Homology modeling in drug discovery: Overview,current applications,and future perspectives

Homology modeling is one of the computational structure prediction methods that are used to determine protein 3D structure from its amino acid sequence. It is considered to be the most accurate of the computational structure prediction methods. It consists of multiple steps that are straightforward and easy to apply. There are many tools and servers that are used for homology modeling. There is no single modeling program or server which is superior in every aspect to others. Since the functionality of the model depends on the quality of the generated protein 3D structure, maximizing the quality of homology modeling is crucial. Homology modeling has many applications in the drug discovery process. Since drugs interact with receptors that consist mainly of proteins, protein 3D structure determination, and thus homology modeling is important in drug discovery. Accordingly, there has been the clarification of protein interactions using 3D structures of proteins that are built with homology modeling. This contributes to the identification of novel drug candidates. Homology modeling plays an important role in making drug discovery faster, easier, cheaper, and more practical. As new modeling methods and combinations are introduced, the scope of its applications widens.     

Disturbed Left Atrial Function is Associated with Paroxysmal Atrial Fibrillation in Hypertension

Background

Hypertension is the most prevalent and modifiable risk factor for atrial fibrillation. The pressure overload in the left atrium induces pathophysiological changes leading to alterations in contractile function and electrical properties.

Objective

In this study our aim was to assess left atrial function in hypertensive patients to determine the association between left atrial function with paroxysmal atrial fibrillation (PAF).

Method

We studied 57 hypertensive patients (age: 53±4 years; left ventricular ejection fraction: 76±6.7%), including 30 consecutive patients with PAF and 30 age-matched control subjects. Left atrial (LA) volumes were measured using the modified Simpson''s biplane method. Three types of LA volume were determined: maximal LA(LAVmax), preatrial contraction LA(LAVpreA) and minimal LA volume(LAVmin). LA emptying functions were calculated. LA total emptying volume = LAVmax−LAVmin and the LA total EF = (LAVmax-LAVmin )/LAVmax, LA passive emptying volume = LAVmax− LAVpreA and the LA passive EF = (LAVmax-LAVpreA)/LAVmax, LA active emptying volume = LAVpreA−LAVmin and LA active EF = (LAVpreA-LAVmin )/LAVpreA.

Results

The hypertensive period is longer in hypertensive group with PAF. LAVmax significantly increased in hypertensive group with PAF when compared to hypertensive group without PAF (p=0.010). LAAEF was significantly decreased in hypertensive group with PAF as compared to hypertensive group without PAF (p=0.020). A'' was decreased in the hypertensive group with PAF when compared to those without PAF (p = 0.044).

Conclusion

Increased LA volume and impaired LA active emptying function was associated with PAF in untreated hypertensive patients. Longer hypertensive period is associated with PAF.     

New inflammatory markers in pre-eclampsia: echocardiographic epicardial fat thickness and neutrophil to lymphocyte ratio

Background: Increased epicardial fat thickness (EFT) has been proposed as a new cardiometabolic risk factor. The neutrophil/lymphocyte ratio (NLR) has predictive and prognostic value in several cardiovascular diseases. The aim of this study was to explore the association between EFT and NLR in patients with pre-eclampsia.

Methods: Hundred and eight pregnant patients with a mean age of 30.6?±?6.3 years were included in the study. Patients were divided into two groups based on the presence of pre-eclampsia. All participants underwent transthoracic echocardiography imaging, and complete blood counts were measured by an automated hematology analyzer. Statistical analysis was performed using the Chi-square, Mann–Whitney U, correlation and logistic regression tests, and receiver operating characteristic (ROC) analysis.

Result: The mean EFT value of the pre-eclampsia group was significantly higher than the control group (6.9?±?0.6 versus 5.6?±?0.6; p?p?Conclusion: Unlike many other inflammatory markers and bioassays, NLR and echocardiographic EFT are inexpensive and readily available biomarkers that may be useful for risk stratification in patients with pre-eclampsia.     

Editorial

It has been proven that the jaw rehabilitation not only has a crucial role in treatment of both trismus and mandibular hypomobility but also in the rehabilitation of surgical conditions of the temporomandibular joint and the jaw.(1) Today, the commercially available jaw motion rehabilitation systems are specifically designed to treat these conditions.(2) These systems utilize repetitive passive motion and stretching to restore mobility and flexibility of the jaw musculature, associated joints and connective tissues. Major advantages of these systems are that they reduce patients' anxiety by allowing them to control the extent and length of each stretching and provide passive motion for effective jaw rehabilitation therapy allowing patients to perform their necessary therapy while continuing in their daily life.(3) However, these systems are very expensive and mostly unavailable in our country. So, a new alternative jaw motion rehabilitation device 'The Okbite' was developed recently in our hospital (Fig. 1). It is simply adapted from the commercially available nasal specula. The blades of the specula are cut distally and metal bite pads are attached to these sites. The lower bite pad was placed posteriorly and curved anatomically. This device can be produced in a custom-made form according the occlusal pattern and the size of the mandible of the patient. The metal bite pads are covered with plaster bandage by the patient for a soft bite. In our practice, we used this device for the rehabilitation of total temporomandibular joint prosthesis, temporomandibular gap arthroplasties and temporomandibular joint disorders with great success. It costs nearly 1/50 of the commercially available jaw motion rehabilitation systems with almost equal outcomes of pain relief and total mouth opening. The major disadvantage of this system is that it can mimic the anatomical motion pattern of the mandible to a limited extend. We propose the application of this Okbite system, which provides jaw rehabilitation in such conditions.     

Histopathology of surgically treated renal tumours in young adults: a developing country perspective

Background  

There is no data on the histopathological characteristics of renal tumours in young adults in Pakistan.     

Nonsense β-thalassemia mutation at codon 37 (TGG>TGA), detected for the first time in three Turkish cases

Thalassemias are genetically heterogeneous group of disorders with reduced or absent production of globin. β-Thalassemia major can be caused by homozygosity or compound heterozygosity for β-globin gene mutation. Here we report, for the first time in Turkey, three cases who carry the nonsense β-thalassemia (β-thal) mutation at codon 37 (TGG>TGA; Trp→Stop) causing premature stop codon.     

Contribution of β-phenethylamine, a component of chocolate and wine, to dopaminergic neurodegeneration： implications for the pathogenesis of Parkinson＇s disease

While the cause of dopaminergic neuronal cell death in Parkinson＇s disease（PD）is not yet understood,many endogenous molecules have been implicated in its pathogenesis.β-phenethylamine（β-PEA）,a component of various food items including chocolate and wine,is an endogenous molecule produced from phenylalanine in the brain.It has been reported recently that long-term administration ofβ-PEA in rodents causes neurochemical and behavioral alterations similar to that produced by parkinsonian neurotoxins.The toxicity ofβ-PEA has been linked to the production of hydroxyl radical（.OH）and the generation of oxidative stress in dopaminergic areas of the brain,and this may be mediated by inhibition of mitochondrial complex-I.Another significant observation is that administration ofβ-PEA to rodents reduces striatal dopamine content and induces movement disorders similar to those of parkinsonian rodents.However,no reports are available on the extent of dopaminergic neuronal cell death after administration ofβ-PEA.Based on the literature,we set out to establishβ-PEA as an endogenous molecule that potentially contributes to the progressive development of PD.The sequence of molecular events that could be responsible for dopaminergic neuronal cell death in PD by consumption ofβ-PEA-containing foods is proposed here.Thus,long-term over-consumption of food items containingβ-PEA could be a neurological risk factor having significant pathological consequences.