Computational Drug Designing

Molecular docking, QPLD, and ADME prediction studies on HIV-1 integrase leads.

by Chandrabose Selvaraj

Med Chem Res DOI 10.1007/s00044-011-9940-6 (Published)

HIV-1 integrase (IN) is an important drug target over the years with diverse therapeutic potential with the objective... more HIV-1 integrase (IN) is an important drug target over the years with diverse therapeutic potential with the objective of designing new chemical entities with enhanced inhibitory potencies against HIV-1 IN. We performed molecular docking, quantum polarized ligand docking (QPLD), ADME screening, and PASS biological activity prediction studies on Raltegravir, Elvitegravir, and newly searched compounds of Cambridge crystallographic database. Best docking and QPLD scores of known and unknown searched compounds were compared using docking score, docking energy, and emodel energy. Moreover, correlation between docking score, docking energy with emodel energy yielded a statistically significant correlation coefficient. The searched compounds were also evaluated with ADME properties and biological activity prediction analysis. These compounds also show good pharmacokinetic properties under the acceptable range including antiviral biological activity prediction. Hence, these compounds could be employed to design ligands with enhanced inhibitory potencies and to predict the potencies of analogs to guide synthesis/or prepare synthetic analogs for second generation drug development against HIV-1 IN.

Targeting the human DEAD-box polypeptide 3 (DDX3) RNA helicase as a novel strategy to inhibit viral replication

by Marco Radi

Compounds currently used for the treatment of HIV-1 Infections are targeted to viral proteins. However, the high... more Compounds currently used for the treatment of HIV-1 Infections are targeted to viral proteins. However, the high intrinsic mutation and replication rates of HIV-1 often lead to the emergence of drug resistant strains and consequent therapeutic failure. On this basis, cellular cofactors represent attractive new targets for HIV-1 chemotherapy, since targeting a cellular factor that is required for viral replication should help to overcome the problem of viral resistance. We and others have recently reported the identification of compounds suppressing HIV-1 replication by targeting the cellular DEAD-box helicase DDX3. These results provide a proof-of-principle for the feasibility of blocking HIV-1 infection by rendering the host cell environment less favorable for the virus. The rationale for such an approach and its implications in potentially overcoming the problem of drug resistance related to drugs targeting viral proteins will be discussed in the context of the known cellular functions of the DEAD-box helicase DDX3.

Identification of Potential Inhibitors against Acetylcholinesterase Associated With Alzheimer's Diseases: A Molecular Docking Approach

by jagmohan sharma

Cholinesterase inhibitors (ChE-Is) are the standard of therapy for treatment of patients with Alzheimer’s disease (AD)... more Cholinesterase inhibitors (ChE-Is) are the standard of therapy for treatment of patients with Alzheimer’s disease (AD) and are the only class of drugs approved by the Food and Drug Administration (FDA) for treatment of this condition. In this paper we used the new approach utilizing cheminformatics tools such as CORINA, Yet Another Scientific Artificial Reality Application (YASARA), and molecular docking program to identify binding affinity and mechanism of interaction between the ChE-Is with the target proteins. This approach should be helpful to understand the selectivity of the given drug molecule in the treatment of Alzheimer’s disease.

Molecular docking studies of dithionitrobenzoic acid and its related compounds to protein disulfide isomerase: computational screening of inhibitors to HIV-1 …

by Jayakanthan M

Background: Entry of HIV-1 into human lymphoid requires activities of viral envelope glycoproteins gp120 and gp41, and... more Background: Entry of HIV-1 into human lymphoid requires activities of viral envelope glycoproteins gp120 and gp41, and two host-cell proteins, the primary receptor CD4 and a chemokine co-receptor. In addition, a third cell-surface protein called protein disulfide isomerise (PDI) is found to play a major role in HIV-1 entry. PDI is capable of mediating thio-disulfide interchange reactions and could enable the reduction of gp120 disulfide bonds, which triggers the major conformational changes in gp120 and gp41 required for virus entry. In this scenario, inhibition of HIV-1 entry can be brought about by introducing agents that can block thiol-disulfide interchange reaction of cell surface PDI. There have been studies with agents that inhibit PDI activity, but the exact mode of binding remains to be elucidated; this might provide insights to develop new drugs to target PDI. This study attempts to perceive the mode of binding of dithionitrobenzoic acid (DTNB), and its structurally related compounds on PDI enzyme.
Results: We performed molecular docking simulation with six different inhibitors (ligand), which includes DTNB, NSC695265, thionitrobenzoic acid, 2-nitro-5-thiocyanobenzoic acid, 2-nitro-5-sulfo-sulfonyl-benzoic acid and NSC517871 into the redox-active site [C37-G38-H39-C40] of the PDI enzyme and the activity was inferred by redox inhibitory models. All ligands showed favourable interactions and most of them seemed to bind to hydrophobic amino acids Ala34, Trp36, Cys37, Cys40, His39, Thr68 and Phe80. The redox inhibitory conformations were energetically and statistically favored and supported the evidence from wet laboratory experiments reported in the literature.
Conclusion: We demonstrated that in silico docking experiment can be effectively carried out to recognize the redox inhibitory models of PDI with inhibitor molecules. Interestingly we found that number of docked clusters with each ligand varies in the range of five to eight and conveys that the binding specificity of each inhibitor varies for PDI. We also identified that Cys37 of the enzyme plays an important role in hydrogen bonding with inhibitors. This residue can be considered to being an active site for anti-HIV drug design. Therefore, by inhibiting PDI, one can, not only prevent the viral entry but also circumvent the problem of viral resistance