Liganx blog

Drug targets, resistance mutations, ADMET properties, and molecular docking methodology — written for researchers in structure-based drug discovery.

• ESR1 Y537S and D538G: the mutations that switch ER on

  How the two most common ESR1 ligand-binding-domain mutations lock the estrogen receptor in its active state, why aromatase inhibitors fail, and which SERD still works.

• Ultra-large library docking: billions of compounds, better hits

  Why screening hundreds of millions of make-on-demand compounds raised docking hit rates instead of drowning them, and the tricks that make billion-compound screens tractable.

• KIT D816V: the mutation that defines systemic mastocytosis

  Why the KIT D816V activation-loop mutation is intrinsically resistant to imatinib, and how avapritinib's type-I design finally drugged it across advanced and indolent disease.

• Reactive metabolites: the hidden liability in your scaffold

  Bioactivation turns benign drugs into reactive electrophiles tied to idiosyncratic toxicity. A primer on structural alerts, GSH trapping, and why dose and intrinsic reactivity both matter.

• Acalabrutinib + venetoclax: all-oral, fixed-duration CLL

  The FDA cleared acalabrutinib plus venetoclax for frontline CLL on the AMPLIFY trial. Why pairing a BTK inhibitor with a BCL-2 inhibitor changes the treatment math.

• Caco-2 permeability: the gatekeeper for oral drugs

  How the Caco-2 monolayer assay predicts intestinal absorption, what Papp values mean, and why a potent compound that cannot cross the gut wall is a dead candidate.

• Sizing the docking search box: the parameter people get wrong

  How the grid box (search space) size and placement quietly determine docking accuracy, why too big and too small both fail, and a defensible rule of thumb.

• PIK3CA E545K and E542K: the helical-domain mutants

  Why PIK3CA exon 9 mutations E545K and E542K activate PI3K alpha by breaking the nSH2 brake, how they differ from kinase-domain H1047R, and what that means for inhibitor design.

• Ligand efficiency metrics: LE, LLE, and LELP explained

  Why raw potency lies, how ligand efficiency, lipophilic efficiency, and LELP keep optimization honest, and how to read them off your docking scores.

• RET-driven cancer: the selective inhibitor landscape

  How RET fusions and activating mutations drive lung and thyroid cancer, the two approved selective inhibitors, and why G810 resistance is the next wall.

• BCR-ABL in CML: from imatinib to the allosteric STAMP inhibitor

  Five ATP-site TKIs, one notorious gatekeeper mutation, and a sixth drug that binds a completely different pocket. The BCR-ABL drug landscape, structurally.

• Redocking and RMSD: validating a docking protocol before you trust it

  Before a docking score means anything, the protocol has to reproduce a known pose. How redocking, the 2 angstrom RMSD rule, and pose validity actually work.

• The Ames test, structural alerts, and predicting mutagenicity

  What the Ames test measures, why a handful of reactive substructures predict most positives, and how ICH M7 lets two QSAR models stand in for the wet assay.

• MET D1228 and Y1230: the wall after capmatinib and tepotinib

  Why the two most common acquired resistance mutations break every approved type I MET inhibitor, the structural reason, and the type II switch that sometimes rescues it.

• AKT1 E17K and capivasertib: drugging below PI3K-alpha

  AKT sits downstream of PI3K-alpha and PTEN, so hitting it catches pathway activation from any of three upstream alterations. Here is the biology and the drugs.

• Consensus scoring: why combining docking functions beats one

  Every scoring function is wrong in its own way. Consensus scoring cancels the uncorrelated errors. Here is how rank-by-rank, rank-by-vote, and ECR actually work.

• Cryptic and allosteric pockets in docking

  Some of the best drug targets have no visible pocket in their resting structure. Why rigid docking misses cryptic sites, and what to do about it.

• FLT3 in AML: the inhibitor landscape

  Midostaurin, gilteritinib, and quizartinib are all FLT3 inhibitors, but they bind different conformations and fail against different mutations. A field guide.

• The first all-oral AML regimen: oral decitabine plus venetoclax

  The FDA cleared oral decitabine/cedazuridine with venetoclax for unfit AML in May 2026. Here is the pharmacology behind the first clinic-free frontline option.

