Keemiliste, biokeemiliste ja biomeditsiiniliste omaduste arvutuslik modelleerimine

Väitekirja elektrooniline versioon ei sisalda publikatsioone.Modelleerimise areng ja tähtsus ravimiarenduses on tõusuteel. Käesolevas töös on selleks kasutatud erinevaid arvutuskeemilisi võtteid, konformatsioonianalüüsi, kvantitatiivseid struktuur-omadus sõltuvusi, molekulaarsildamist ning fragmendi- ja ligandipõhised meetodeid. Töö tulemusena arendati ennustavad mudelid järgmiste bioloogiliselt ja biomeditsiiniliselt oluliste sihtmärkide jaoks: 1) HPV antiviraalsed agendid; 2) uut tüüpi sääsetõrje vahendid; 3) duaalsed inhibiitorid diabeedi (tüüp 2, mellitus) ning Alzheimeri tõvega seotud bioloogilistele märklaudadele. 4) suhtelised saagised peptiidide sünteesil keemilise seondamise (chemical ligation) teel. Arendatud mudelite peamine suunitlus on ennustada omadusi uutele, seni on eksperimentaalselt testimata ainetele. Mudelite laiem eesmärk on kiirendada ravimiarenduse protsessi tervikuna.Computational modelling plays an important role in the initial phase of drug discovery and has considerably improved in the last decade. Current thesis is focused on several applications in computational chemistry, i.e. conformational analysis, QSAR modelling, fragment-, ligand- based methods, and molecular docking methodologies. As a result, predictive models were generated for following targets: i) the activities of HPV antiviral agents and mosquito repellents; ii) the dual inhibition of Type 2 diabetes mellitus and Alzheimer’s disease; and iii) the relative abundance in chemical ligation. The main task of developed models is to predict the respective activities for novel structures, which are not yet experimentally tested. These models are oriented to strengthen the drug discovery process faster

Combined Ligand and Structure Based Approaches Towards Developing Novel Renin Inhibitors for the Treatment of Hypertension

Hypertension is considered as the predominant risk factor for the onset of Cardiovascular disease (CVD) in the elder population. The chronic activation of Renin Angiotensin System (RAS) is considered as the primary causative factor for the inception of hypertension in geriatric population. Angiotensin Converting Enzyme (ACE) is a highly explored druggable target in the context of hypertension since this enzyme catalyses the conversion of angiotensin I to angiotensin II, a potent vasoconstrictor. But clinical trials conducted on ACE inhibitors reported their incompetence in the effective treatment of hypertension. Hence, recent studies are focussing on renin, which is a central component of RAS in the regulation of blood pressure. The present study focuses on the elucidation of physicochemical properties of chemical compounds essential for renin inhibition and identification of novel renin inhibitors possessing enhanced potency as well as bioavailability. We have employed Molecular Field Topology Analysis (MFTA) as well as Structure Based Drug Design (SBDD) approaches for the accomplishment of above-mentioned objectives. MFTA approach were piloted on 45 indole-3-carboxamide derivatives by elucidating the significance of charge distribution as well as molecular size of chemical species in eliciting renin inhibition. Optimal model was obtained with Nf = 3, r2 = 0.81 , Q2 = 0.65. Molecular docking, atom-based binding free energy contributions and bioavailability assessments were carried out to identify most potent lead molecule among 45 compounds reported for renin inhibition. Further, new derivative molecules were predicted for the best lead molecule by employing chemical space exploration. All datasets, descriptor values, QSAR models for predictions usage and plots will be available in https://github.com/giribio/agingdata</p

In-silico driven design and development of spirobenzimidazo-quinazolines as potential DNA gyrase inhibitors

DNA gyrase and Topoisomerase IV are promising antibacterial drug targets as they regulate bacterial DNA replication and topology. In a quest for novel DNA topoisomerase inhibitors, a multidisciplinary approach was adopted that involves computational prediction of binding sites and molecular modelling followed by green synthesis and biological evaluation of antibacterial activity of spirobenzimidazo quinazolines derivatives. Using basic quantum chemistry principles, we evaluated spirobenzimidazo quinazolines derivatives with their pharmacokinetic profiles. Based on the results of the aforesaid in-silico studies, we synthesized a series of titled compounds using green synthetic methodology that were validated as potential antimicrobial agents. Quantum chemoinformatics based predicted activity for the synthesized compounds 9b, 9c, and 9j was concomitant with biological evaluation of broadspectrum antibacterial activity. Biological evaluation revealed that inhibition of biofilm formation was due to their potential antibacterial activity. We believe that the novel spirobenzimidazo quinazolines have the potential to be alternatives to aminocoumarins and classical quinazolines upon detailed target specific biological studies

