A combined 3D-QSAR and docking studies for the In-silico prediction of HIV-protease inhibitors

BACKGROUND: Tremendous research from last twenty years has been pursued to cure human life against HIV virus. A large number of HIV protease inhibitors are in clinical trials but still it is an interesting target for researchers due to the viral ability to get mutated. Mutated viral strains led the drug ineffective but still used to increase the life span of HIV patients. RESULTS: In the present work, 3D-QSAR and docking studies were performed on a series of Danuravir derivatives, the most potent HIV- protease inhibitor known so far. Combined study of 3D-QSAR was applied for Danuravir derivatives using ligand-based and receptor-based protocols and generated models were compared. The results were in good agreement with the experimental results. Additionally, docking analysis of most active 32 and least active 46 compounds into wild type and mutated protein structures further verified our results. The 3D-QSAR and docking results revealed that compound 32 bind efficiently to the wild and mutated protein whereas, sufficient interactions were lost in compound 46. CONCLUSION: The combination of two computational techniques would helped to make a clear decision that compound 32 with well inhibitory activity bind more efficiently within the binding pocket even in case of mutant virus whereas compound 46 lost its interactions on mutation and marked as least active compound of the series. This is all due to the presence or absence of substituents on core structure, evaluated by 3D-QSAR studies. This set of information could be used to design highly potent drug candidates for both wild and mutated form of viruses

Molecular docking simulation studies on potent butyrylcholinesterase inhibitors obtained from microbial transformation of dihydrotestosterone

BACKGROUND: Biotransformation is an effective technique for the synthesis of libraries of bioactive compounds. Current study on microbial transformation of dihydrotestosterone (DHT) (1) was carried out to produce various functionalized metabolites. RESULTS: Microbial transformation of DHT (1) by using two fungal cultures resulted in potent butyrylcholinesterase (BChE) inhibitors. Biotransformation with Macrophomina phaseolina led to the formation of two known products, 5α-androstan-3β,17β-diol (2), and 5β-androstan-3α,17β-diol (3), while biotransformation with Gibberella fujikuroi yielded six known metabolites, 11α,17β-dihydroxyandrost-4-en-3-one (4), androst-1,4-dien-3,17-dione (5), 11α-hydroxyandrost-4-en-3,17-dione (6), 11α-hydroxyandrost-1,4-dien-3,17-dione (7), 12β-hydroxyandrost-1,4-dien-3,17-dione (8), and 16α-hydroxyandrost-1,4-dien-3,17-dione (9). Metabolites 2 and 3 were found to be inactive, while metabolite 4 only weakly inhibited the enzyme. Metabolites 5–7 were identified as significant inhibitors of BChE. Furthermore, predicted results from docking simulation studies were in complete agreement with experimental data. Theoretical results were found to be helpful in explaining the possible mode of action of these newly discovered potent BChE inhibitors. Compounds 8 and 9 were not evaluated for enzyme inhibition activity both in vitro and in silico, due to lack of sufficient quantities. CONCLUSION: Biotransformation of DHT (1) with two fungal cultures produced eight known metabolites. Metabolites 5–7 effectively inhibited the BChE activity. Cholinesterase inhibition is among the key strategies in the management of Alzheimer’s disease (AD). The experimental findings were further validated by in silico inhibition studies and possible modes of action were deduced

Structural insight into TNF-α inhibitors through combining pharmacophore-based virtual screening and molecular dynamic simulation

Tumor Necrosis Factor-alpha (TNF-α), a multifunctional cytokine responsible for providing resistance against infections, inflammation, and cancers. TNF-α has emerged as a promising drug target against several autoimmune and inflammatory disorders. Several synthetic antibodies (Infliximab, Etanercept, and Adalimumab) are available, but their potential to cause severe side effects has prompted them to develop alternative small molecules-based therapies for inhibition of TNF-α. In the present study, combined in silico approaches based on pharmacophore modeling, virtual screening, molecular docking, and molecular dynamics studies were employed to understand significant direct interactions between TNF-α protein and small molecule inhibitors. Initially, four different small molecule libraries (∼17.5 million molecules) were virtually screened against the selected pharmacophore model. The identified hits were further subjected to molecular docking studies. The three potent lead compounds (ZINC05848961, ZINC09402309, ZINC04502991) were further subjected to 100 ns molecular dynamic studies to examine their stability. Our docking and molecular dynamic analysis revealed that the selected lead compounds target the TNF receptor (TNFR) and efficiently block the production of TNF. Moreover, in silico ADMET (Absorption, Distribution, Metabolism, Excretion and Toxicity) analysis revealed that all the predicted compounds have good pharmacokinetic properties with high gastrointestinal absorption and a decent bioavailability score. Furthermore, toxicity profiles further evidenced that these compounds have no risk of being mutagenic, tumorigenic, reproductive and irritant except ZINC11915498. In conclusion, the present study could serve as the starting point to develop new therapeutic regimens to treat various TNF- related diseases

Exploration of the structural requirements of Aurora Kinase B inhibitors by a combined QSAR, modelling and molecular simulation approach