• The state you dock matters: protonation and tautomers

  Docking the wrong protonation state or tautomer quietly wrecks your scores. Here is what pKa, microspecies, and ligand prep actually do to a docking run.

• Giredestrant's lidERA win: oral SERDs reach the adjuvant setting

  The phase 3 lidERA trial made giredestrant the first oral SERD to improve invasive disease-free survival as adjuvant therapy. What it means for ER+ disease.

• KRAS G12R: the atypical PDAC mutant that signals differently

  G12R is the third most common KRAS mutation in pancreatic cancer and is biochemically odd: impaired for PI3K and macropinocytosis. Here is why it matters.

• Induced-fit docking: when the rigid receptor lies to you

  Most docking treats the protein as a frozen statue. Real pockets reshape around the ligand. Here is when receptor flexibility matters and how to handle it.

• ROS1 G2032R: the solvent-front mutation that breaks crizotinib

  A single glycine-to-arginine swap at the edge of the ROS1 pocket ends crizotinib and entrectinib. How repotrectinib and taletrectinib were built to fit around it.

• EGFR uncommon mutations: G719X, L861Q, S768I

  The atypical EGFR mutations are not interchangeable. Why afatinib has the broadest label, where osimertinib wins, and why L861Q behaves differently.

• Lipophilicity: logP, logD, and why they drive ADMET

  Lipophilicity is the single property that touches solubility, permeability, clearance, hERG, and tox. A practical guide to logP vs logD and the 3/75 rule.

• HER2 exon 20 insertions in NSCLC: zongertinib and the YVMA problem

  Why HER2 exon 20 insertions resisted pan-HER inhibitors for a decade, and how a HER2-selective covalent TKI finally cleared the EGFR-toxicity barrier.

• Water networks in docking: the waters you displace decide potency

  Binding pockets are full of water, not vacuum. Which waters you displace and which you keep often explains potency better than the ligand contacts themselves.

• Metabolic stability: why a potent compound still washes out

  A drug can hit its target at nanomolar potency and still fail because the liver clears it in minutes. Here is what intrinsic clearance, microsomal half-life, and hepatic clearance actually mean, and how they decide dose and dosing frequency.

• Pivekimab sunirine approved for BPDCN: the CD123 story

  The FDA approved pivekimab sunirine, the first antibody-drug conjugate for blastic plasmacytoid dendritic cell neoplasm. Here is the CD123 rationale, the CADENZA data, and where small molecules like venetoclax still fit.

• BRAF beyond V600: class II and III mutations and RAF dimers

  Why vemurafenib only works on V600, how class II and III BRAF mutants signal as dimers, and why paradoxical activation makes non-V600 disease a different drug-design problem.

• Relative binding free energy (FEP): when docking isn't enough

  What free energy perturbation actually computes, why it reaches ~1 kcal/mol on congeneric series, and where it fits between fast docking triage and wet-lab assays.

• EGFR exon 19 deletions: the deletion that drugs love

  Exon 19 deletions are the most common EGFR driver in lung cancer and the most TKI-sensitive. Here is how losing four residues locks the kinase on, and why ex19del responds better than L858R.

• P-glycoprotein: the pump that keeps drugs out of the brain

  P-gp efflux is why a potent, brain-targeted kinase inhibitor can still fail in CNS metastases. Here is what the transporter does, how the efflux ratio is measured, and which oncology drugs it blocks.

• CDK4/6 inhibitors in HR+ breast cancer: three approvals, one class

  Palbociclib, ribociclib, and abemaciclib all hit the same kinase pair but differ on selectivity, dosing, and toxicity. Here is how the class actually splits.

• DFG-out and Type II kinase inhibitors: where selectivity comes from

  Imatinib, sorafenib, ponatinib, nilotinib — Type II inhibitors all bind a conformation the ATP-mimetic Type I drugs never see. Here is what DFG-out is and why it matters.

• Ensemble docking: when one rigid receptor isn't enough

  Why docking against a single crystal structure misses real binders, and how docking across multiple receptor conformations recovers the ones a rigid pocket throws away.

