Evaluation of ACE inhibitors lipophilicity using in silico and chromatographically obtained hydrophobicity parameters

Abstract

The aim of this study was to compare different calculation methods to determine the lipophilicity, expressed as log P value, of seven ACE inhibitors (enalapril, quinapril, fosinopril, lisinopril, cilazapril, ramipril and benazepril) with significantly different structures. Experimentally determined n-octanol/water partition coefficients, log PO/W values, were obtained from relevant literature. The correlations between all collected log P values were studied and the best agreement between calculated log P and experimentally determined log PO/W values was observed for KOWWINlog P or Milog P values (r = 0.999 or r = 0.974, respectively). The correlations between all collected log P values and chromatographically (reversed-phase thin-layer chromatography) obtained hydrophobicity parameters, RM 0 and C0, were established. Good correlations (r > 0.90) were obtained in the majority of relationships. The KOWWINlog P was established as the most suitable hydrophobicity parameter of the investigated group of ACE inhibitors with r = 0.981 for correlation with RM 0 and r = = 0.977 for correlation with C0 parameters (water-methanol mobile phase). Using multiple linear regressions, it was established that application of two selected log P, calculated by different mathematical approaches, led to very good correlation due to the benefits of both calculation methods. The good relationships indicate that the computed log P, with careful selection of method calculation, can be useful in ACE inhibitors lipophilicity evaluation, as a high-throughput screening technique.

U radu je analizirana lipofilnost sedam ACE inhibitora (enalapril, kvinapril, fosinopril, lizinopril, cilazapril, ramipril i benazepril) različitih hemijskih struktura. Primenom programskih paketa izračunato je deset različitih deskriptora lipofilnosti, log P vrednosti, za ispitivane ACE inhibitore dok su njihovi eksperimentalno određeni n-oktanol/voda koeficijenti raspodele (log PO/W) preuzeti iz stručne literature. Između izračunatih log P vrednosti uočene su značajne razlike zbog razlika u primenjenim metodama izračunavanja. Ispitane su korelacije između svih log P vrednosti. Najbolje slaganje je dobijeno između eksperimentalnih log PO/W i izračunatih KOWWINlog P (r = 0,999) ili Milog P vrednosti (r = 0,974). Analiziran je odnos između svih log P vrednosti i hromatografski određenih parametara hidrofobnosti, RM 0 i C0 (reverzno-fazna hromatografija na tankom sloju). Za najveći broj zavisnosti dobijene su dobre korelacije (r > 0,90). Najbolja korelacija dobijena je između KOWWINlog P i RM 0 (r = 0,981), odnosno C0 (r = 0,977) (voda-metanol mobilna faza). Multiplom linearnom regresionom analizom utvrđeno je da se primenom dve odabrane log P vrednosti, koje su izračunate korišćenjem različitih metoda, dobijaju odlične zavisnosti zahvaljujući prednostima primenjenih metoda. Dobijene dobre zavisnosti ukazuju da matematičke metode izračunavanja, kao tehnike za analizu velikog broja rezultata u kratkom vremenskom periodu (eng. high-throughput screening techniques), mogu biti od velike koristi u proceni lipofilnosti ACE inhibitora.