IN SILICO EVALUATION OF ANGIOTENSIN II RECEPTOR ANTAGONIST’S PLASMA PROTEIN BINDING USING COMPUTED MOLECULAR DESCRIPTORS

The discovery of new pharmacologically active substances and drugs modeling led to necessity of predicting drugs properties and its ADME data. Angiotensin II receptor antagonists are a group of pharmaceuticals which modulate the renin-angiotensin-aldosterone system and today represent the most commonly prescribed anti-hypertensive drugs. The aim of this study was to compare different molecular properties of seven angiotensin II receptor antagonists / blockers (ARBs), (eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan) and their plasma protein binding (PPB) data. Several ARBs molecular descriptors were calculated using software package Molinspiration Depiction Software as well as Virtual Computational Chemistry Laboratory (electronic descriptor – PSA, constitutional parameter – Mw, geometric descriptor – Vol, lipophilicity descriptors - logP values, aqueous solubility data – logS). The correlations between all collected descriptors and plasma protein binding data obtained from relevant literature were established. In the simple linear regression poor correlations were obtained in relationships between PPB data and all calculated molecular descriptors. In the next stage of the study multiple linear regression (MLR) was used for correlation of PPB data with two different descriptors as independent variables. The best correlation (R2=0.70 with P<0.05) was established between PPB data and molecular weight with addition of volume values as independent variables. The possible application of computed molecular descriptors in drugs protein binding evaluation can be of great importance in drug research

Critical comparison of shake-flask, potentiometric and chromatographic methods for lipophilicity evaluation (log Po/w) of neutral, acidic, basic, amphoteric, and zwitterionic drugs

In the present study three different procedures have been compared for the determination of the lipophilicity of the unionized species (log Po/w) of neutral, acidic, basic, amphoteric, and zwitterionic drugs. Shake-flask, potentiometric and chromatographic approaches have been assayed in a set of 66 representative compounds in different phases of advanced development. An excellent equivalence has been found between log Po/w values obtained by shake-flask and potentiometry, while the chromatographic approach is less accurate but very convenient for screening purposes when a high-throughput is required. In the case of zwitterionic and amphoteric compounds, either for shake-flask and chromatographic methods, the pH has to be accurately selected in order to ensure the compound to be in its neutral form

Lipofilnost salicilamida

Molecular lipophilicity was studied using salicylamide as a model drug. Log P value for the target compound was experimentally determined by the "shake-flask" method and calculated using nine different computer programs based on atom/fragment contributions, structural parameters, atom-type electrotopological-state indices and neural network modeling, and on topological structure descriptors. Our analysis demonstrates good agreement between the experimentally observed log P value of salicylamide and the value calculated by the CSLogP program, based on topological structure descriptors and electrotopological indices.U radu je dan pregled istraživanja molekularne lipofilnosti na primjeru salicamida. Log P vrijednost određena je eksperimentalnom («shake-flash») metodom i izračunata je pomoću devet različitih računalnih programa koji se temelje na atom/fragmentarnoj metodi, strukturnim parametrima, atom elektrotopologijskim indeksima uz modeliranje putem neuronskih mreža i topologijskim deskriptorima. Statistička obrada dobivenih rezultata pokazala je najbolju korelaciju eksperimentalno dobivene vrijednosti s log P vrijednošću dobivenom računalnim programoma CslogP, koji se temelji na topologijskim deskriptorima i elektrotopologijskim indeksima

Investigation of the Usability of Some Triazole Derivative Compounds as Drug Active Ingredients by ADME and Molecular Docking Properties

In this study, some important ADME parameters such as physicochemical properties, lipophilicity, water solubility, pharmacokinetics, medicinal chemistry and drug-likeness properties of ten triazole derivative compounds, which may be drug active ingredients, were performed on the SwissADME a web tool worked on-line. Bioavailability radar plotted for each molecule for rapid assessment of drug-likeness. The BOILED-Egg graph was plotted for each molecule to assess passive gastrointestinal absorption (HIA) and brain penetration (BBB) relative to the position of the molecules. SwissTargetPrediction a web tool worked on-line was used to predict the most likely protein targets of molecules. Docking programs have a wide range of applications ranging from computer aided to drug design. Molecules were docked with the determined target protein using the SwissDock a web tool worked on-line

The impact of aromatic ring count on the bioavailability of chemical compounds.