• KRAS codon 61: why Q61 mutations break the GTPase

  Codon 61 mutations disable the catalytic glutamine that hydrolyzes GTP, locking KRAS in the ON state. What that means for SHP2 resistance and pan-RAS drugs.

• Aqueous solubility: the property that quietly kills oral programs

  Kinetic vs thermodynamic solubility, the BCS map, and why a beautiful nanomolar binder can still fail because it will not dissolve. A practical explainer.

• EGFR L858R: the activating mutation that built a drug class

  L858R is one of the two classic EGFR drivers in lung cancer. Here is how a single residue swap in the activation loop turns a kinase on, and which drugs shut it back off.

• ALK L1196M: the gatekeeper mutation and the lorlatinib answer

  L1196M was the first crizotinib-resistant ALK mutation found. Here is the gatekeeper mechanism, the drugs that overcome it, and why compound mutants are the real wall.

• MM-GBSA rescoring: when physics beats the docking score

  MM-GBSA re-ranks docking poses with a physics-based endpoint. Here is what it does well, where it fails, and when it is worth the extra compute over a raw score.

• Why ΔΔ beats absolute docking scores

  Docking scores are bad at predicting binding affinity but good at ranking. Here is why the wild-type-minus-mutant difference is the number you should trust.

• Sonrotoclax: the first new BCL-2 inhibitor in a decade

  The FDA just approved sonrotoclax for relapsed mantle cell lymphoma, the first new BH3-mimetic since venetoclax. What it hits, and why molecular docking cares.

• EGFR C797S: the mutation behind osimertinib resistance

  C797S is the mutation that breaks osimertinib's covalent bond. Here's the mechanism, why allelic context decides treatment, and the fourth-generation inhibitors chasing it.

• The first PROTAC is approved: vepdegestrant in ESR1+ breast cancer

  The FDA approved vepdegestrant on May 1, 2026, the first PROTAC degrader ever cleared. What the VERITAC-2 data showed and why catalytic degradation matters.

• KRAS G12V: the common mutation still without a drug

  G12C has two approved drugs and G12D has clinical candidates, but KRAS G12V still has none. Here is the structural reason, and the pan-RAS programs trying to fix it.

• Plasma protein binding and the free drug hypothesis

  Only unbound drug reaches the target. Why chasing lower plasma protein binding usually wastes a med-chem program, and what fraction unbound really tells you.

• Boltz-2 and co-folding: when to use it instead of docking

  Co-folding models predict the protein-ligand complex from sequence and SMILES. Here is where Boltz-2 helps, where classical docking still wins, and how to combine them.

• KIT in GIST: the four-line resistance ladder

  Imatinib, sunitinib, regorafenib, ripretinib, avapritinib — how five drugs map onto KIT's primary and secondary mutations, and why each line eventually fails.

• PAINS: the compounds that fake their own activity

  What pan-assay interference compounds are, the chemistry behind their false hits, and why a PAINS flag is a prompt to confirm, not a verdict to discard.

• ROS1 fusion NSCLC: the TKI landscape in 2026

  A field guide to the four approved ROS1 inhibitors, why G2032R breaks most of them, and how the newest drugs were built to survive the solvent-front mutation.

• MET exon 14 skipping in NSCLC — capmatinib, tepotinib, and what skipping really means

  Why MET exon 14 skipping is an oncogenic event even without a kinase-domain mutation, how capmatinib and tepotinib exploit the resulting half-life increase, and where resistance shows up.

• PIK3CA H1047R and inavolisib — the mutant-selective degrader story

  Why PIK3CA H1047R activates PI3K alpha, how inavolisib goes beyond inhibition by degrading the mutant protein, and what the INAVO120 results mean for HR+/HER2- breast cancer.

• Blood-brain barrier and kinase inhibitors — what actually predicts CNS exposure

  Why most oral kinase inhibitors miss the brain, what physicochemical properties and efflux transporters predict CNS exposure, and how osimertinib, alectinib, and lorlatinib got it right.

