Science Punch Man

  What I need to know.  

[sciencepunchman]

COPD Exacerbation

hx, COPD, smoking, home o2, meds, old pft, lung ct, echo

sx, wheezing, sputum, dyspnea, cardiopulm exam + ent

labs, paco2, pao2, bnp, hco3, cxr

tx initial, iv methylpredbisolone, duonebs q4h, doxy or azithro, sat 88-92%, if co2 high or worsening admit icu and bipap, intubation if ams and bipap failure.

tx dc, switch po prednisone, taper duonebs till prn then switch to MDI, cont doxy or azithro, ?outpt meds.

[sciencepunchman]

Treatment of Mitral Stenosis

Treatment considerations are relied on the symptom severity, severity of stenosis, the existence or risk of complications, age of diagnosis, condition of the valve and the heart.

Condition of the valve and heart, severity of the stenosis is characterized by echocardiography,

Valvular orifice:

Normal: 4-5cm2, 

moderate: 1.5-2.5cm2, 

severe: less than 1.5cm2, 

very severe: less than 1cm2.

Complications of the disease: Mitral regurgitation, Atrial fibrillation, pulmonary edema, pulmonary hypertension, tricuspid regurgitation, cerebrovascular embolism, sinus tachicardia, Right ventricular heart failure, endocarditis

Reasons for mortality:

cerebrovascular embolism, 

pulmonary embolism, 

heart failure

Penicillin profilaxis for rheumatic heart disease:

When: History of rheumatic fever and Asymptomatic patients

Pros: Preventive treatment, oral administration or monthly IM injections 

Cons: Very long duration of treatment, compliance issues 

Diuretics

When: Mildly symptomatic, Pulmonary edema

Pros: Oral therapy 

Cons: Not sufficient for moderate and severe stenosis, risk of Electrolite imbalance / ototoxicity / dehidration 

Beta blockers or Calcium channel blockers

When: Control of ventricular rate if sinus tachicardia or AF is present 

Pros: Oral therapy

Cons: Asthma or COPD execerbation (BBlockers) 

Warfarin (do not use direct acting oral anticoagulants)

When: To prevent thromboembolism (emboli history, AF, left atrial clot, enlarged left atrium) 

Pros: Oral therapy 

Cons: Risk of bleeding, regular INR follow up, drug interactions, teratogen 

Percutaneous balloon commissurotomy

When: Young, without valvular calcification / subvalvular distortion / severe MR / left atrium thrombi 

Pros: Minimal invasive, as effective as open heart surgery, lower complications

Cons: Limitations of the procedure, need for valvular replacement in the long run for certain cases.

Surgical commissurotomy

When: Contraindications with percutaneous intervention except valvular calcification

Rarely done in modern days 

Cons: Need for sternotomy or thoracotomy, invasive 

Valvular replacement

When: If the valve is not suitable for perc. or surg. commissurotomy 

Pros: Effective, treatment of last resort 

Cons: Highly invasive, lifelong warfarin for mechanical valves, 3-6m warfarin for bioprothesis, high mortality and morbidity

[sciencepunchman]

Problems of Structure Based Drug Design and Molecular Docking Softwares

The ultimate docking is to determine the binding probability of two molecules by calculating the geometric shape compatibility and molecular affinity with computer algorithms.

Protein-ligand or protein-protein interaction modelling softwares have been developed over years. Computers have become stronger, different algorithms are made, more complex functions implemented. All of these factors contributed to simulate a real life molecular interaction software. Unfortunately we haven’t achieved yet. 

For the sake of drug discovery, we’ve screened drug candidates and tried to find novel therapeutics in medicine and predict the outcome of the complex molecular interaction. It did give us valuable information but also gave false positive results.

The physiology of the docking software

Docking is all about posing and scoring. Posing means depicting molecular geometric compatibility in a 3D space whereas scoring is to calculate simulative reaction free energy and predicting the binding affinity of the molecules. Docking is more probable if the molecules are geometrically favorable, has negative free energy and high affinity.

The inputs of the docking software are 3D x-ray crystallography or nmr spectroscopy images of interacting molecules and the output is the score function result and final geometric shape.

Of course the crystal image is not how the molecule behaves or does not show its’ all possible configurations. One can say, the crystal image is the snapshot of the molecule.

Prediction of protonation in certain pH environments is one of the most important calculations that the computer must address.

The problems

Imperfect x-ray crystallography or nmr spectroscopy images.

Challenge to differentiate O, N or double bonded carbon atoms in crystallography.

Low density images

Xray structures don’t have information about protonation of O or N atoms.

The challenge of chemistry itself.

The 360 degree rotating nature of single C-C bonds

Tautomerism

Pseudorotation

Unsatisfied hydrogen bonds vs hydrophobicity

Protonation

Limitations of computers

Insufficient computer power to analyze all the conformational changes

Complexity of H2O-water molecules.

Q & A

How does a software deal with some of the problems of imperfect crystallography images, the nature of chemistry and the limitations of computer power?

> You can use prediction tools for most of the situations including rotations, tautomers, protonations, side chain flips or water orientations.

> Crystallography problems might be solved by using multiple crystal structure if available.

> For torsional and rotational problems, you can split the molecule into pieces and try to fit into the pocket. First, the base portion docking construction is optimized and several possible solution are made. The next step is docking the 2nd part of the molecule. Again, several variations are made, but the variations should be continuous with the ligand base. This method is called incremental construction.

> Using triangles for the ligands’ head and tail sites and matching the proteins’ pocket with the donor - acceptor interaction is what the program does. After the possible solutions are found, the RMSD (root mean square deviation, basically a function of atomic distances) is calculated.

> For scoring or estimating the affinity, many different methods are being used. Force fields approach (has too many paramethers to be calculated, dG intermolecular bonds), Quantum mechanics, statistical approach (you must know some real interactions before), HYDE etc. It is a hot topic in bioinformatics.