Aurora kinase B plays an important role in the cell cycle to orchestrate the mitotic process. The amplification and overexpression of this kinase have been implicated in several human malignancies. Therefore, Aurora kinase B is a potential drug target for anticancer therapies. Here, we combine atom-based 3D-QSAR analysis and pharmacophore model generation to identify the principal structural features of acylureidoindolin derivatives that could potentially be responsible for the inhibition of Aurora kinase B. The selected CoMFA and CoMSIA model showed significant results with cross-validation values (q(2)) of 0.68, 0.641 and linear regression values (r(2)) of 0.971, 0.933 respectively. These values support the statistical reliability of our model. A pharmacophore model was also generated, incorporating features of reported crystal complex structures of Aurora kinase B. The pharmacophore model was used to screen commercial databases to retrieve potential lead candidates. The resulting hits were analyzed at each stage for diversity based on the pharmacophore model, followed by molecular docking and filtering based on their interaction with active site residues and 3D-QSAR predictions. Subsequently, MD simulations and binding free energy calculations were performed to test the predictions and to characterize interactions at the molecular level. The results suggested that the identified compounds retained the interactions with binding residues. Binding energy decomposition identified residues Glu155, Trp156 and Ala157 of site B and Leu83 and Leu207 of site C as major contributors to binding affinity, complementary to 3D-QSAR results. To best of our knowledge, this is the first comparison of WaterSwap field and 3D-QSAR maps. Overall, this integrated strategy provides a basis for the development of new and potential AK-B inhibitors and is applicable to other protein targets

ARHITEKTONSKE SLOŽENOSTI I MORFOLOŠKE VARIJACIJE SEDIMENTNIH VALOVA PLIO-PLEISTOCENSKIH KANALA U DELTI INDA

The architecture of the turbidity current sediment waves exhibits intricate morphologies and patterns on the Indus Fan channel levee backslope. The sediment waves are present on the channel levee of Plio-Pleistocene age and are absent in the deeper sections of the study area. The architecture of channel levee backslope on the Indus Fan is poorly understood. We used seismic interpretation techniques and modelling by utilizing high-resolution seismic data to approach this problem. The morphological variations in wavelength, crest dimensions and potential wave formation patterns suggest the autogenic and allogenic processes associated with wave development. Wavelengths reach up to 1473 m with an average of 486.84 m and the height of the levee ranges between 10 m and 60 m (average 30 m). The angle of the channel levee and dimension of the sediment wave here are independent of each other. Low angle levees have accommodated high dimension sediment waves and vice versa at multiple points downslope. Characteristically, the waves have formed on the outer levee (usually left) of the channels marked by steep margins suggesting that flow overspill caused the development of the waves. Generally, the younger sediment waves followed the patterns of older sediment waves, but the varying trends are often observed in the study area. The patterns of the sediment waves towards the younger sections of the levee indicate the modified and varying architectural style of growth. Sediment waves are generated by downslope turbidity currents. However, the deformation features have also possibly triggered the development of sediment waves.Arhitektura sedimentnih valova nastalih uslijed turbiditnih struja pokazuje zamršenu morfologiju i obrasce unutar kanala i njihovih rubova u prostoru deltne lepeze Inda. Tragovi taloženja energijom valova prisutni su u plio-pleistocenskim kanalima i oko njih, no izostaju u dubljim dijelovima istraživanoga područja. Arhitektura rubova kanala u delti Inda do sada nije bila detaljno opisana. U istraživanju ovoga problema korištene su seizmičke metode i modeliranje podataka visoke razlučivosti. Morfološke varijacije u duljinama valova, dimenzijama kresta i potencijalnim obrascima stvaranja valova upućuju na autogene i alogene procese povezane s razvojem valova. Dujine valova dosežu do 1473 m s prosjekom od 486,84 m, a visina se kreće između 10 m i 60 m (prosječno 30 m). Kut rubova kanala i dimenzija vala u ovome slučaju bili su neovisni jedno o drugome. Mali kut omogućio je na nekoliko točaka u nižim dijelovima akomodiranje valova velikih dimenzija i obrnuto. Karakteristični valovi nastajali su na vanjskome dijelu nasipa kanala (obično lijevome) sa strmim rubovima, što upućuje na to da je njihovo prelijevanje utjecalo na energiju. Općenito, mlađi valni sedimenti slijedili su obrasce starijih, ali se ponekad može uočiti i promjena trenda. Obrasci valnih taložina u mlađim naslagama rubova upućuju na promjenu, pa i inverziju oblika. Općenito su valni sedimenti posljedica aktivnosti turbiditnih struja u podnožju rubova kanala, a i njihov nastanak vrlo je usko povezan s deformacijskim strukturama