• EGFR exon 20 insertions — the third resistance pocket

  Why classical EGFR TKIs fail on exon 20 insertions, and how amivantamab, sunvozertinib, and zipalertinib are building out a real treatment ladder for this 10% of EGFR-mutant NSCLC.

• BTK C481S and pirtobrutinib — the reversible bet that paid off

  How three generations of covalent BTK inhibitors hit the same C481S wall, why pirtobrutinib's non-covalent design escapes it, and what the docking actually shows.

• ProLIF interaction fingerprints — what your poses are actually doing

  Why an interaction fingerprint tells you more than a docking score, how ProLIF encodes the eight interaction types that matter, and where this fits in a screening workflow.

• KRAS G12D — drugging the bigger cousin in pancreatic cancer

  G12D is the most common KRAS mutation and the dominant driver in PDAC. With no cysteine to hook, the field had to invent two new playbooks. Here is where they stand.

• PROTACs and oral bioavailability — what bRo5 chemistry actually requires

  PROTACs blow past Lipinski on every count. Vepdegestrant still got oral. Here is the empirical bRo5 window that separates an oral degrader from an IV-only one.

• ALK G1202R: the solvent-front mutation that resets the ladder

  Why one ALK mutation knocks out crizotinib, ceritinib, alectinib and brigatinib at once, why lorlatinib still works, and what comes after it.

• Covalent docking: how it differs from the non-covalent kind

  Standard docking assumes reversible binding. For warhead-bearing drugs that form a real bond with the target, you need a different method. Here is how it works.

• DILI: the hepatotoxicity liability you can't fully design away

  Drug-induced liver injury is the leading cause of drug withdrawals. What causes it, why kinase inhibitors are prone, and how to flag it during molecular docking.

• HER2: the drug landscape across breast, gastric, and lung

  A field guide to HER2-amplified, HER2-low, and HER2-mutant cancer, the drugs that hit each, and where molecular docking fits the small-molecule TKIs.

• AlphaFold for docking: when the predicted structure is usable

  What the validation literature actually says about AlphaFold2 and AlphaFold3 structures as docking targets, and the pre-flight checks that catch the failure modes before they cost you a screen.

• FLT3 in AML: ITD, D835Y, and the type-I vs type-II pivot

  Why quizartinib works on FLT3-ITD but fails on D835Y, why gilteritinib doesn't, and what the F691L gatekeeper means for the next generation of FLT3 inhibitors.

• IDH1 R132H: one mutation, two diseases, two FDA approvals

  How a gain-of-function arginine-to-histidine swap in IDH1 produces an oncometabolite, drives both glioma and AML, and finally has clean drugs against it.

• PoseBusters: why your top-ranked pose can still be nonsense

  RMSD under 2 angstroms is not the same as a pose you can hand to a chemist. PoseBusters showed how often deep-learning docking violates chemistry, and what to check.

• BCR-ABL T315I: the gatekeeper that broke imatinib

  How a single threonine-to-isoleucine swap at position 315 walled off four BCR-ABL inhibitors, and how ponatinib and asciminib eventually got around it.

• CYP3A4: the metabolic bottleneck behind half your DDI risk

  Why CYP3A4 metabolizes most marketed oncology drugs, how strong inhibitors and inducers blow up exposure, and what to screen for early in lead optimization.

• BRAF V600E: same mutation, different drugs by tissue

  Why vemurafenib works in melanoma but fails in colorectal, how paradoxical RAF activation shapes the chemistry, and what BEACON changed about the standard of care.

• Vina, GNINA, and Glide: what each scoring function buys you

  An honest comparison of the three workhorse docking scoring functions in 2026 — what they actually optimize for, where they fail, and how to combine them.

• KRAS G12C — clinical landscape, 2026

  A field guide to the four approved KRAS G12C inhibitors, what's known about resistance pathways, and where the medicinal chemistry is going next.

• T790M, C797S, and the EGFR resistance staircase

  How EGFR resistance mutations evolved across three generations of inhibitors, what the docking actually shows, and why C797S is harder than T790M ever was.

• hERG: the silent killer of kinase programs

  Why a basic amine and a couple of aromatic rings are enough to wipe out a clinical candidate, and what the cardiac liability actually looks like in screening data.