Masters Degree. University of KwaZulu-Natal, Pietermaritzburg.Aromatic rings are a negative contributing factor in the bioavailability of chemical compounds in drug discovery. Due to the inevitable effect the aromatic rings possess on the bioavailability of chemical compounds, methods to continuously evaluate their effect should be ceaseless. As such, this study aimed at investigating the impact of aromatic ring count on the bioavailability of chemical compounds by screening a small collection compound library comprising 13 compounds. The permeability of chemical compounds was evaluated using the PAMPA assay; the results further analysed through spectrophotometry. The PAMPA assay is an automated system and was used to allow for rapid screening of compounds and the screening was successful. Overall, only four chemical compounds showed poor permeability: ammonium bromide, gibberellic acid, salicylic acid, and PMSF. Osiris Property Explorer was used to screen all 13 compounds for cLogP, LogS, TPSA, Toxicity risks, drug-likeness and drug score. Most of these compounds produced suitable logP (< 5) and were therefore predicted to possess good absorption and permeability properties. Percentage protein binding was assessed separately; all chemical compounds were screened for percentage protein binding using Amicon Ultra-15 Centrifugal Filter method. The results indicated a broad range of protein binding for all chemical compounds tested (70.29 – 98.23%). Lipinski’s Rule of Five was applied to all chemical compounds and compounds were scored against the four rules. Most compounds adhered to all four rules with only two compounds violating one or two rules. A relationship between parameters: permeability, drug-score, and percentage protein binding, against the aromatic ring count of chemical compounds, was explored. Overall, no real relationship existed between any of these parameters and aromatic ring count, as was indicated by low correlation coefficients (R2) (< 0.95). Overall, this study resulted in the successful screening of 13 chemical compounds and the establishment of effective permeability, percentage protein binding assays for future studies

Aqueous solubility of drug-like compounds

New effective experimental techniques in medicinal chemistry and pharmacology have resulted in a vast increase in the number of pharmacologically interesting compounds. However, the possibility of producing drug candidates with optimal biopharmaceutical and pharmacokinetic properties is still improvable. A large fraction of typical drug candidates is poorly soluble in water, which results in low drug concentrations in gastrointestinal fluids and related acceptable low drug absorption. Therefore, gaining knowledge to improve the solubility of compounds is an indispensable requirement for developing compounds with drug-like properties. The main objective of this thesis was to investigate whether computer-based models derived from calculated molecular descriptors and structural fragments can be used to predict aqueous solubility for drug-like compounds with similar structures. For this purpose, both experimental and computational studies were performed. In the experimental work, a novel crystallization method for weak acids and bases was developed and applied for European patent. The obtained crystalline materials could be used for solubility measurements. A novel recognition method was developed to evaluate the tendency of compounds to form amorphous forms. This method could be used to ensure that only solubilities of crystalline materials were collected for the development of solubility prediction. In the development of improved in silico solubility models, lipophilicity was confirmed as the major driving factor and crystal information related descriptors as the second important factor for solubility. Reasons for the limited precision of commercial solubility prediction tools were identified. A general solubility model of high accuracy was obtained for drug-like compounds in congeneric series when lipophilicity was used as descriptor in combination with the structural fragments. Rules were derived from the prediction models of solubility which could be used by chemists or interested scientists as a rough guideline on the contribution of structural fragments on solubility: Aliphatic and polar fragments with high dipole moments are always considered as solubility enhancing. Strong acids and bases usually have lower intrinsic solubility than neutral ones. In summary, an improved solubility prediction method for congeneric series was developed using high quality solubility results of drugs and drug precursors as input parameter. The derived model tried to overcome difficulties of commercially available prediction tools for solubility by focusing on structurally related series and showed higher predictive power for drug-like compounds in comparison to commercially available tools. Parts of the results of this work were protected by a patent application1, which was filed by F. Hoffmann-La Roche Ltd on August 30, 2005

Toxicokinetics and bioconcentration of polycyclic aromatic hydrocarbons in freshwater isopods

A novel method based on a first-order two-compartment model was used to determine the bioconcentration and toxicokinetic rate constants of six different polycyclic aromatic hydrocarbons (PAHs) in the freshwater isopod Asellus aquaticus, a common species in most European freshwater systems. Numerical integration and iterative parameter estimation techniques were applied to account for time-varying aqueous exposure concentrations. All PAHs exhibited a rapid uptake. Monophasic elimination patterns were observed for benzo[e]pyrene and benzo[a]-pyrene (biological half-life

On the Inhibition of COVID-19 Protease by Indian Herbal Plants: An In Silico Investigation

COVID-19 has quickly spread across the globe, becoming a pandemic. This disease has a variable impact in different countries depending on their cultural norms, mitigation efforts and health infrastructure. In India, a majority of people rely upon traditional Indian medicine to treat human maladies due to less-cost, easier availability and without any side-effect. These medicines are made by herbal plants. This study aims to assess the Indian herbal plants in the pursuit of potential COVID-19 inhibitors using in silico approaches. We have considered 18 extracted compounds of 11 different species of these plants. Our calculated lipophilicity, aqueous solubility and binding affinity of the extracted compounds suggest that the inhibition potentials in the order; harsingar > aloe vera > giloy > turmeric > neem > ashwagandha > red onion > tulsi > cannabis > black pepper. On comparing the binding affinity with hydroxychloroquine, we note that the inhibition potentials of the extracts of harsingar, aloe vera and giloy are very promising. Therefore, we believe that these findings will open further possibilities and accelerate the works towards finding an antidote for this malady