Design, Synthesis, and Molecular Docking Studies of Curcumin Hybrid Conjugates as Potential Therapeutics for Breast Cancer

Curcumin (CUR) has received great attention over the past two decades due to its anticancer, anti-inflammatory, and antioxidant properties. Similarly, Dichloroacetate (DCA), an pyruvate dehydrogenase kinase 1 (PKD1) inhibitor, has gained huge attention as a potential anticancer drug. However, the clinical utility of these two agents is very limited because of the poor bioavailability and unsolicited side effects, respectively. We have synthesized fusion conjugates of CUR and DCA with an amino acids linker to overcome these limitations by utilizing the molecular hybridization approach. The molecular docking studies showed the potential targets of Curcumin-Modified Conjugates (CMCs) in breast cancer cells. We synthesized six hybrid conjugates named CMC1-6. These six CMC conjugates do not show any significant toxicity in a human normal immortalized mammary epithelial cell line (MCF10A) in vitro and C57BL/6 mice in vivo. However, treatment with CMC1 and CMC2 significantly reduced the growth and clonogenic survival by colony-formation assays in several human breast cancer cells (BC). Treatment by oral gavage of a transgenic mouse BC and metastatic BC tumor-bearing mice with CMC2 significantly reduced tumor growth and metastasis. Overall, our study provides strong evidence that CUR and DCA conjugates have a significant anticancer properties at a sub-micromolar concentration and overcome the clinical limitation of using CUR and DCA as potential anticancer drugs

Similarity analysis, synthesis, and bioassay of antibacterial cyclic peptidomimetics

The chemical similarity of antibacterial cyclic peptides and peptidomimetics was studied in order to identify new promising cyclic scaffolds. A large descriptor space coupled with cluster analysis was employed to digitize known antibacterial structures and to gauge the potential of new peptidomimetic macrocycles, which were conveniently synthesized by acylbenzotriazole methodology. Some of the synthesized compounds were tested against an array of microorganisms and showed antibacterial activity against Bordetella bronchistepica, Micrococcus luteus, and Salmonella typhimurium

Differential Potency of 2,6-Dimethylcyclohexanol Isomers for Positive Modulation of GABAA Receptor Currents

GABAA receptors meet all of the pharmacological requirements necessary to be considered important targets for the action of general anesthetic agents in the mammalian brain. In the following patch-clamp study, the relative modulatory effects of 2,6-dimethylcyclohexanol diastereomers were investigated on human GABAA (a1b3g2s) receptor currents stably expressed in human embryonic kidney cells. Cis,cis-, trans,trans-, and cis, trans-isomers were isolated from commercially available 2,6- dimethylcyclohexanol and were tested for positive modulation of submaximal GABA responses. For example, the addition of 30 mM cis,cis-isomer resulted in an approximately 2- to 3-fold enhancement of the EC20 GABA current. Coapplications of 30 mM 2,6-dimethylcyclohexanol isomers produced a range of positive enhancements of control GABA responses with a rank order for positive modulation: cis,cis . trans,trans $ mixture of isomers . . cis,transisomer. In molecular modeling studies, the three cyclohexanol isomers bound with the highest binding energies to a pocket within transmembrane helices M1 and M2 of the b3 subunit through hydrogen-bonding interactions with a glutamine at the 224 position and a tyrosine at the 220 position. The energies for binding to and hydrogen-bond lengths within this pocket corresponded with the relative potencies of the agents for positive modulation of GABAA receptor currents (cis,cis . trans,trans . cis,trans-2,6-dimethylcyclohexanol). In conclusion, the stereochemical configuration within the dimethylcyclohexanols is an important molecular feature in conferring positive modulation of GABAA receptor activity and for binding to the receptor, a consideration that needs to be taken into account when designing novel anesthetics with enhanced therapeutic indices