MODELIRANJE TRANSPORTA OTOPINE U NISKOPROPUSNOME, HOMOGENOME I ZASIĆENOME TLU

Fickian and non-Fickian behaviors were often detected for contaminant transport activity owed to the preferential flow and heterogeneity of soil media. Therefore, using diverse methods to measure such composite solute transport in soil media has become an important research topic for solute transport modeling in soil media. In this article, the continuous-time random walk (CTRW) model was applied to illustrate the relative concentration of transport in low-permeability homogeneous and saturated soil media. The solute transport development was also demonstrated with the convection-dispersion equation (CDE) and Two Region Model (TRM) for comparison. CXTFIT 2.1 software was used for CDE and TRM, and CTRW Matlab Toolbox v.3.1 for the CTRW simulation of the breakthrough curve. It was found that higher values of determination coefficient (R2) and lower values of root mean square error (RMSE) concerning the best fits of CDE, TRM, and CTRW. It was found that in the comparison of CDE, TRM, and CTRW, we tend to use CTRW to describe the transport behavior well because there are prevailing Fickian and non-Fickian transport. The CTRW gives better fitting results to the breakthrough curves (BTCs) when β has an increasing pattern towards 2.00. In this study, the variation of parameters in three methods was investigated and results showed that the CTRW modeling approach is more effective to determine non-reactive contaminants concentration in low-permeability soil media at small depths.Fickovo i nefickovo ponašanje često se opaža kod prijenosa gdje postoji preferencijski tok i heterogenost tla (medija) kroz koji se događa protok. Stoga je uporaba različitih metoda mjerenja prijenosa otopina u takvim medijima važno područje istraživanja. Ovdje je prikazan model kontinuiranoga i vremenski slučajnoga gibanja (engl. skr. CTRW) kako bi se opisala relativna koncentracija tijekom prijenosa kroz niskopropustan, homogen i zasićen medij. To je demonstrirano konvekcijsko-disperzijskom jednadžbom (engl. skr. CDE) te dvočlanim modelom (engl. skr. TRM) i njihovom usporedbom. Programskim paketom CXTFIT 2.1 opisani su CDE i TRM, a paketom CTRW Matlab Toolbox v.3.1 model CTRW. Uočeno je kako veće vrijednosti koeficijenta determinacije (R2) te manje srednje kvadratne pogrješke (engl. skr. RMSE) najbolje opisuju podudaranje između CDE-a, TRM-a i CTRW-a. Usporedbom tih triju vrijednosti odabran je CTRW za opis ponašanja prijenosa, kako Fickova, tako i nefickova. CTRW se bolje podudara s krivuljama protoka (engl. skr. BTC), gdje β raste prema vrijednosti 2. Istražena je i promjena parametara u svim trima metodama, što je ponovno istaknulo CTRW kao najprimjereniji model u određivanju koncentracije nereaktivnih čestica u slabopropusnome tlu na malim dubinama

Purification and Characterization of a Nonspecific Lipid Transfer Protein 1 (nsLTP1) from Ajwain (\u3cem\u3eTrachyspermum ammi\u3c/em\u3e) Seeds

Ajwain (Trachyspermum ammi) belongs to the family Umbelliferae, is commonly used in traditional, and folk medicine due to its carminative, stimulant, antiseptic, diuretic, antihypertensive, and hepatoprotective activities. Non-specific lipid transfer proteins (nsLTPs) reported from various plants are known to be involved in transferring lipids between membranes and in plants defense response. Here, we describe the complete primary structure of a monomeric non-specific lipid transfer protein 1 (nsLTP1), with molecular weight of 9.66 kDa, from ajwain seeds. The nsLTP1 has been purified by combination of chromatographic techniques, and further characterized by mass spectrometry, and Edman degradation. The ajwain nsLTP1 is comprised of 91 amino acids, with eight conserved cysteine residues. The amino acid sequence based predicted three dimensional (3D) structure is composed of four α-helices stabilized by four disulfide bonds, and a long C-terminal tail. The predicted model was verified by using different computational tools; i.e. ERRAT, verify 3D web server, and PROCHECK. The docking of ajwain nsLTP1 with ligands; myristic acid (MYR), and oleic acid (OLE) was performed, and molecular dynamics (MD) simulation was used to validate the docking results. The findings suggested that amino acids; Leu11, Leu12, Ala55, Ala56, Val15, Tyr59, and Leu62 are pivotal for the binding of lipid molecules with ajwain nsLTP1

Synthesis and biological activity of oxadiazole and triazolothiadiazole derivatives as tyrosinase inhibitors

A series of 16 oxadiazole and triazolothiadiazole derivatives were designed, synthesized and evaluated as mushroom tyrosinase inhibitors. Five derivatives were found to display high inhibition on the tyrosinase activity ranging from 0.87 to 1.49 lM. Compound 5 exhibited highest tyrosinase inhibitory activity with an IC50 value of 0.87 ± 0.16 lM. The in silico protein–ligand docking using AUTODOCK 4.1 was successfully performed on compound 5 with significant binding energy value of 5.58 kcal/mol. The docking results also showed that the tyrosinase inhibition might be due to the metal chelating effect by the presence of thione functionality in compounds 1–5. Further studies revealed that the presence of hydrophobic group such as cycloamine derivatives played a major role in the inhibition. Piperazine moiety in compound 5 appeared to be involved in an extensive hydrophobic contact and a 2.9 Å hydrogen bonding with residue Glu 182 in the active site