Akshay Patny

Homology Modeling of G-Protein-Coupled Receptors and Implications in Drug Design

G-protein-coupled receptors (GPCRs) are considered therapeutically important due to their involvement in a variety of processes governing several cellular functions, and their tractability as drug targets. A large percentage of drugs on the market, and in development stages, target the super family of the GPCRs. The enormous interest in GPCR drug design is, however, limited by the scarcity of structural information. The only GPCR for which a three dimensional (3D) structure is reported is bovine rhodopsin and it belongs to class A of the GPCR family. As a result, there has been considerable interest in alternative techniques, for example, homology modeling of GPCRs, in order to derive useful three dimensional models of other proteins for use in structure-based drug design. However, homology modeling of GPCRs is not straightforward, and encounters several problems, owing to the availability of a single structural template, as well as the low degree of sequence homology between the template and target sequences. There are several key issues which need to be considered during every stage of GPCR homology modeling, in order to derive reasonable 3D models. Homology modeling of GPCRs has been utilized increasingly in the past few years and has been successful, not only in furthering the understanding of ligand-protein interactions, but also in the identification of new and potent ligands. Thus, with the lessons learned from past experiences and new developments, homology modeling in case of GPCRs can be harnessed for developing more reliable three dimensional models. This, in turn, will provide better tools to use in structure-based drug design leading to the identification of novel and potent GPCR ligands for several therapeutic indications.

Mollamides B and C, Cyclic Hexapeptides from the Indonesian Tunicate Didemnum molle

Two new cyclic hexapeptides, mollamides B (1) and C (2), were isolated from the Indonesian tunicate Didemnum molle along with the known peptide keenamide A (3). The structures were established using 1D and 2D NMR experiments. The relative configuration of mollamide B at the thiazoline moiety was determined using molecular modeling coupled with NMR-derived restraints. Their absolute configuration was determined using Marfeyʼs method. The new peptides have been evaluated for their antimicrobial, antimalarial, anticancer, anti-HIV-1, anti-Mtb, and anti-inflammatory activities. Keenamide A and mollamide B show cytotoxicity against several cancer cell lines.

Design, synthesis, biological evaluation and docking studies of pterostilbene analogs inside PPARα

Pterostilbene, a naturally occurring analog of resveratrol, has previously shown PPARalpha activation in H4IIEC3 cells and was found to decrease cholesterol levels in animals. In this study, analogs of pterostilbene were synthesized and their ability to activate PPARalpha was investigated. Among analogs that was synthesized (E)-4-(3,5-dimethoxystyryl)phenyl dihydrogen phosphate showed activity higher than pterostilbene and control drug ciprofibrate. Docking of the stilbenes inside PPARalpha showed the presence of important hydrogen bond interactions for PPARalpha activation.

Ligand-supported homology modeling of the human angiotensin II type 1 (AT1) receptor: Insights into the molecular determinants of telmisartan binding

Angiotensin II type 1 (AT1) receptor belongs to the super‐family of G‐protein‐coupled receptors, and antagonists of the AT1 receptor are effectively used in the treatment of hypertension. To understand the molecular interactions of these antagonists, such as losartan and telmisartan, with the AT1 receptor, a homology model of the human AT1 (hAT1) receptor with all connecting loops was constructed from the 2.6 Å resolution crystal structure (PDB i.d., 1L9H) of bovine rhodopsin. The initial model generated by MODELLER was subjected to a stepwise ligand‐supported model refinement. This protocol involved initial docking of non‐peptide AT1 antagonists in the putative binding site, followed by several rounds of iterative energy minimizations and molecular dynamics simulations. The final model was validated based on its correlation with several structure‐activity relationships and site‐directed mutagenesis data. The final model was also found to be in agreement with a previously reported AT1 antagonist pharmacophore model. Docking studies were performed for a series of non‐peptide AT1 receptor antagonists in the active site of the final hAT1 receptor model. The docking was able to identify key molecular interactions for all the AT1 antagonists studied. Reasonable correlation was observed between the interaction energy values and the corresponding binding affinities of these ligands, providing further validation for the model. In addition, an extensive unrestrained molecular dynamics simulation showed that the docking‐derived bound pose of telmisartan is energetically stable. Knowledge gained from the present studies can be used in structure‐based drug design for developing novel ligands for the AT1 receptor. Proteins 2006.

Design, Synthesis, and Docking Studies of Novel Benzimidazoles for the Treatment of Metabolic Syndrome

In addition to lowering blood pressure, telmisartan, an angiotensin (AT(1)) receptor blocker, has recently been shown to exert pleiotropic effects as a partial agonist of nuclear peroxisome proliferator-activated receptor gamma (PPAR gamma). On the basis of these findings and docking pose similarity between telmisartan and rosiglitazone in PPAR gamma active site, two classes of benzimidazole derivatives were designed and synthesized as dual PPAR gamma agonist/angiotensin II antagonists for the possible treatment of metabolic syndrome. Compound 4, a bisbenzimidazole derivative showed the best affinity for the AT(1) receptor with a K(i) = 13.4 nM, but it was devoid of PPAR gamma activity. On the other hand 9, a monobenzimidazole derivative, showed the highest activity in PPAR gamma transactivation assay (69% activation) with no affinity for the AT(1) receptor. Docking studies lead to the designing of a molecule with dual activity, 10, with moderate PPARgamma activity (29%) and affinity for the AT(1) receptor (K(i) = 2.5 microM).

Discovery of Clinical Candidate 1-{[(2S,3S,4S)-3-Ethyl-4-fluoro-5-oxopyrrolidin-2-yl]methoxy}-7-methoxyisoquinoline-6-carboxamide (PF-06650833), a Potent, Selective Inhibitor of Interleukin-1 Receptor Associated Kinase 4 (IRAK4), by Fragment-Based Drug Design

Through fragment-based drug design focused on engaging the active site of IRAK4 and leveraging three-dimensional topology in a ligand-efficient manner, a micromolar hit identified from a screen of a Pfizer fragment library was optimized to afford IRAK4 inhibitors with nanomolar potency in cellular assays. The medicinal chemistry effort featured the judicious placement of lipophilicity, informed by co-crystal structures with IRAK4 and optimization of ADME properties to deliver clinical candidate PF-06650833 (compound 40). This compound displays a 5-unit increase in lipophilic efficiency from the fragment hit, excellent kinase selectivity, and pharmacokinetic properties suitable for oral administration.

Design, synthesis, and docking studies of novel telmisartan–glitazone hybrid analogs for the treatment of metabolic syndrome

A novel hybrid class of telmisartan–rosiglitazone molecules was synthesized in an attempt to discover a dual peroxisome proliferator-activated receptor gamma (PPARγ) agonist/angiotensin II antagonist for treatment for metabolic syndrome. Almost all the synthesized molecules showed moderate PPARγ activity. However, none of the hybrid analogs showed binding affinity toward the AT1 receptor.