A 3D-QSAR Study on a Series of Benzimidazole Derivatives Acting as Hepatitis C Virus Inhibitors: Application of kNN-Molecular Field Analysis

A 3D-QSAR study using comparative molecular field analysis (CoMFA) was carried out on anti-tubulin agents with indole as a nucleus core. The structures of the compounds were obtained using docking calculations, and were then subjected to alignment procedures. CoMFA calculations for the 42 ligands that were examined as the training set gave a q2 value of 0.623 in correlation with experimental IC50 values for the inhibition of MKN-45 gastric cancer cells. Calculation for the test set of 17 ligands resulted in an r2 value of 0.714. The calculated results suggest that the R3 functional group site (see structure in Fig. 1) favored bulky groups while R1, R2, and R4 sites favored the opposite. At the R5 and R6 sites, parts of the region favored bulky groups while other parts favored the opposite. As for the electrostatic aspect, the R3 site was found to favor groups with a negative partial charge. At the R2 site, part of the region favored the group with a negative partial charge while other regions favored groups with a positive partial charge. The R4 and R5 sites favored groups with negative and positive partial charges, respectively, with a less favorable magnitude when compared with the R2 and R3 sites. The R1 and R6 sites did not exhibit significant electrostatic favor. Correlation of the results with IC50 values of ligands were analyzed and discussed.

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A 3D-QSAR Study on the Antitrypanosomal and Cytotoxic Activities of Steroid Alkaloids by Comparative Molecular Field Analysis

10.20944/preprints201804.0282.v1 ◽

2018 ◽

Author(s):

Charles Okeke Nnadi ◽

Julia Barbara Althaus ◽

Ngozi Justina Nwodo ◽

Thomas Jürgen Schmidt

Keyword(s):

Cytotoxic Activity ◽

3D Qsar ◽

Field Analysis ◽

Molecular Field ◽

Comparative Molecular Field Analysis ◽

Qsar Study ◽

Molecular Field Analysis ◽

Antitrypanosomal Activity ◽

Buxus Sempervirens ◽

Starting Point

As part of our research for new leads against human African trypanosomiasis (HAT), we report on a 3D-QSAR study for antitrypanosomal activity and cytotoxicity of aminosteroid-type alkaloids recently isolated from the African medicinal plant Holarrhena africana A. DC. (Apocynaceae), some of which are strong trypanocides against Trypanosoma brucei rhodesiense (Tbr) with low toxicity against mammalian cells. Fully optimized 3D molecular models of seventeen congeneric Holarrhena alkaloids were subjected to a comparative molecular field analysis (CoMFA). CoMFA models were obtained for both, the anti-Tbr and cytotoxic activity data. Model performance was assessed in terms of statistical characteristics (R2, Q2 and P2 for partial least squares (PLS) regression, internal cross-validation (leave-one-out) and external predictions (test set), respectively, as well as the corresponding SDEP and F-values). With R2=0.99, Q2=0.83 and P2=0.79 for anti-Tbr activity and R2=0.94, Q2=0.64, P2=0.59 for cytotoxicity against L6 rat skeletal myoblasts, both models were of good internal and external predictive power. The regression coefficients of the models representing the most prominent steric and electrostatic effects on anti-Tbr and for L6 cytotoxic activity were translated into contour maps and analyzed visually, allowing suggestions for possible modification of the aminosteroids to further increase the antitrypanosomal potency and selectivity. Very interestingly, the 3D-QSAR model established with the Holarrhena alkaloids also applied to the antitrypanosomal activity of two aminocycloartane-type compounds recently isolated by our group from Buxus sempervirens L. (Buxaceae), which indicates that these structurally similar natural products share a common SAR and, possibly, mechanism of action with the Holarrhena steroids. This 3D-QSAR study has thus resulted in plausible structural explanations of the antitrypanosomal activity and selectivity of aminosteroid- and aminocycloartane-type alkaloids as an interesting new class of trypanocides and may represent a starting point for lead optimization.

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