecule drug discovery. The degrader molecule consists of a target binding moiety, linker, and ligase binding moiety, which covalently attaches to an E3 ubiquitin ligase. Once the ternary complex is formed, the ubiquitin system is activated for targeted protein degradation. iTitrate can scan E3 ligases for reactive cysteines and other amino acids to assist PROTAC design.
Lead Discovery and Optimization: Protonation/Tautomer State Assignment
Docking, molecular dynamics, and binding affinity calculations are often used in computer-aided drug discovery programs. iTitrate accurately determines the protonation and tautomer states for Asp/Glu/His/Cys/Lys of any protein at any pH condition, thus improving ligand docking predictions and molecular dynamics characterization of protein conformations. iTitrate also provides corrections to binding affinity calculations by predicting ligand-induced protonation state changes.
Small Molecule Properties: Small Molecule pKa Predictions
Absorption, distribution, metabolism, excretion, and toxicity of drug molecules are significantly affected by the ionization states. Correct assignment of protons for small molecules is also critical for a variety of computer-aided drug design and evaluation tasks. Using Machine learning models trained on large databases, iKa accurately predicts pKa’s of drug-like small molecules.
COVID-Targeting Drug Design: Targeting SARS-CoV-2 Main Protease
Severe acute respiratory syndrome coronavirus 2 (SARS-COV-2), the instigator of the COVID-19 pandemic, has a critical enzyme called main protease that cleaves the viral polyproteins to initiate the replication process. The main protease has many His and Cys residues, some of which are in or near the substrate binding site, and their protonation state switches modulate the conformational dynamics and binding. iTitrate can accurately predict the protonation states of His and Cys residues, to assist with structure-based drug design targeting the main protease.
TCI Design: Cys and Lys Reactivity Predictions
Targeted covalent inhibitor (TCI) design is gaining increased interest and success in kinase drug discovery programs. Instead of trial and error, it is desirable to know the locations of highly nucleophilic amino acid residues that can react with mild electrophilic warheads. iTitrate can accurately predict the reactivities of cysteines and lysines in kinases and other drug targets, to facilitate TCI design.
Kinome-wide Scanning: Covalently Targetable Kinases
Despite the development of a large number of clinical TCIs in recent years, the fraction of kinases that have been targeted remains small. iTitrate can systematically assess the reactivities of cysteines and lysines in the entire kinome, to identify covalently druggable kinases and assist the evaluation of target selectivities. This cost-saving in silico approach complements current efforts to discover new covalently druggable kinases.
Undruggable Targets Targeting KRAS
KRAS is the most frequently mutated oncogene in cancer. However, KRAS proteins have been considered “undruggable” targets for decades because they do not have suitable pockets for traditional small molecule inhibitors to bind. Recently, several TCIs have entered clinical trials, offering hope for new cancer drugs. iTitrate can identify druggable cysteines and lysines in KRAS proteins, to help expedite these efforts.
PPI Inhibition: Reactive Amino Acids at PPIs
Protein-protein interactions (PPIs) are notoriously challenging to inhibit via traditional methods. For example, the anti-apoptotic protein myeloid cell leukemia 1 (Mcl-1) serves as a key cancer survival factor through interactions with pro-apoptotic proteins. Recently, a clinical proof-of-concept covalent inhibitor was developed to engage a nucleophilic lysine. iTitrate can accurately predict the locations of reactive amino acids to accelerate PPI drug discoveries.